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115 Background: BI 905711 is a tetravalent bispecific antibody that cross-links TRAILR2 with CDH17. This cross-linking drives CDH17-dependent TRAILR2 oligomerization, leading to caspase activation and eventual apoptosis, inhibiting tumor growth in preclinical models of GI cancer. Methods: This Phase Ia/b study of BI 905711 in patients (pts) with advanced GI cancers (NCT04137289) aimed to determine the maximum tolerated dose (MTD) based on the proportion of pts with dose-limiting toxicities (DLT) and explore preliminary antitumor activity. In Phase Ia, pts received BI 905711 every 14 days. One pt with colorectal cancer (CRC) was enrolled at each of the 2 lowest dose levels (0.02/0.06 mg/kg) and 4 pts with CRC were enrolled at each subsequent level (0.2/0.6/1.2/2.4/3.6/4.8 mg/kg). Up to 4 pts with non-CRC GI cancers were included at the dose level below the CRC cohort. Dose escalation was guided by a Bayesian logistic regression model. Results: As of 01 August 2022, 48 pts (CRC: n = 26; non-CRC: n = 22, including 13 with pancreatic ductal adenocarcinoma [PDAC]) had received BI 905711 (dose range 0.02–4.8 mg/kg); pts had a median age of 61 years (range 27–78) and had received a median of 3 (range 1–11) prior lines of treatment. No DLTs were observed and the MTD was not reached. 41 pts had AEs (grade [G] 3–5: 14 pts; serious: 13 pts). 17 pts had treatment-related AEs (TRAEs); 4 TRAEs were G3: AST increased (2 pts), fatigue and ALT increased (1 pt each). 1 pt had serious TRAEs: G2 decreased appetite and G3 fatigue. 2 pts had G1/2 infusion-related reactions that resolved and did not prevent resumption of treatment. PD biomarker modulation on the level of plasma caspase-3/7 activity was most common at 0.6 mg/kg (4/7 pts) or 1.2 mg/kg (2/6 pts). 13 pts achieved stable disease (SD) and 8 pts were progression-free for ≥4 months (PFS4). In pts with CRC, 6 pts achieved SD and 3 had PFS4. Among non-CRC pts, 7 pts achieved SD (PDAC: n = 6) and 5 had PFS4 (PDAC: n = 4). Median duration of treatment was 30.5 days (range 15–246) overall and 71 days (range 15–211) in the 0.6 mg/kg group (n = 8, predicted therapeutic dose; of whom 3 pts had PFS4: CRC: n = 1/4 [all CDH17+]; non-CRC: n = 2/4). Conclusions: In heavily pretreated pts, BI 905711 was associated with a tolerable safety profile and early signs of disease control. BI 905711 will be further assessed in Phase Ib in 4 dose groups: 0.6/1.2/2.4 mg/kg every 14 days, and 0.6 mg/kg weekly. Clinical trial information: NCT04137289 .

9085 Background: Aberrant activation of the RAS-RAF-MEK-ERK pathway is common in human cancers. This is an open-label Phase 1 study of ASTX029, a dual-mechanism extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor, in subjects with relapsed/refractory solid tumors (NCT03520075). Methods: The primary objective is to identify a recommended Phase 2 dose. Subjects with relapsed/refractory solid tumors were eligible for Phase 1A with any molecular feature and for Phase 1B if the tumor demonstrated RAS or BRAF mutations. ASTX029 was administered orally daily on a continuous basis in 21-day cycles. Phase 1A was a modified 3+3 dose-escalation design based on dose-limiting toxicity (DLT) events. Phase 1B subjects were treated at the recommended dose for expansion (RDE) based on emerging safety, pharmacokinetic (PK), and pharmacodynamic (PD) data. Disease response was evaluated by RECIST v1.1. Results: 76 subjects were treated with at least one dose of ASTX029 in Phase 1A (n = 56) and Phase 1B (n = 20). In Phase 1A, ASTX029 was evaluated from 10 mg to 280 mg daily. Two subjects experienced grade 2 central serous retinopathy (CSR) within a few days of dosing at the 280 mg daily dose level (one event was declared a DLT). Both subjects recovered to baseline within days of dose interruption. CSR is an expected AE based on the class of drugs. At the selected RDE dose level of 200 mg daily, the mean PK exposure was 109% of target exposure (13,022 ng*hr/ml), defined as the level expected to have biological activity based on mouse models. As of the data cut-off of February 7, 2022, the most frequent grade ≥2 AEs experienced by subjects (≥5%) assessed as related to ASTX029 included ocular AEs (n = 6: all Grade 2); nausea (n = 7: all Grade 2); diarrhea (n = 6: 5 Grade 2, 1 Grade 3); fatigue (n = 4: all Grade 2); rash (n = 4, 3 Grade 2, 1 Grade 3). There were 52 serious AEs, all unrelated to ASTX029 except for one subject with Grade 3 malaise. Four subjects had a partial response, including KRAS-G12A BRAF-D549N non-small cell lung cancer (NSCLC; Phase 1A: 120 mg treated 20.0 months); KRAS-G12D pancreatic cancer (Phase 1A: 200 mg treated 2.1 months); KRAS-G13D NSCLC (Phase 1B; treated 10.6 months); KRAS-G12S NSCLC (Phase 1B; treated 10.4 months and ongoing). In all, two partial responses were observed out of 3 NSCLC subjects enrolled in Phase 1B. Phospho-ERK and phospho-RSK were evaluated for PD effect on fresh tumor biopsies obtained at baseline and cycle 2. A PD effect and decreased cell proliferation (Ki-67) were observed in 6 of 9 and 3 of 8 evaluable Phase 1B samples, respectively. The most common reason for ASTX029 discontinuation was disease progression. Conclusions: This Phase 1 study of the ERK1/2 inhibitor ASTX029 has identified a dose level of 200 mg daily continuously for investigation in the Phase 2 study. PK and PD data suggest target exposures are achieved with preliminary clinical activity, especially in KRAS-mutated NSCLC. Clinical trial information: NCT03520075.

TPS2688 Background: The major histocompatibility complex (MHC) class I-related proteins MICA and MICB are stress-inducible, surface glycoproteins that are up-regulated on human tumors. MICA/MICB are ligands for the activating receptor, Natural Killer Group 2 member D (NKG2D) expressed on Natural Killer (NK) cells, CD8+ T cells, γδ T cells and iNKT cells. Proteases in the tumor microenvironment cleave MICA/MICB from the cell surface which enables tumor cells to evade immune cell recognition and destruction by NKG2D-expressing cells. Increased concentrations of shed MICA have been observed in serum from patients across multiple tumor types and correlate with poor survival. CLN-619 is a humanized, clinical-stage, MICA/MICB-specific IgG1 monoclonal antibody that prevents the proteolytic release of MICA/MICB thereby exposing tumor cells for immune destruction through both NKG2D-mediated and antibody-dependent cell-mediated cytotoxicity (ADCC). The antibody has been shown to restore the MICA/MICB-NKG2D axis to promote NK-mediated tumor cell lysis (AACR Annual Meeting abstract 3506, April 2022). In mice bearing MICA/MICB-expressing human tumor xenografts, CLN-619 treatment yielded robust anti-tumor activity at low doses. MICA/MICB is expressed in a wide range of solid tumors. Therefore, CLN-619 is expected to have broad anti-tumor activity. Methods: CLN-619 is being evaluated in an open-label, non-randomized, dose-escalation (phase 1) study as monotherapy, and in combination with pembrolizumab, in patients with advanced solid tumors. Cohort expansion in patients with specific indications as monotherapy and in combination with pembrolizumab will be conducted. The phase 1 study explores ascending intravenous doses of CLN-619 as monotherapy (0.1, 0.3, 1.0, 3.0, 6.0 and 10.0 mg/kg) and in combination with pembrolizumab (200 mg) in 21-day cycles to identify the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). Key eligibility criteria include 1) histological or cytological diagnosis of cancer and 2) refractory metastatic disease, or locally advanced disease not amenable to local therapy. At the RP2D, CLN-619 monotherapy will be evaluated in non-small cell lung and cervical cancer. In parallel, a cohort of patients will be administered CLN-619 in combination with pembrolizumab. Serum levels of soluble MICA/MICB, identity of MICA/MICB alleles, phenotypes of peripheral blood mononuclear cells, cytokines and tumor biopsies will be investigated for correlative pharmacodynamic and predictive biomarkers. This clinical trial is in progress (NCT05117476) and has completed accrual of three participants at the first dose level. Clinical trial information: NCT05117476.

2506 Background: SUMOylation is a post-translational modification with a role in limiting type 1 interferon (IFN-1)-dependent immune responses. Subasumstat is a small-molecule inhibitor of SUMOylation with the potential to increase antitumor immunity and overcome tumor resistance to checkpoint inhibitors (CPI) by inducing IFN-1 signaling. Preclinical data suggest that subasumstat enhances antigen cross-presentation, promoting T cell dependent antitumor responses; subasumstat plus an anti-PD-1 CPI has shown synergistic tumor growth inhibition and activation of CD8+ T cells and natural killer cells in syngeneic mouse models. We report data from the dose escalation part of a phase 1b study of subasumstat with pembrolizumab in pts with relapsed/refractory, CPI-exposed, non-squamous non-small-cell lung cancer (NSCLC) or microsatellite-stable colorectal cancer (MSS-CRC). Methods: Pts received escalating doses (40, 60, 90, and 120 mg) of subasumstat IV in 3 dosing schedules: days 1 and 8 (QW), days 1, 4, 8, and 11 (BIW), or days 1, 8, and 15 (90 mg only) of 21-day cycles, plus pembrolizumab 200 mg IV on day 1 of each cycle for 2 years or until disease progression or unacceptable toxicity. Dose escalation was guided by Bayesian optimal interval design. Phase 1b primary objectives were safety, tolerability, and the recommended phase 2 dose of subasumstat with pembrolizumab. Results: As of October 13, 2021, 43 (35 MSS-CRC; 8 NSCLC) pts had received ≥1 dose of subasumstat (22 BIW [40–120 mg]; 15 QW [90 –120 mg]; 6 on days 1, 8, 15 [90 mg)]. Median number of treatment cycles was 3; 28 (65%) pts had discontinued treatment, 21 (49%) due to progressive disease. Median age was 58 years (range 34–77); 56% of pts were male. One pt had a dose-limiting toxicity of grade 3 angioedema at 120 mg BIW. The maximum tolerated dose was not identified. Treatment-emergent adverse events (TEAEs) occurred in 38 (88%) pts; subasumstat-related TEAEs occurred in 34 (79%) pts, and included chills in 20 (47%), pyrexia in 16 (37%), fatigue in 9 (21%), anemia in 6 (14%), and stomatitis in 5 pts (12%; 3 [50%] in the 120 mg BIW cohort). Grade ≥3 TEAEs occurred in 24 (56%) pts; subasumstat-related grade ≥3 TEAEs reported in 10 (23%) pts included anemia, pyrexia, and increased aspartate aminotransferase (2 [5%] pts each). Pharmacokinetic activity of subasumstat was linear and decreased in a tri-phasic manner. Subasumstat exerted pharmacodynamic activity including target engagement, SUMOylation inhibition and increased IFN-1 signaling. Partial responses were observed at ≥40 mg dose levels in pts with NSCLC and MSS-CRC. Conclusions: Subasumstat plus pembrolizumab showed a favorable safety profile and promising anti-tumor activity in pre-treated NSCLC and MSS-CRC pts. Updated data will be presented at the meeting. Subasumstat plus pembrolizumab is currently in phase 2 clinical development (NCT04381650). Clinical trial information: NCT04381650.

2521 Background: MT-6402 is a unique and potent PD-L1-targeted engineered toxin body (ETB) capable of directly killing PD-L1 expressing tumor and immune cells by internalization of a fused Shiga-like toxin A subunit (SLTA) resulting in permanent SLTA-mediated ribosomal inactivation. The targeting of PD-L1 expressing tumor cells may directly drive tumor regression whereas targeting of PD-L1 expressing immune cells may release immunosuppression and drive immune recognition of the tumor. MT-6402 also delivers an HLA-A*02 restricted cytomegalovirus (CMV) class I antigen into PD-L1 expressing cells (antigen seeding) that can be recognized by existing CMV-specific cytotoxic T cells. Methods: A first-in-human dose escalation and expansion study in patients with PD-L1-expressing advanced solid tumors was initiated in 2021. As of 1 Jan 2022, 6 patients received at least one dose of MT-6402, 4 of whom were eligible for Dose Limiting Toxicity (DLT) assessment in Cohort 1. Results: A significant reduction in CD14+ monocytes starting in cycle 2 was observed in patients on therapy after each MT-6402 administration, indicating an HLA-independent PD effect consistent with preclinical observations. 5 of 6 patients had a marked decrease in Monocytic Myeloid Derived Suppressor Cells (MDSC). The reduction in MDSC and monocytes in the periphery overlapped with increased CCL2 levels, a chemokine that directs movement of myeloid cells. One patient with osseous metastases from non-small cell lung cancer (NSCLC) who is HLA-A*02 and CMV+ showed complete CMV-specific T-cell extravasation at day 8 and serum cytokine signatures consistent with antigen dependent responses and T cell mobilization. This patient had reduced tracer uptake of metastatic bone lesions with 3/4 lesions resolving completely. A second HLA A*02 CMV+ patient followed a similar trend towards loss of peripheral CMV-specific T cells with a concurrent increase in total CD8 T cells. The CD8 T cells from these 2 patients had elevated T-bet expression from baseline, indicating antigen specific TCR stimulation and expansion. The activated immune response was also accompanied by increased IP-10 and IL-2 cytokine signatures in the serum. Consistent with these findings, one of these two patients had transient (1-12 h) grade 2 infusion related reaction and the other had transient (1-12 h) grade 2 cytokine release syndrome, both on Day 15. These results describe a novel approach to checkpoint modulation by MT-6402, that adds antigen seeding to PD-L1 directing mechanisms. MT-6402 was well tolerated and no DLT was observed in Cohort 1 (16 µg /kg, QW in 4-week cycles). Conclusions: Dose escalation is ongoing. The results hold promise for development of MT-6402 for solid tumors, including in the R/R setting. Data for additional patients will be presented at the meeting. Clinical trial information: NCT04795713.

375 Background: In the Study 111/KEYNOTE-146 trial (NCT02501096; N=147), lenvatinib (lenva) + pembrolizumab (pembro) showed encouraging antitumor activity and a manageable safety profile in treatment-naive (n=23) or previously treated metastatic RCC (n=105, previously treated with immune checkpoint inhibitor [ICI]; n=19, previously treated ICI naive); 145 had clear cell RCC and 2 had non-clear cell RCC. In this exploratory analysis, we evaluated the association between clinical outcomes and gene expression signatures and DNA variants for individual RCC-specific driver genes of interest based on published reports. Methods: Patients (pts) with metastatic RCC were treated with lenva 20 mg orally once daily + pembro 200 mg intravenously once every 3 weeks. The analysis population included pts with treatment-naive (n=10) and ICI pretreated (n=70) disease with evaluable RNA-sequencing data for the 18-gene T-cell–inflamed gene expression profile (TcellinfGEP) and for 11 other signatures (angiogenesis; glycolysis; gMDSC; hypoxia; mMDSC; MVD; MYC; proliferation; RAS; stroma/EMT/TGFβ; WNT) and whole exome sequencing (WES) data for DNA variants for individual genes ( VHL, PBRM1, BAP1, and SETD2). Specimens were collected prior to the start of treatment. The associations between each signature score and ORR and PFS per immune-related RECIST were evaluated using logistic regression and Cox proportional hazards, respectively. One-sided P values for TcellinfGEP (hypothesized positive association) and two-sided P values for all other signatures (no hypothesized association) were adjusted for multiplicity using the Hochberg step-up procedure; significance was prespecified at α=0.05. The association between DNA variants for individual genes and ORR was evaluated descriptively. Clinical data cutoff was August 18, 2020. Results: Of 147 treated pts, RNA sequencing and WES data were available for 80 (54%) and 60 (41%), respectively. TcellinfGEP was not associated with ORR ( P=0.827) or PFS ( P=0.741), nor were the other 11 signatures before or after adjustment for TcellinfGEP. ORR for DNA variants reported in the table. Conclusions: In this exploratory analysis of pts with metastatic RCC enrolled in Study 111/KEYNOTE-146 treated with lenva + pembro, responses were observed regardless of biomarker status. There were no statistically significant associations between gene signatures and clinical outcomes. Clinical benefit was observed regardless of VHL, PBRM1, BAP1, or SETD2 mutation status. Analyses in larger randomized datasets will provide additional information on the role of biomarkers in RCC. Clinical trial information: NCT02501096. [Table: see text]

TPS222 Background: Activation of the tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAILR2) induces apoptosis via caspase activation. Targeting TRAILR2 is an attractive therapeutic strategy, but some early TRAILR2 agonists were associated with severe hepatotoxicity. Cadherin 17 (CDH17), a membrane protein highly expressed in GI cancers, is not expressed in normal hepatocytes so using CDH17 as a liver-sparing anchor may avoid hepatotoxicity. BI 905711 is a tetravalent bispecific antibody that cross-links TRAILR2 with CDH17 to induce CDH17-dependent TRAILR2 oligomerisation. In preclinical assays, BI 905711 demonstrated a potency shift of ̃1000 fold versus the 1st-generation TRAILR2 agonist lexatumumab. BI 905711 induced apoptosis in CDH17-positive tumor cells in vitro, impaired tumor growth in pt-derived colorectal cancer (CRC) xenografts, and no hepatotoxicity was observed. Methods: This phase Ia/Ib study (NCT04137289) aims to determine the safety, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of BI 905711 in pts with advanced, refractory GI cancers. Up to 140 adult pts with histologically confirmed, advanced unresectable/metastatic colorectal, gastric, esophageal or pancreatic adenocarcinoma, cholangiocarcinoma, or gallbladder or small intestine carcinoma, who have progressed on standard-of-care therapies, will be enrolled. In phase Ia, pts will receive intravenous BI 905711 at escalating doses (range 0.02–4.8 mg/kg) every 14 days, until disease progression or unacceptable toxicities. Dose escalation will be guided by a Bayesian logistic regression model with overdose control based on dose-limiting toxicities (DLTs) in the first 28 days. In phase Ia, a minimum number of CRC pts will be enrolled to each cohort: ≥1 CRC pt at each of the 2 lowest dose levels (0.02/0.06 mg/kg) and 4 pts at each subsequent dose level (0.2/0.6/1.2/2.4/3.6/4.8 mg/kg). In parallel to dose escalation in CRC pts, up to 4 pts with non-CRC GI cancers will be included at the dose level below that of the CRC cohort. If an objective response (OR) per RECIST v1.1 is observed in CRC or non-CRC GI pts at a safe dose level, up to 10 additional pts with the same tumor type will be recruited at that dose level. In phase Ib, CRC pts will be randomized into up to 4 dose cohorts (as determined in phase Ia; n=20 each) to define the recommended phase II dose. The primary endpoints are determination of the MTD based on the proportion of pts with DLTs (phase Ia) and OR rate based on RECIST v1.1 (phase Ib). Secondary endpoints include PK parameters and OR in pts with measurable disease (phase Ia), and disease control, tumor shrinkage, duration of response, and progression-free survival (phase Ib). Trial enrollment is ongoing, with 33 pts enrolled to date. Clinical trial information: NCT04137289.

TPS637 Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by stromal fibrosis, hypoxia, and nutritional deprivation. PDAC tumors grow aggressively, diagnosis is typically made after metastasis and the disease remains associated with poor outcomes. The triplet chemotherapy regimen of gemcitabine, nab-paclitaxel with cisplatin was associated with a median overall survival of 16.4 months in patients with metastatic pancreatic cancer in the first-line setting (Jameson et al., 2020). Nutritional, metabolic interventions offer an opportunity to fundamentally change the tumor microenvironment and improve outcomes for patients. A ketogenic diet defined as lower carbohydrate, lower protein, and higher fat can significantly reduce glucose and insulin and increase metabolically active ketone bodies and has been evaluated in patients with a variety of solid tumors (Weber et al, 2020). Recently, a ketogenic diet combined with triplet chemotherapy was shown to inhibit murine pancreatic KPC tumor growth and significantly prolong animal survival over chemotherapy alone. Tumor growth inhibition was associated with glucose depletion, altered TCA substrate usage, and NADH elevation. Methods: In this Phase II randomized clinical trial (NCT04631445), we are evaluating a medically supervised ketogenic diet (MSKD) versus a standard diet when combined with the triplet therapy in patients with treatment-naive advanced pancreatic cancer. The primary endpoint is progression free survival for triplet therapy while on MSKD or non-MSKD. Secondary endpoints include disease control rate (PR+ CR+ SD for at least 9 weeks), change in CA 19-9 (or CA125, or CEA if not expressers of CA 19-9), average insulin levels, HbA1c, body weight, a comparison of gut microbial diversity, changes in serum metabolites and quality of life via the EORTC QLQ-C30 assessment. Unlike prior ketogenic intervention studies, the MSKD is being supported by a continuous care nutrition intervention through Virta Health Corp, that offers tracking of daily ketone and glucose levels, a web-based software application, education, and communication with a remote care team to ensure sustained nutritional ketosis. A total of 40 patients with untreated metastatic PDAC are planned for enrollment, 20 randomized to each arm. The trial opened for accrual November 2020. Clinical trial information: NCT04631445.

2512 Background: BDB001 is an intravenously administered TLR 7/8 dual agonist immune modulator capable of reprogramming dendritic cells to produce antitumor activities. BDB001 monotherapy has demonstrated favorable tolerability and robust systemic immune activation leading to durable clinical responses in a phase I dose escalation trial. Here, we report on the safety and efficacy of BDB001 in combination with pembrolizumab in a phase I dose escalation trial in advanced solid tumors (NCT03486301). Methods: BDB001-101 is a phase 1, open label, dose escalation/expansion trial of BDB001 (IV, Q1W) in combination with pembrolizumab (IV, Q3W) in patients with advanced solid tumors. The primary endpoint was safety and tolerability. Secondary endpoints included efficacy, pharmacokinetics and pharmacodynamic profiling of immune activation. Results: Twenty-three subjects with 13 different tumor types were enrolled across 4 dose levels. Sixty one percent were female, median age was 63 years (range, 33-86), median number of prior therapies was 3 (range, 1-8), and 48% of tumors had progressed on prior anti-PD-(L)1 therapy. Overall, BDB001 in combination with pembrolizumab was well tolerated and dose-limiting toxicities were not observed. The most common treatment related adverse events (TRAEs) were fever (39.1%), fatigue (39.1%), chills/rigor (34.8%), pruritus/rash (21.7%), and nausea (13.0%). Most of these TRAEs were grade 1 or 2 and transient. Only 3 (13.0%) subjects experienced grade 3 TRAEs of fatigue, rash, stomatitis, and alkaline phosphatase elevation. There were no grade 4 or 5 TRAEs. Pharmacodynamic evaluation of plasma cytokine levels showed robust increases in interferon gamma and interferon inducible protein-10 (IP-10) at BDB001 Dose Level 3 and 4. Preliminary efficacy evaluation of the 14 subjects treated at Dose Level 3 and 4 showed durable and deep clinical responses in 4 (29%) subjects with anti-PD-(L)1 mAb refractory melanoma, hepatocellular carcinoma, cholangiocarcinoma, and platinum-resistant ovarian carcinoma. The responses were observed by the initial efficacy assessment at 9-weeks, with some seen as early as 4-weeks. In addition, 4 (29%) subjects had stable disease for a disease control rate of 57%. To date, median time on treatment is 14.4 weeks (range, 6.0 – 42.1+) with 3 subjects still active on treatment. Conclusions: Intravenously administered BDB001 in combination with pembrolizumab is well tolerated. Rapid and deep clinical responses were observed, supported by robust systemic immune activation. BDB001 in combination with pembrolizumab is a promising novel therapeutic option for patients with advanced solid tumors and is being evaluated in an ongoing dose expansion trial. Clinical trial information: NCT03486301.

3104 Background: Enhancer of Zeste homolog 2 (EZH2) is a histone methyltransferase and the catalytic subunit of Polycomb Repressive Complex 2 (PRC2). EZH2 is frequently overexpressed in cancers and correlates with poor prognosis. CPI-0209 is an oral, small molecule, second-generation, selective inhibitor of EZH2 designed to achieve comprehensive target coverage through extended on-target residence time. The compound demonstrates more potent anti-tumor activity in preclinical cancer models, compared to first-generation EZH2 inhibitors. CPI-0209 is currently being evaluated in a Phase 1/2, open-label, FIH study (NCT04104776). Methods: Patients (pts) with advanced tumors were enrolled in a 3+3 design. Primary objective is to determine maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of CPI-0209. Secondary objectives are to evaluate the safety, PK, and PD in pts who received CPI-0209 QD in 28 days cycles (C). Results: As of December 16, 2020, 33 pts were treated: pancreatic cancer (n = 6), mesothelioma, breast, colorectal, and ovarian cancer (n = 5 each), leiomyosarcoma, melanoma, cholangiocarcinoma, prostate, bladder, endometrial clear cell and gastric cancer (n = 1 each). Pts received CPI-0209 at 50 mg (n = 4), 100 mg, 137.5 mg, and 187.5 mg (n = 6 each), 225 mg (n = 7), and 275 mg (n = 4) daily dose. Median treatment duration was 43 days (range 1-239); 4 pts are ongoing. Median age was 64 yrs (range 24-79); 15 (45%) pts were male. Patients were heavily pretreated, with 67% of pts had ≥ 3 prior lines of therapy. No dose limiting toxicities have been observed. The most frequent treatment-emergent adverse events (TEAEs) (≥10%) were fatigue (27%), diarrhea (24%), nausea (21%), abdominal pain, alopecia, anemia, thrombocytopenia, and dysgeusia (15% each), and vomiting, headache, decreased appetite, and alkaline phosphatase increased (12% each); usually grade 1 or 2 in severity. Thrombocytopenia was dose-dependent and not associated with bleeding or clinical sequalae. Three pts (9%) discontinued CPI-0209 due to TEAEs. Comprehensive target engagement (assessed by global reduction in H3K27me3 levels in monocytes) was observed within the first cycle at all dose levels. CPI-0209 also increased the expression of PRC2-controlled gene sets in blood in a dose-dependent manner. Updated safety, PK, PD, and preliminary efficacy results from Phase 1 will be presented. Conclusions: CPI-0209 achieved robust PD effects and a PK-PD relationship has been established. CPI-0209 monotherapy was generally well tolerated, and treatment related AEs were manageable and reversible. The MTD has not been reached. Clinical trial information: NCT04104776.

2504 Background: COM701 is a novel first in class humanized IgG4 monoclonal antibody that binds with high affinity to poliovirus receptor related immunoglobulin domain containing (PVRIG), blocking its interaction with its ligand, PVRL2. Blocking of PVRIG leads to enhanced activation of T/NK cells and in mouse models inhibits tumor growth. We report new and updated results on safety/tolerability/pharmacokinetics and antitumor activity from this ongoing study including final results in dose escalation combination cohort, monotherapy expansion cohort (MEC). Methods: We enrolled a total of 51 DLT-evaluable pts: Arm A (COM701 mono dose escalation), 16 pts in 8 cohorts (0.01 – 20 mg/kg IV Q3/4 wks); Arm B (COM701 0.3 – 20 mg/kg + nivolumab (NIVO) 360 mg/480 mg IV Q3/Q4 wks), 15 pts in 5 cohorts; 20 pts in MEC (NSCLC, OVCA, breast, endometrial and CRC) at the recommended dose for expansion(RDFE), 20 mg/kg IV Q4 wks. Key inclusion criteria: Age ≥18 yrs, histologically confirmed metastatic solid malignancy, has exhausted available standard tx, ECOG 0-1, prior ICI permissible (except prior tx with a PVRIG inhibitor). Key exclusion criteria: active autoimmune disease requiring systemic tx, hx inflammatory lung disease. Primary objectives – safety/tolerability of COM701 ± NIVO (AEs, CTCAE v4.03), PK, RDFE. Key secondary/exploratory objectives - antitumor activity of COM701 ± NIVO (RECIST v1.1), evaluation of PVRL2 expression in tumor biopsy, blood cytokines and immunophenotyping. Results: No DLTs were reported in Arms A or B. COM701 PK profile similar in Arm A, 20 mg/kg IV Q4 wks (cohort 8) and Arm B cohort 5 (COM701 20 mg/kg + NIVO 480 mg; all IV Q4 wks). Frequency of TEAEs in safety population (N=54 pts): pts on COM701 mono (N=38)- No AE (4), Grade≤2 (21), G3 (11), G4 (1), G5 (1, PD), pts on combo (N=16) - Grade≤2 (8), G3 (7), G5 (1, PD). Serious TEAE: pts on COM701 mono 11/38, pts on combo 6/16. Most frequent AEs in Arm A: Grade ≤2 fatigue 12/38 pts (31%), nausea 9/38 (23%); Arm B: fatigue 7/16 pts (44%) and AST increased 4/16 pts (25%). Antitumor activity - in Arm A (cohort 8), a pt with platinum resistant primary peritoneal cancer had confirmed PR ongoing 14 months. In Arm B (COM701 10 mg/kg + NIVO 480 mg, all IV Q4 wks), a pt with anal SCCA; confirmed CR, ongoing 18 months, last tx with prior PD on NIVO. In addition, a pt with renal cell CA had confirmed SD [ongoing 13 months, COM701 0.3 mg/kg + NIVO 360mg; IV Q3 wks],] In MEC, 30% (6/20 pts) had best response of SD [1-endometrial, 3 NSCLC, 2 OVCA], 2 pts [NSCLC, OVCA] ongoing at 6/4 months. Overall 16pts had prior tx-refractory disease, 9(56%) had best response of ≥SD. Of 18 pts with prior tx with ICI, 13 (72%) had best response of ≥SD. Datacut 14Dec2020. Conclusions: COM701 ± NIVO well tolerated with no new safety signals. Encouraging signal of antitumor activity including in pts with prior tx with ICI or prior tx-refractory disease. Clinical trial information: NCT03667716..

2505 Background: GB1275 is a first-in-class, oral CD11b modulator that reduced myeloid-derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs), repolarized M2 immunosuppressive TAMs to an M1 phenotype, resulting in increased tumor infiltration of activated CD8+ T cells and antitumor efficacy in preclinical models. Here, we report preliminary results from an ongoing, first-in-human dose-escalation study in specific advanced tumors using GB1275 alone or with pembrolizumab. (NCT04060342) Methods: Phase 1 comprises dose escalation and expansion. During dose escalation, cohorts of 3 to 6 subjects were sequentially assigned to ascending dose levels of GB1275 from 100 mg to 1200 mg BID in one of two dosing regimens: Regimen A [GB1275 monotherapy orally (PO) twice a day (BID)] and Regimen B [GB1275 PO BID plus pembrolizumab 200 mg IV every 3 weeks (q3wks)]. Dose escalation was based on safety including dose-limiting toxicities (DLTs). Following dose escalation, up to 40 subjects with specific tumor types are to be treated in expansion with the selected GB1275 dose plus pembrolizumab to assess safety, pharmacokinetics, and preliminary clinical and biomarker activity. Results: As of January 8, 2021, 45 subjects were treated [44 in dose escalation: 23, Regimen A; 21, Regimen B. 1 in expansion, Regimen B], with median (range) GB1275 exposure of 42.0 days (4-263). No DLTs were reported. GB1275-related adverse events occurred in 24/45 (53.3%) subjects; photosensitivity reaction (20.0%), dysesthesia (13.3%) and pruritus (13.3%) were most frequent (≥10%). Stable disease was reported in 6/19 (31.6%) response-evaluable subjects in Regimen A and 9/16 (56.3%) in Regimen B. In Regimen B (800 mg), one partial response was reported in a subject with MSS-CRC treated for 263 days, and one prolonged stable disease (227 days) was reported in a gastric cancer (GC) subject previously treated with pembrolizumab plus bavituximab for less than 3 months due to progression; both subjects are continuing study treatment. A dose-dependent increase in GB1275 systemic exposure was observed up to 800 mg BID. Down-regulation of peripheral MDSCs was seen with both regimens. Regimen-dependent gene clusters in whole blood were noted. An increase in tumor infiltrating lymphocyte (TIL) counts was noted in both Regimens A and B. Conclusions: Dose escalation of GB1275, up to 1200 mg in Regimens A and B, demonstrated tolerability as monotherapy and combined with pembrolizumab in subjects with advanced cancers. Encouraging antitumor activity in Regimen B (800 mg) was observed in subjects with MSS-CRC and GC. Biological activity reflected by MDSC modulations in blood and TIL Increases in tumor biopsies with GB1275 alone and with pembrolizumab supports the mechanism of GB1275. GB1275 800 mg BID plus pembrolizumab 200 mg IV q3wks was selected for evaluation in the expansion phase. Clinical trial information: NCT04060342.

2549 Background: BDC-1001 is a novel ISAC consisting of an investigational trastuzumab biosimilar chemically conjugated to a TLR 7/8 agonist with a non-cleavable linker. BDC-1001 was designed to activate the innate immune system, eliciting antibody-mediated effector functions (eg, antibody-dependent cellular phagocytosis) and a durable adaptive immune response. In preclinical tumor models resistant to anti-HER2 treatments, BDC-1001 demonstrated potent and durable immune-mediated antitumor efficacy. Methods: A 4-part, phase 1/2 dose-escalation/expansion study was initiated to evaluate BDC-1001 ± PD1 inhibitor pembrolizumab in pts with HER2-expressing solid tumors who had progressive disease on standard of care (NCT04278144). Preliminary results of the monotherapy dose escalation (Part 1) are reported. Pts with advanced metastatic HER2-expressing (IHC2/3+) or amplified solid tumors received BDC-1001 IV q3w in a 3+3 design w/ 12 pts/cohort backfill allowed. Primary objectives were to evaluate safety, tolerability, dose-limiting toxicities (DLTs) and determine a phase 2 dose; secondary objectives were to assess pharmacokinetics (PK), pharmacodynamics and preliminary anti-tumor activity. Results: As of Jan 29, 2021, 20 pts w/ a median age of 65 (46-85) have enrolled in 4 dose levels (0.15mg/kg to 5 mg/kg). Cancer types include breast, biliary, cervical, colorectal (CRC), lung, gastroesophageal, salivary, urinary tract and endometrial. Pts had received a median of 4 (1-7) prior therapies; 65% received >1 prior anti-HER2 therapy. All pts completed the 21-day DLT period; no DLTs or drug-related serious adverse events (AEs) have been observed. AEs deemed related to BDC-1001 have been mild to moderate including infusion-related reactions. The MTD has not been reached (treatment duration 5-17+wk); enrollment is ongoing. PK evaluations showed Cmax levels consistent with predicted modeling based on non-human primates (NHP). One pt with microsatellite stable (MSS) HER2+ CRC with lung metastases had a confirmed partial response after 4 cycles and remains on study; 2 additional pts with metastatic MSS HER2+ CRC had stable disease (SD) and a pt with heavily pretreated MSS endometrial cancer with lung metastases had confirmed SD and remains on treatment 17+ wk; 3 of these pts had received 2 prior anti-HER2 therapies. Conclusions: In this first-in-human study, BDC-1001 appears to be well-tolerated up to the dose tested to date (5 mg/kg), with Cmax levels achieved as predicted by NHP modeling. Evidence of clinical activity have been observed, including in pts previously treated with anti-HER2 therapy. Dose escalation is ongoing and will be followed by combination dosing with CPI and the phase 2 component in selected tumors. Clinical trial information: NCT04278144.

3508 Background: APG-1387 is an IAP (inhibitor of apoptosis proteins) antagonist that has strong antitumor activity in multiple xenograft cancer models and acts as a host immune modulator, supporting its exploration for use in combination with checkpoint inhibitors for cancer therapy. Methods: This “3+3” dose escalation and dose expansion study evaluated APG-1387 combined with pembrolizumab in patients with refractory or intolerant advanced solid tumors (NCT03386526). APG-1387 was administered IV once weekly with pembrolizumab 200 mg on day 1 of a 21-day cycle. Study aims were to assess safety/tolerability, recommended phase 2 dose (RP2D), pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. Results: As of December 25, 2019, total 28 patients had been treated in 3 dose cohorts of APG-1387: 20 mg (n = 4), 30 mg (n = 3), and 45 mg (n = 21, 18 in dose expansion). The median line of prior systemic cancer therapies was 3.0 (1-12). No dose-limiting toxicity was observed. The most common treatment-related adverse events (TRAEs; ≥10%) were fatigue (28.6%), arthralgia (14.3%), headache (14.3%), and tumor pain (10.7%). One patient in the 45-mg cohort had grade 2 Bell’s Palsy. G3+ TRAEs were autoimmune colitis, hypoxia, increased lipase, mucosal inflammation, pneumonitis, and tumor pain in 1 patient each (3.6%). Treatment-related SAEs were 1 G3 autoimmune colitis, 1 G2 myocarditis, and 1 G3 pneumonitis. The maximum tolerated dose (MTD)/RP2D for APG-1387 was 45 mg. Among 25 efficacy-evaluable patients, 1 with ER+, HER2‒ breast cancer receiving APG-1387 30 mg after failing 5 lines of therapy (PD-1 treatment-naïve, microsatellite stable) achieved confirmed PR (-79.2%) for 6 cycles but discontinued due to pneumonitis; another patient with PD-L1‒ non‒small-cell lung cancer treated at 45 mg had confirmed PR (-65.0%) for 6 cycles (ongoing). Other 11 patients had SD for 2-11 cycles. The disease control rate was 52%. Preliminary PK data showed a dose-proportional increase in APG-1387 exposure from 20 mg to 45 mg. Preliminary PD data showed that APG-1387 induced rapid degradation of cellular IAP1 and X-linked IAP in peripheral blood mononuclear cell samples; Increased serum release of interleukins (IL-12, IL-10) and monocyte chemotactic protein 4 was dose and time dependent. Conclusions: APG-1387 combined with pembrolizumab is well tolerated. Encouraging antitumor effects were observed in patients with several tumor types. The ongoing study will further evaluate the efficacy of this combination. Clinical trial information: NCT03386526 .

3509 Background: Targeting Bcl-2/Bcl-xL proteins is considered as an important approach for anticancer drug development. Palcitoclax (APG-1252) was being developed to reduce on-target platelet toxicity without diminishing antitumor potency. Methods: The phase 1 study was to evaluate the safety/tolerability, pharmacokinetics (PK), and preliminary efficacy (assessed per RECIST 1.1) of palcitoclax in US patients with metastatic small-cell lung cancer (SCLC) or other solid tumors (NCT03080311). A standard “3+3” design was applied to the dose-escalation stage. Palcitoclax was administered IV infusion for 30 minutes, twice a week (BIW) or once a week (QW) for 3 weeks in a 28-day cycle. Once the maximum tolerated dose / recommended phase 2 dose (MTD/RP2D) was determined, additional patients were treated in a dose-expansion stage. Results: The dose-escalation phase has been completed with 42 patients (31 on BIW and 11 on QW) who received palcitoclax at 8 dose cohorts ranging 10 mg - 400 mg. Most adverse events (AEs) were grade 1 or 2 (G1 or G2), and 26.2% patients had ≥ G3 TRAEs. The most common TRAEs were platelet count decreased (14.3%), aspartate aminotransferase increased (9.5%), and alanine aminotransferase increased (7.1%). Rapid platelet drop was observed in patients treated at 320 mg and 400 mg, which was transient and resolved rapidly within 2-6 days. Palcitoclax at 240 mg once weekly was determined to be MTD/RP2D. Of 36 efficacy-evaluable patients, 3 patients with SCLC, neuroendocrine prostate cancer, and ovarian cancer respectively achieved partial response (PR) and 8 patients had stable disease (SD) as their best overall response. One patient with SCLC had a PR that lasted over 21 cycles. Preliminary PK analyses showed that Cmax and AUC were approximately dose proportional over the range of 10 mg to 320 mg following the IV infusion on Day 1, with a mean T1/2 of 3.0-13.0 hours. Conclusions: Palcitoclax is safe and well tolerated, with a favorable platelet toxicity profile. Its promising antitumor effect supports its further development in combination therapies for treatment of patients with SCLC and other solid tumors. Clinical trial information: NCT03080311 .

3085 Background: GB1275 is a first-in-class CD11b modulator that reduced myeloid-derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs) at the tumor site, repolarized M2 immunosuppressive TAMs to an M1 phenotype, and increased tumor infiltration of activated CD8+ T cells in preclinical models. When combined with an anti-PD-1 antibody or chemotherapy, these immunomodulatory effects translated into potent anti-tumor effects and prolonged survival in orthotopic PDAC models [Panni RZ, et al. Sci Transl Med. 2019 Jul 3;11(499)]. This ongoing first-in-human study consists of dose escalation of GB1275 monotherapy (Regimen A), GB1275 + pembrolizumab (Regimen B), and GB1275 + nab-paclitaxel + gemcitabine (Regimen C), followed by Phase 2 expansion in newly diagnosed metastatic pancreatic, MSS colorectal, and PD-L1-positive gastric/GEJ cancers. Here we report interim results of the dose escalation portion of the trial. Methods: The dose escalation phase is based on a standard oncology phase 1, 3+3 design. Cohorts of 3 to 6 patients (pts) with histologically confirmed locally advanced/metastatic pancreatic, esophageal, gastric, MSS colorectal, prostate, or breast cancer were sequentially assigned to ascending dose levels of GB1275 taken orally twice daily (BID) in 1 of 3 regimens: Regimen A was initiated first; Regimen B commenced after completion of the first two cohorts of Regimen A, and Regimen C will be initiated when Regimen A is completed. Dose escalation was based on assessment of safety including dose-limiting toxicity (DLT). Serial blood and tumor samples were collected for pharmacokinetic (PK) and biomarker analyses. Results: As of January 21, 2020, 13 pts were treated, with 3 each in Regimen A (GB1275 100mg, 200 mg and 400 mg BID) dose levels and 4 in Regimen B with GB1275 100 mg BID + pembrolizumab. No DLTs have been reported. GB1275 treatment-related adverse events were reported in 5 pts; all were Grade 1 in severity. Preliminary PK analyses showed a mean elimination half-life of ~7 hours. Reduction in peripheral MDSCs was observed in the majority of pts with serial samples. Biomarker analysis in serial tumor tissue is ongoing. Conclusions: Preliminary data show minimal treatment-related toxicities with the studied regimens. PK data support BID dosing. Dose escalation is ongoing. Updated data will be presented. Clinical trial information: NCT04060342 .

TPS23 Background: COM701 is a novel 1st-in-class monoclonal antibody that binds with high affinity to poliovirus receptor related immunoglobulin domain containing (PVRIG) blocking its interaction with its ligand, PVRL2. In preclinical experiments inhibition of PVRIG alone and in combination with a PD-1 inhibitor leads to activation of T cells in the tumor microenvironment generating an anti-tumor immune response leading to tumor growth inhibition. Novel checkpoint therapies are needed for the treatment of patients with advanced malignancies. We hypothesized that COM701 monotherapy and in combination with nivolumab will be safe and tolerable and demonstrate preliminary antitumor activity in pts with advanced solid malignancies. Methods: This ongoing phase 1 study (NCT03667716) is evaluating the safety and tolerability of escalating doses of COM701 monotherapy IV Q3 or Q4 weekly and in combination with nivolumab 360 mg IV Q3 weekly or 480 mg IV Q4 weekly. Key Inclusion Criteria: Age ≥18 yrs, histologically or cytologically confirmed advanced solid malignancy and has exhausted all available standard therapy, ECOG performance status 0-1, prior ICI permissible. Key Exclusion Criteria: Symptomatic interstitial lung disease or inflammatory pneumonitis, untreated or symptomatic central nervous system metastases. Primary outcome measures are the incidence of adverse events and dose-limiting toxicities (21-day or 28-day DLT window), pharmacokinetics of COM701 and to identify the maximum tolerated dose and/or the recommended dose for expansion. Key secondary outcome measures are to characterize the immunogenicity and preliminary antitumor activity of COM701 as monotherapy and in combination with nivolumab. Study Design: Hybrid accelerated titration and 3+3 study design. Statistical Considerations: Adverse events graded as per CTCAE v4.03, responses as per RECIST v1.1. Analyses of all study objectives are descriptive and hypothesis generating. As of the date of this submission dose level 8 of COM701 monotherapy and dose level 3 of the combination arm are open to enrollment. Updated data will be presented at the conference. Clinical trial information: NCT03667716.

3013 Background: ABBV-621 is a potent tumor-necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor agonist fusion protein that induces apoptotic cell death, particularly in DR4/5 expressing tumor models. Methods: Patients (pts) with previously treated solid tumors and ECOG 0–2 were administered ABBV-621 (2.5–15 mg/kg IV) on day (D) 1 (dose level [DL] 1) or D1D8 (DL2 and beyond) of each 21-day cycle. Dose escalation (DE) was guided by a Bayesian continual reassessment method. In addition to PK studies, blood-based PD markers of apoptosis (M30, M65) and drug binding were assessed. Results: As of 14 December 2018, 57 pts were enrolled in the DE portion, of which 30% had pancreatic, 23% colorectal cancer, and 47% other tumor types; 13 were KRAS mutant. Median age was 61 yrs. 60% were male; pts had a median of 4 prior regimens (range 1–10). Pts per DL: 2.5 (5 on D1, 16 on D1D8), 3.75 (12), 5 (6), 6.5 (6), 8.5 (4), 11 (4), and 15 mg/kg (4). Median duration of ABBV-621 exposure was 2 cycles (range 1–11). Seven pts had dose-limiting toxicities: respiratory failure (5 mg/kg; Grade 5, the only treatment-related death), blood bilirubin increased (3.75, 6.5 mg/kg), nausea (3.75 mg/kg), fatigue (3.75 mg/kg), increased ALT (2.5, 3.75, 6.5, 15 mg/kg), and increased AST (6.5 mg/kg). Summary of AEs is shown in Table. Clinical trial information: NCT03082209. A partial response (duration 20 weeks) was observed in a pt with pancreatic cancer (2.5 mg/kg D1D8). 27 pts had stable disease (6 pts for > 12 weeks). ABBV-621 PK was linear (mean ± SD clearance was 1.79 mL/h/kg ± 0.44) with a terminal half-life of 36.7 ± 5.55 h (n = 49). ABBV-621 bound to decoy receptors on neutrophils for up to 168 h; the duration of binding was dose-dependent. M30 and M65 increased at 8, 24, and 48 h following ABBV-621, but effect was independent of dose. Conclusions: ABBV-621 shows evidence of antitumor activity and effect on blood-based markers of apoptosis, with acceptable toxicity (MTD not reached). NCT03082209.[Table: see text]

3097 Background: APX3330 is an orally administered anti-cancer, anti-CIPN agent targeting the APE1 protein. APE1 maintains NFkB, STAT3, AP-1 and HIF-1a in a reduced form, acting as a regulator of transcription factors. A dual function protein, APE1 also plays a role in protecting against oxidative DNA damage in neurons. APX3330 is a highly selective inhibitor of APE1 redox function in tumors that enhances the neuronal protection function of APE1. Methods: We report on study NCT03375086 evaluating APX3330 in patients with incurable malignancies. Eligibility required adequate organ function, PS 0-2 and tumors not amenable to curative therapy. 1° and 2° objectives included determining the recommended phase 2 dose (RP2D), the safety and PK/PD profiles of APX3330 and reporting any RECIST anti-tumor activity. Patients received APX3330 b.i.d, in 21-day cycles. AE evaluation included 1 pt/cohort until the occurrence of ≥ G2 toxicity at which time the study proceeded in a 3+3 design. Additional patient were also recruited in cohorts in order to attain PK/PD and biopsy samples. Results: Between 2/18 and 8/18, 19 subjects (13M, 6F) with median age of 69 y started therapy. Dose (mg/d) escalation and number of patients treated (n) per each cohort proceeded as follows: 240 mg (1), 360 (4), 480 (2), 600 (6) and 720 (6). APX3330 was well tolerated at dose levels from 240-600 mg/d. The most frequent treatment-related adverse event (all grades) was G1 fatigue. A G3 rash occurred in two subjects at the 720 mg level defining 600 mg/d as the RP2D for further development. Six subjects had disease stabilization for ≥ 4 cycles, and of these, four subjects with the following diagnosis, RECIST response and days on study included: (CRC, PR, 356), (Endometrial, SD, 316), (Melanoma, SD, 245), (Prostate, SD, 246). Final PK and PD data, including proteomic, transcriptome, APE1 serum levels and CTC analyses are pending and will be reported at the conference. Conclusions: APX3330 is an orally administered inhibitor of APE1. This phase I study identified 600 mg PO daily as the RP2D for further development. RECIST evaluation identified signs of clinical activity in this un-selected population of patients with advanced cancer. PD analyses indicate APX3330 mediated targeting of the APE1 protein. Clinical trial information: NCT03375086.

2558 Background: An ongoing multicenter, open-label, phase 1 study of the anti–CTLA-4 antibody MK-1308 in combination with pembro in advanced solid tumors (NCT03179436) revealed a manageable safety profile and promising efficacy in pts with first-line (1L) advanced NSCLC. Data from a larger sample size and longer follow-up are presented. Methods: In dose escalation (DE), pts with advanced solid tumors received MK-1308 by IV administration at 25, 75, or 200 mg Q3W ×1 cycle then in combination with pembro 200 mg Q3W ×4 cycles followed by pembro monotherapy (up to 35 cycles). In dose confirmation (DC), pts with 1L advanced NSCLC received MK-1308 at 25 or 75 mg—Q3W or Q6W—plus pembro 200 mg Q3W (up to 35 cycles). Safety (all treated pts), efficacy (subset of 1L NSCLC pts), pharmacokinetics (PK, all treated pts), and PD-L1 tumor expression (subset of 1L NSCLC pts) were analyzed. Results: 213 pts were treated (DE, n=39; DC, n=174). All pts were included in the safety analyses (median follow-up, 8 months); 113 pts from DC were included in the efficacy analyses (median follow-up, 8 months). PK showed a dose-dependent increase in MK-1308 exposure. Neither target dose-limiting toxicity (≥10%) nor maximum tolerated dose were reached for MK-1308 plus pembro; however, toxicity increased with increasing MK-1308 dose and shorter dosing intervals. Treatment-related adverse events grade ≥3 occurred at the lowest rates at 25 mg Q3W in DE (0%) and 25 mg Q6W in DC (25%) and at the highest rates at 200 mg Q3W in DE (75%) and 75 mg Q3W in DC (50%). Efficacy was observed at all MK-1308 dose levels and intervals: confirmed ORR per RECIST 1.1 by central review in 1L advanced NSCLC was 39% at 25 mg Q3W, 33% at 25 mg Q6W, 22% at 75 mg Q6W, and 25% at 75 mg Q3W; 6-month PFS and OS rates are 67% and 89% for the 25 mg Q6W arm. There was a 25% ORR in PD-L1–negative 1L advanced NSCLC pts. Conclusions: MK-1308 plus pembro was generally well tolerated with no unexpected toxicity and conferred encouraging antitumor activity in 1L advanced NSCLC pts. Efficacy, safety, and PK data suggest that 25 mg given Q6W is the recommended phase 2 dose for MK-1308 in combination with pembro. Clinical trial information: NCT03179436.

TPS2657 Background: There is a high unmet medical need for the treatment (tx) of patients (pt) who are refractory to or relapse following tx with checkpoint inhibitors. Newer checkpoint therapies with novel mechanisms of action that can activate T cells and demonstrate antitumor activity in this pre-tx pt population are urgently needed. COM701 is a novel first-in-class humanized IgG4 monoclonal antibody that binds with high affinity to PVRIG (poliovirus receptor related immunoglobulin domain containing) blocking its interaction with its ligand, PVRL2. Both PVRIG and PVRL2 are part of the DNAM axis as are TIGIT and PD1. Inhibition of PVRIG leads to enhanced activation of T and NK cells, and PVRIG results in tumor growth inhibition in mouse tumor models. We hypothesize that COM701 will demonstrate antitumor activity in pts who are checkpoint inhibitor pre-tx. Methods: NCT03667716 is an ongoing open-label first-in-human phase 1 study in pts with advanced solid tumors. The initial part of this study (Arm A) will evaluate escalating doses of COM701 monotherapy IV Q3 weekly with single pt cohorts for the initial 4 and then 3+3 design. Key Inclusion Criteria: Age ≥18 yrs, histologically confirmed locally advanced/ metastatic solid malignancy and has exhausted available standard therapy, ECOG 0-1, prior anti-PD-1, anti-PD-L1, anti-CTLA-4, OX-40, CD137 permissible. Key Exclusion Criteria: Active autoimmune disease requiring systemic therapy in the last 2 years, symptomatic interstitial or inflammatory lung disease, untx or symptomatic central nervous system metastases. Primary objectives are safety and tolerability of COM701 as measured by the incidence of adverse events (AEs) and dose-limiting toxicities (21-day DLT window), pharmacokinetics of COM701, and to identify the maximum tolerated dose and/or the recommended dose for expansion. Secondary objectives are to characterize the immunogenicity and preliminary antitumor activity of COM701. Statistical Considerations: AEs graded as per CTCAE v4.03, responses as per RECIST v1.1. The analyses of all study objectives will be descriptive and hypothesis generating. No DLTs have been observed in the single pt cohorts. Assessment of pts enrolled into cohort 5 is ongoing at the time of this submission. Clinical trial information: NCT03667716.

3126 Background: APG-115 is a potent and orally active small-molecule MDM2 protein inhibitor. Binding to MDM2 protein, APG-115 restores p53 tumor suppressive function via induction of apoptosis in tumor cells retaining wild-type p53. In addition, enhanced antitumor activity was demonstrated in the syngeneic tumor models after APG-115 combined with PD-1 blockade. Methods: This Phase I study (APG-115-US-001) was designed to enroll the patients with advanced solid tumors in US (NCT02935907). Study objectives included to assess safety, dose limited toxicity (DLT), pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity (assessed every 8 weeks per RECIST v1.1). The patients received APG-115 orally every other day (QOD) at the designated dose (ranging from 10 to 300 mg) for first 21 days of a 28-day cycle, until disease progression. Results: Up until Jan 4 2019, total 28 patients were treated with APG-115 at various doses (one patient at 10mg, 20mg and 50mg, respectively; 14 patients at 100mg, 6 patients at 200mg, and 5 patients at 300mg). The median number of prior systemic anticancer therapies was 4 (range 0-15). The DLTs were observed during cycle 1, including one grade 2 thrombocytopenia at 200mg, one grade 3 thrombocytopenia at 300mg, and one grade 3 fatigue at 100mg and 300mg respectively. The most common AEs (reported in ≥10% of pts) included: fatigue, nausea, vomiting, diarrhea, decreased appetite, dehydration, neutrophil count decreased, white blood cell count decreased, pain in extremity, thrombocytopenia. The most common Grade 3 or 4 treatment related AEs were fatigue (10.7%), and thrombocytopenia (10.7%). Six patients had stable disease (SD) after two cycle treatments, two of them are continuing in this study. PK analyses indicated that exposure (Cmax and AUC) generally increases with the increase of dose level from 20 mg to 300 mg. Conclusions: APG-115 was well tolerated and had manageable adverse events. The MTD/RP2D of APG-115 monotherapy with oral administration, QOD for 21 days of a 28-day cycle for treatment of patients with advanced solid tumors was determined as 100 mg. Further evaluation of APG-115 in combination with pembrolizumab in patients with advanced solid tumors is ongoing. Clinical trial information: NCT02935907.

3125 Background: APG-1387 is a novel, bivalent small molecule IAP (inhibitor of apoptosis proteins) inhibitor. It has shown strong antitumor activities in multiple human xenograft cancer models. APG-1387 also acts as host immune modulator, supporting the notion that APG-1387 in combination with anti-PD1 antibody for cancer therapy. Methods: This study consists of two parts (NCT03386526). Part 1 is the dose escalation study of APG-1387 including a mPC (metastatic pancreatic cancer) cohort expansion. Part 2 is the dose escalation and cohort expansion study of APG-1387 in combination with pembrolizumab. APG-1387 is administrated IV for 30 minutes once weekly in a 21-day-cycle. Pembrolizumab is administrated at 200mg IV on day1 of a 21-day-cycle. The study objectives are to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy (assessed per RECIST v1.1 every 6 weeks). Results: Through Jan 4, 2019, total 23 patients had been treated in 4 cohorts of APG-1387 (20mg, 30mg, 45mg, 60mg). Two DLTs were observed at 60mg including lipase increase and Bell’s palsy, MTD was determined as 45mg. Nineteen of 23 patients experienced at least 1 TEAE. The most common TEAEs were nausea (21.7%), fatigue (17.4%), decreased appetite (13.0%), and abdominal pain (13.0%). Three grade 3 TEAEs including elevated bilirubin, lipase increase, and shortness of breath were documented at 45mg and 60mg. Three out of six mPC patients (one at 60mg, two at 45mg) achieved SD, one of them at 45mg has been treated > 5 cycles with confirmed SD (-18%). Two patients, who were treated with APG-1387 at 20mg in combination with pembrolizumab, had no DLT observed during the first cycle. Preliminary PK data of APG-1387 showed a dose proportionality in exposure (Cmax and AUC) over the dose range of 20-60 mg. Conclusions: APG-1387 was well tolerated and had manageable adverse events. The potential effects of APG-1387 alone or in combination with pembrolizumab deserve further exploration in patients with advanced solid tumors, especially in the mPC patients. Clinical trial information: NCT03386526.

TPS40 Background: Novel checkpoint therapies are needed for the treatment of patients who relapse/refractory to treatment with checkpoint inhibitors. COM701 is a novel first-in-class humanized IgG4 monoclonal antibody that binds with high affinity to poliovirus receptor related immunoglobulin domain containing (PVRIG) blocking its interaction with it's ligand, PVRL2. We have demonstrated in preclinical experiments that inhibition of PVRIG leads to activation of T cells in the tumor microenvironment generating an anti-tumor immune response leading to tumor growth inhibition. We hypothesize that COM701 will be safe and tolerable and demonstrate antitumor activity in pts with R/R solid tumors. Methods: NCT03667716 is an ongoing open-label first-in-human phase 1 study in pts with R/R solid tumors. The initial part of this study will evaluate the safety and tolerability of escalating doses of COM701 monotherapy IV Q3 weekly. Key Inclusion Criteria: Age ≥18 yrs, histologically or cytologically confirmed, locally advanced or metastatic solid malignancy and has exhausted all the available standard therapy or is not a candidate for the available standard therapy, ECOG performance status 0-1, prior anti-PD-1, anti-PD-L1, anti-CTLA-4, OX-40, CD137. Key Exclusion Criteria: Active autoimmune disease requiring systemic therapy in the last 2 years prior to the first dose of COM701, symptomatic interstitial lung disease or inflammatory pneumonitis, untreated or symptomatic central nervous system metastases. Primary outcome measures are the incidence of adverse events and dose-limiting toxicities (21-day DLT window), pharmacokinetics of COM701 and to identify the maximum tolerated dose and/or the recommended dose for expansion. Secondary outcome measures are to characterize the immunogenicity and preliminary antitumor activity of COM701. Study Design: Accelerated titration design consisting of single subject cohorts has been implemented for the initial cohorts. Statistical Considerations: Adverse events graded as per CTCAE v4.03, responses as per RECIST v1.1. The analyses of all study objectives will be descriptive and hypothesis generating. As of the date of this submission a third single subject dose cohort has been filled.

15 Background: Lenvatinib (LEN) is a multikinase inhibitor of VEGFR 1−3, FGFR 1−4, PDGFRα, RET, and KIT. Pembrolizumab (PEM), an anti-PD-1 antibody, is approved for first-line treatment of advanced melanoma (objective response rates [ORR], 21–34%). In preclinical studies, LEN decreased tumor-associated macrophage populations, increased CD8+ T cell infiltration, and augmented PD-1 inhibitor activity; thus, LEN is a rational combination partner for PEM. We report interim results of an ongoing phase 1b/2 trial of LEN + PEM in solid tumors, focusing on advanced melanoma. Methods: In this multicenter, open-label study, patients (pts) with measurable, confirmed, metastatic melanoma and ECOG PS ≤1 received oral LEN (20 mg/day) + PEM (200 mg Q3W, IV). Pts were not preselected for PD-L1 status. Tumor assessments were by investigator per immune-related RECIST (irRECIST). Phase 2 primary end point was ORR at 24 weeks (ORRWK24). Secondary end points included ORR, progression-free survival (PFS) and duration of response (DOR). Results: At data cutoff (March 1, 2018), 21 pts were enrolled: 14 (67%) were PD-L1+, 4 (19%) were PD-L1-; 3 (14%) not tested. 38% had ≥1 prior anticancer therapy. ORRWK24 was 47.6% (95% CI, 25.7–70.2). All pts had ≥1 treatment-related adverse event (TRAE). Grade 3 and 4 TRAEs occurred in 13 (62%) and 1 (5%; adrenal insufficiency) pts respectively. There were no fatal TRAEs. Most common any-grade TRAEs were fatigue (52%), decreased appetite (48%), diarrhea (48%), hypertension (48%), dysphonia (43%), and nausea (43%). Dose reduction and interruption due to TRAEs occurred in 13 (62%) and 10 (48%) pts, respectively. Conclusions: LEN + PEM was well-tolerated and had encouraging clinical activity. The combination may potentially improve on the antitumor activity of anti-PD-1 monotherapies, supporting further evaluation in advanced melanoma. Clinical trial information: NCT02501096. [Table: see text]

16 Background: Lenvatinib (LEN) is a multikinase inhibitor of VEGFR 1−3, FGFR 1−4, PDGFRα, RET, and KIT. Pembrolizumab (PEM), an anti-PD-1 antibody, is an approved monotherapy for previously treated patients (pts) with PD-L1 (+) (tumor proportion score ≥1%) metastatic non-small cell lung cancer (mNSCLC; objective response rate [ORR] 18%). We report interim results of an ongoing phase 1b/2 trial of LEN + PEM in pts with solid tumors, focusing on the mNSCLC cohort. Methods: In this multicenter, open-label study (NCT02501096), pts with measurable, confirmed mNSCLC, ECOG PS ≤1, ≤ 2 prior systemic therapies (phase 2 only) received oral LEN (20 mg/day) and PEM (200 mg Q3W, IV). Pts were not preselected by PD-L1 status. The phase 2 primary end point was ORR at 24 weeks (ORRWK24) by investigator-assessed immune-related RECIST (irRECIST). Secondary end points included ORR, progression-free survival (PFS) and duration of response (DOR). Results: At data cutoff (March 1, 2018), 21 pts were enrolled: 9 (43%) PD-L1(+), 5 (24%) PD-L1(-), and 7 (33%) not tested. Pts were treatment-naïve (14%); or had 1 (33%), 2 (48%), or ≥3 (5%) prior lines of systemic therapy. ORRWK24 was 33.3% (95% CI, 14.6–57.0); other efficacy outcomes are summarized in the table. Grade 3 and 4 treatment-related adverse events (TRAEs) occurred in 48% and 5% (increased aspartate aminotransferase) of pts. There was 1 fatal TRAE (exsanguination; “possibly related” to study treatment). The most common grade 3 TRAEs were hypertension (24%), fatigue (14%), diarrhea (14%), proteinuria (10%), and arthralgia (10%). Conclusions: LEN + PEM showed promising clinical activity and a manageable safety profile in previously treated pts with mNSCLC who were not preselected for PD-L1 status. Further study is warranted.[Table: see text]

11 Background: Pembrolizumab (PEM), an anti-PD-1 antibody, is approved for advanced urothelial cancer in the second-line setting (objective response rate [ORR] 21%) and in the first-line setting for patients (pts) ineligible for cisplatin with combined positive score ≥10 or ineligible for platinum-based chemotherapy (ORR 29%). Tyrosine kinase inhibitors such as lenvatinib (LEN; a multikinase inhibitor of VEGFR 1-3, FGFR 1-3, PDGFRα, RET and KIT) have demonstrated activity in urothelial cancer and may reverse the immunosuppressive environment that leads to immuno-oncology (IO) failure. We present a phase 1b/2 trial of LEN + PEM in advanced urothelial cancer. Methods: In this multicenter, open-label study, pts with confirmed metastatic urothelial cancer and ECOG PS of 0 or 1 received oral LEN 20 mg/day + PEM (200 mg Q3W, IV). Pts were not preselected for PD-L1 status. The phase 2 primary end point was investigator-assessed ORR at week 24 (ORRwk24) per immune-related RECIST (irRECIST). Secondary end points included ORR, duration of response (DOR), and progression-free survival (PFS). Results: At data cutoff (March 1, 2018), 20 pts were enrolled: 9 (45%) PD-L1(+), 5 (25%) PD-L1(-); 6 (30%) not tested. 4 Pts (20%) were treatment-naïve; 11 (55%) and 5 (25%) pts had had 1 and 2 lines of prior anticancer therapies, respectively. No pt had received prior IO. ORRwk24 was 25% (95% CI: 8.7–49.1). 18 (90%) pts had ≥1 treatment-related adverse event (TRAE). Grade 3 and 4 TRAEs occurred in 5 (25%) and 5 (25%) pts, respectively. There was 1 fatal TRAE (gastrointestinal hemorrhage). The most common any-grade TRAEs were proteinuria (45%), diarrhea (40%), fatigue (30%), hypertension (30%), and hypothyroidism (30%). Conclusions: LEN + PEM demonstrated activity in this study of pts with advanced urothelial cancer, which included pts receiving later-line treatment, and deserves further investigation. Clinical trial information: NCT02501096. [Table: see text]

2578Background: Ibrutinib (ibr), a first-in-class, once-daily inhibitor of BTK, is approved in the US for the treatment of various B-cell malignancies. In solid tumors, ibr may inhibit EGFR, HER2, ...

2594Background: We have developed a unique strategy to tactically reduce on-target platelet toxicity with APG-1252, a novel dual Bcl-2/Bcl-xL inhibitor, while maintaining strong in vivo antitumor a...

6016Background: Lenvatinib (LEN) is a multikinase inhibitor of vascular endothelial growth factor receptor 1−3, fibroblast growth factor receptor 1−4, platelet-derived growth factor receptor α, RET...

5597Background: Lenvatinib (LEN) is a multikinase inhibitor of VEGFR 1−3, FGFR 1−4, and other targets; pembrolizumab (PEM) is an anti–PD-1 antibody. We report biomarker analyses from a phase 1b/2 t...

TPS7084Background: ASN002 is a novel, potent inhibitor of Janus Kinases (JAK) and Spleen Tyrosine Kinase (SYK). Pre-clinical studies indicate that ASN002 has low nM IC50s against SYK and JAK, decre...

4560Background: Lenvatinib, a multikinase inhibitor of vascular endothelial growth factor (VEGF) receptors and other targets, has been approved in combination with everolimus to treat advanced rena...

5596Background: Lenvatinib (LEN) is an inhibitor of VEGFR 1−3, FGFR 1−4, and other kinases. Pembrolizumab (PEM) is an anti-PD-1 antibody. We report updated interim results from a phase 1b/2 study e...

396 Background: RX-3117 is an oral small-molecule antimetabolite, cyclopentyl pyrimidyl nucleoside that is activated by uridine cytidine kinase 2. RX-3117 has shown efficacy in xenograft models of gemcitabine resistant pancreatic, bladder and colorectal cancer. Data from stage 2 of the Phase 1b/2a clinical study of RX3117 as a single agent in subjects with metastatic pancreatic cancer is described below. Methods: Stage 2 of the Phase 1b/2a study (NCT02030067) is designed to evaluate safety, tolerability and efficacy following treatment with 700 mg administered orally once-daily for 5 consecutive days with 2 days off per week for 3 weeks with 1 week off in each 4 week cycle. Eligible subjects (aged ≥ 18 years) had relapsed/refractory metastatic pancreatic cancer. The primary endpoint is a ≥ 20% rate of progression free survival (PFS) benefit (i.e., proportion of subjects with stable disease for at least 4 months) and/or a 10% of evaluable subjects with a partial response rate or better. Results: As of Sep 2017, 44 subjects have been enrolled (22 females, 22 males). The median age was 68 years, ECOG performance statuses were 0 (13 subjects) and 1 (31 subjects) and 6 subjects had received 4 or more prior therapies. One subject had an unconfirmed partial response and 21 subjects met the primary endpoint of stable disease with a duration of 30-224 days. The most frequent adverse events were mild to moderate anemia (19%), mild to moderate fatigue (15%), mild to moderate diarrhea (11%), and severe anemia (9%). Conclusions: This ongoing trial shows an early efficacy signal where RX-3117 is active against advanced pancreatic cancer. The study continues to enroll subjects with advanced pancreatic cancer into stage 2. A phase 2 study with nab-paclitaxel in first-line patients with advanced pancreatic cancer has been started. Clinical trial information: NCT02030067.

e14102 Background: RAS-RAF-MEK and PI3K-AKT-mTOR are two major signaling pathways involved in tumorigenesis. Components of these two pathways are frequently mutated in a broad range of tumors. ASN003 is a novel and highly selective small-molecule inhibitor of the RAS-RAF-MEK and PI3K pathways. Methods: The activity of ASN003 was determined using PI3K and BRAF enzymes, and efficacy was studied in human tumor xenograft models in mice. ASN003 is currently being investigated in patients with solid tumors in a Phase 1 trial using an accelerated dose titration design. In Part A, safety and tolerability of ASN003 is being studied in patients with advanced solid tumors. In Part B, safety, tolerability and preliminary efficacy of ASN003 will be evaluated in melanoma, CRC and NSCLC patients with a BRAF, PIK3CA or PTEN mutation. Pharmacokinetic (PK) profile and the pharmacodynamic (PD) effects of ASN003 on biomarkers such as pERK and pS6 are investigated in both parts of the study. Results: ASN003 showed potent and highly selective inhibition of BRAF and PI3K-α and -δ, and low affinity for PI3K-ß. ASN003 showed strong antiproliferative activity in cell lines and caused significant tumor growth inhibition in xenograft models harboring BRAF and PIK3CA or PTEN mutations. ASN003 showed antiproliferative activity in B-RAF and MEK inhibitor resistant cell lines. ASN003 had a strong antitumor activity in a BRAFV600mutant melanoma PDX model resistant to BRAF inhibitors, vemurafenib and dabrafenib. In humans, to date, ASN003 was well tolerated at 10 and 20 mg QD. Adverse events were mild and peak plasma level of 120 nM at 10 mg QD was achieved with a half-life of > 12 h. Dose escalation is ongoing. Conclusions: ASN003 is a unique small molecule, with highly selective and potent inhibition of BRAF, PI3-α and -δ kinases. ASN003 has strong antitumor activity in various xenograft tumor models harboring both BRAF and PIK3CA/PTEN mutations, and in a BRAF inhibitor resistant melanoma PDX model. To date, ASN003 was well tolerated and achieved good systemic exposure. Updated and detailed clinical, PK and PD results will be presented. Clinical trial information: NCT02961283.

1035 Background: The HER2 receptor is expressed across a range of cancers (ca) although expression and heterogeneity vary greatly within and between tumors. FDA approved HER2-targeted therapies (tx) have shown clinical benefit only in HER2 high (IHC3+ or IHC2+/FISH+) breast and gastric ca. ZW25, built on the Azymetric™ platform which utilizes unique Fc mutations to create IgG1-like bispecific antibodies, binds to the same extracellular domains of HER2 as trastuzumab (T) and pertuzumab (P) with increased binding and internalization compared to T alone. In preclinical studies ZW25 was well tolerated and active in models of HER2 low to high ca. Methods: Eligible pts (HER2 IHC 1-3+, progression after standard of care (SOC) tx, normal LVEF) were enrolled in a 3+3 dose escalation study of ZW25 (5, 10 or 15 mg/kg) IV weekly in 4 week cycles. Assessments included adverse events (AEs), LVEF, tumor response and PK. Results: 9 pts have received ZW25 at 5 (n = 3) or 10 mg/kg (n = 6); 15 mg/kg is ongoing. All pts were HER2 high (breast = 4; gastric/GEJ = 4; adnexal = 1). Prior tx included T in all pts; P and T-DM1 in 4 and lapatinib (L) in 3 of 4 breast pts. The most common AEs (all Gr 1/2) were infusion reaction (IR) (5/9), diarrhea (4/9), and fatigue (3/9), with no DLTs and one related Gr 3 AE of hypophosphatemia. The IRs occurred only with 1st dose and did not recur with prophylactic tx (primarily acetaminophen and diphenhydramine; steroids included for 2 pts). At 5 mg/kg, peak drug levels after C1D1 = ~100 ug/ml, accumulating ~50% higher by dose 4. Best response in 8 pts (1 too early): 2 PR (both breast ca with prior T, P, T-DM1, and L; 10 mg/kg, 55% and 33% target lesion decrease, respectively, after 2 cycles), 1 SD (breast ca, 5 mg/kg, ongoing after 4 cycles), and 5 PD. 5 pts currently active; includes 1 gastric pt (10 mg/kg) with PD (new nodal lesions) and clinical benefit with decrease in target lesions and CEA (33 to 1.5 ng/ml). Conclusions: ZW25 has been well tolerated with promising anti-tumor activity in pts with HER2-expressing ca progressing after SOC therapy. These early signs of activity support the therapeutic potential for bispecific antibodies using the Azymetric platform. Development of ZW25 is ongoing, including in lower HER2-expressing ca. Clinical trial information: NCT02892123.

2524 Background: ARQ 092 is an oral, potent AKT inhibitor with single agent antitumor activity. P or P+C is the standard therapy or the therapy of choice for pts with various solid tumors. ARQ 092 potentiated antitumor activity of P in in vivo xenograft models, providing the rationale for this study. Methods: This is an open-label, phase Ib study of ARQ 092+C+P (CP Arm) or ARQ 092+P (P Arm) in pts with advanced solid tumors to determine safety and tolerability of these 2 combinations. Blood samples are collected for PK. Results: Enrollment into CP Arm has been completed with 13 pts (15% male; median age 62 years, 4 ovarian, 9 others) being treated in 2 dose cohorts (see table and results below). Enrollment into P Arm is ongoing. Data from P Arm (80 mg/m2 weekly) will be presented during the meeting. In CP Arm, 3 DLTs were observed in 2 pts (both received ARQ 092 at 200 mg BID, 1 day/week) including grade (G) 4 neutrophil count decreased, G 4 thrombocytopenia and G 3 diarrhea. ARQ 092-related adverse events (AEs) in ≥10% pts included diarrhea 69%, fatigue 54%, hyperglycemia 31%, maculopapular rash 31%, nausea 23%, mucosal inflammation 23%, anemia 15%, platelet count decreased 15% and hypokalemia 15%. Paclitaxel- and/or carboplatin-related AEs in ≥10% pts included fatigue 77%, alopecia 62%, thrombocytopenia 39%, platelet count decreased 39%, nausea 31%, lymphocyte count decreased 31%, neutrophil count decreased 31%, white blood cell count decreased 31%, anemia 23%, mucosal inflammation 23%, hypomagnesaemia 23%, peripheral sensory neuropathy 23%, neutropenia 15%, vomiting 15% and hypokalemia 15%. Two ovarian pts previously treated with CP achieved complete response (mutant AKT) and partial response (AKT mutation unknown) respectively and 3 pts (Gastroesophageal, pancreatic, ovarian mixed mullerian) experienced stable diseases for >12 weeks. PK data will be presented during the meeting. Conclusions: Encouraging anticancer activity was demonstrated in heavily pretreated ovarian cancer pts, but full dose CP was not tolerated by most patients. Clinical trial information: NCT02476955. [Table: see text]

7545 Background: ASN002 is a novel, potent inhibitor of Spleen Tyrosine Kinase (SYK) and Janus Kinases (JAK). Pre-clinical studies indicate that ASN002 has low nM IC50s against SYK and JAK, decreases proliferation in ibrutinib-resistant cell lines, and suppresses tumor growth in rodent xenograft models of NHL and other hematologic malignancies. Methods: This Phase 1/2 clinical trial in patients with solid tumors and hematologic malignancies evaluates escalating ASN002 oral doses of 10, 20, 30, 40, 50 and’ 75 mg BID and 80 and 120 mg QD mg (NCT02440685). Phase 1 allows patients with solid tumors or hematologic malignancies; Phase 2 allows only patients with diffuse large B-Cell lymphoma (DLBCL), follicular lymphoma (FL) or mantle cell lymphoma (MCL). Endpoints include safety, tolerability, pharmacokinetics, serum markers of inflammation, and response using RECIST or Lugano Classification System. Results: Twenty-eight patients have enrolled in the DLT phase at doses of 10 mg – 75 mg BID and at 80 mg QD. All patients had multiple prior lines of treatment (range: 2 – 8). ASN002 was well tolerated. No dose limiting adverse events have been reported at these dose levels. Most drug-related adverse events were Gr 1/2 (e.g. headache, fatigue). Steady-state systemic exposure was high (Cmax, AUC (0-12h) and T1/2 at 40 mg BID were 0.7 µM, 6.3 µM.h and 18 h, respectively). High systemic exposure was also observed at 80 mg QD. Robust reduction of CRP, IL-18, MIP1β, VCAM-1, TNFR2 was observed at all doses. Stable disease (RECIST, 9+ months) in a patient with primary peritoneal cancer, about 50% reduction in target lesions at 3 months in a FL patient (Lugano, 6 prior lines) and stable disease and reduction of pruritus in a peripheral T-Cell lymphoma patient after 2 months (Lugano, 2 prior lines) of treatment were observed. ASN002 treatment continues in both lymphoma patients. Accrual of patients continues. Conclusions: ASN002 was safe and well tolerated. Encouraging preliminary evidence of efficacy in NHL patients was observed. MTD has not been reached and dose escalation continues. Updated and detailed results will be presented. Clinical trial information: NCT02440685.

5598 Background: LEN is a multikinase inhibitor of vascular endothelial growth factor (VEGF) receptor 1−3, fibroblast growth factor receptor 1−4, platelet-derived growth factor receptor α, RET, and KIT. Pembro, an antibody targeting programmed cell death protein 1 (PD-1), prevents T cell deactivation. In addition to its antiangiogenic effects, LEN may act in part by preventing VEGF-mediated immune suppression, suggesting combination with pembro could improve its activity. We report results in pts with endometrial carcinoma from a phase Ib/II trial of LEN + pembro. Methods: In this multicenter, open-label study, pts had confirmed metastatic endometrial cancer that progressed after approved therapy, measurable disease, and ECOG performance status ≤ 1. Pts received oral LEN 20 mg/day plus pembro 200 mg intravenously every 3 weeks. Tumor assessments were by the investigator. The primary phase II endpoint was objective response rate (ORR) based on immune-related RECIST (irRECIST). Secondary endpoints included progression-free survival (PFS), disease-control rate (DCR; complete response [CR] + partial response [PR] + stable disease [SD]), clinical-benefit rate (CBR; CR + PR + durable SD), and duration of response (DOR), all by irRECIST, and safety. Results: 23 Pts enrolled (phase II: 21; phase Ib: 2); median age was 64 years (range: 51−80); 87% were white; and all had ≥ 1 prior anticancer therapy. Confirmed ORR was 48% (all PR). Median PFS and DOR were not estimable (NE; see table). All pts had a treatment-emergent adverse event (TEAE). The most common TEAEs were hypertension, fatigue, arthralgia, diarrhea, and nausea. Toxicities were manageable with dose interruption and/or modification and no new safety signals were found. Updated data will be presented. Conclusions: Promising efficacy was observed in pts receiving LEN + pembro. In addition, toxicities were generally expected and manageable with dose modification. These results warrant further study of LEN + pembro in pts with endometrial carcinoma. Clinical trial information: NCT02501096. [Table: see text]

240 Background: ASN001 is a novel, non-steroidal, potent inhibitor of CYP17 lyase. It selectively inhibits synthesis of testosterone over cortisol in the adrenals to avoid the need for co-administration of prednisone. ASN001 also exhibits high oral bioavailability and low potential for drug-drug interaction supporting its use in future combination trials. Methods: This Phase 1/2 clinical trial in men with progressive mCRPC evaluates once-daily, oral ASN001 at escalating doses of 50, 100, 200, 300 and 400 mg (NCT02349139). While the Phase 1 also allowed enrollment of pretreated patients, no prior enzalutamide (ENZA) or abiraterone (ABI) is permitted in Phase 2. Endpoints included maximum dose (MTD) and dose limiting toxicities, recommended Phase 2 dose, pharmacokinetics, effect on steroid hormone biosynthesis and clinical efficacy (PSA and imaging). Results: To date, 23 mCRPC pts have been enrolled. No prednisone was administered and no mineralocorticoid excess has been reported. Overall, ASN001 was well tolerated. Most drug-related adverse events were Gr 1/2 and included fatigue, nausea and dizziness. At 400mg, two pts experienced asymptomatic, reversible Gr 3 elevation of ALT/AST, but no recurrence when retreated at a lower dose (300mg). Testosterone decreased to below quantifiable limits and DHEA decrease of up to 80% was observed in ABI/ENZA naïve patients. Systemic exposure was high (Cmax, AUC and T1/2 at 300 mg QD was 6.7 µm, 80 µm.h and 21.5h, respectively). RECIST defined Stable Disease up to 15+ months has been observed at the 100mg cohort despite prior ABI and ENZA exposure. PSA decline of > 50% (51%-70%) was observed in 3 of 3 ABI/ENZA naïve patients at doses of 300/400mg. Conclusions: Overall, ASN001 was safe and well tolerated without need for prednisone co-administration. Encouraging preliminary evidence of efficacy is based on the PSA decline observed in evaluable mCRPC pts not pretreated with ABI or ENZA and based on durable disease stabilization after progression on ABI and ENZA. Enrollment is ongoing at doses below 400mg QD in ABI/ENZA naïve mCRPC pts. Updated and detailed results will be presented at the meeting. Clinical trial information: NCT02349139.

445 Background: RX-3117 is an oral smallmolecule antimetabolite, cyclopentyl pyrimidyl nucleoside that is activated by uridine cytidine kinase 2. RX-3117 has shown efficacy in xenograft models of gemcitabine resistant pancreatic, bladder and colorectal cancer. Data from stage 1 of the Phase 1b/2a clinical study of RX3117 as a single agent in subjects with metastatic pancreatic cancer is described below. Methods: Stage 1 of the Phase 1b/2a study (NCT02030067) is designed to evaluate safety, tolerability and efficacy following treatment with 700 mg administered orally once-daily for 5 consecutive days with 2 days off per week for 3 weeks with 1 week off in each 4 week cycle in a 2-stage Simon design. Eligible subjects (aged ≥ 18 years) were those with relapsed/refractory metastatic pancreatic cancer. The primary endpoint is a ≥ 20% (2 out of 10 subjects) rate of progression free survival (PFS) benefit (i.e., proportion of subjects with stable disease for at least 4 months) and/or a 10% (1 of 10 subjects) with a partial response rate or better. Results: As of Sep 2016, 8 out of 10 subjects have been enrolled (4 females, 4 males), the mean age was 70 years, ECOG performance status was 1 and 5 subjects had received more than 4 prior therapies. Two subjects met the primary endpoint of stable disease with a duration of 140-168 days at the time of this submission. The most frequent adverse events were moderate to severe anemia, mild to moderate fatigue, abdominal pain and diarrhea. Conclusions: This ongoing trial shows an early efficacy signal where RX-3117 is active against advanced pancreatic cancer. As the primary endpoint has been achieved, the study will now move to stage 2 where an additional 40 subjects with advanced pancreatic cancer will be enrolled. Clinical trial information: NCT02030067.

379 Background: CC122 is a novel cereblon-modulating agent with multiple biologic activities including potent immunomodulatory and antiangiogenic effects. CC-122 binding to cereblon promotes ubiquitination and subsequent degradation of lymphoid transcription factors Ikaros and Aiolos resulting in activation of T cells. Methods: Following establishment of oral CC122 3 mg daily (QD) as the MTD in phase 1a (Blood 122:2905 2013), an expansion cohort of advanced Hepatocellular Carcinoma (HCC) subjects was enrolled. All subjects had progressed on or were intolerant to sorafenib. Efficacy was assessed per RECIST 1.1 criteria. Results: As of Jan. 13, 2016, 25 advanced HCC subjects were enrolled. The median age was 59.6 years, median Child-Pugh score was 5 (range 5-8) and all were ECOG 0-1. Viral status was HBV 28%, HCV 28%, HBV/HCV 12% and non-viral 32%. 52% had alpha-fetoprotein ≥ 200. CC122 was well tolerated. Two subjects discontinued due to AEs. Dose reductions occurred in 32% (n = 8). The most common ( ≥ 5%) grade 3/4 AEs were neutropenia, ALT elevation (each n = 4, 16%), AST elevation (n = 3, 12%), asthenia, ascites, anemia, hyperbilirubinemia, pneumonia, and rash (each n = 2, 8%). Drugrelated serious AEs included vomiting and rash. 19 subjects were evaluable for efficacy. ORR was 10.5% (n = 2 PR, 1 confirmed) and Disease Control Rate (CR+PR+SD > 7 weeks) was 36.8%. The duration of response was 108 and 125 days in the 2 PRs. The median PFS was 57 days (MinMax: 28334, 95% CI: 45-135). CC122 treatment resulted in a median increase from baseline in peripheral blood activated and memory cytotoxic T cells by 64% (range: 17-213%, n = 6) and 78% (range: 30-111%, n = 6 (p < 0.05), respectively, and activated helper T cells by 106% (range: 62-218%, n = 7 (p < 0.05). CC122-activated T cells from the blood increased IFNg (2.73 fold; range: 0.45-26.1, n = 13) and IL2 (9.5 fold; range: 0.85-24.3, n = 11) production when compared to baseline (both P < 0.05) upon ex-vivo stimulation. Conclusions: CC122 3 mg QD appears to be well tolerated and activates cytotoxic T cells in HCC patients. Combination studies with sorafenib or nivolumab are recommended and underway. Clinical trial information: NCT01421524.

3082Background: IL-10 induces activation of STAT3 in CD8 T cells leads to increased survival, proliferation and cytotoxicity of CD8 T cells. In preclinical studies, PEG-IL-10 induces CD8 mediated tumor rejection and synergizes with cytotoxic chemotherapies. Anti-tumor activity of AM0010 alone was established in the ongoing phase 1 basket trial. Objective responses were observed in pts with renal cell cancer (RCC; 4 of 15pts), uveal melanoma and cutaneous T cell lymphoma. Methods: Pts with advanced pancreatic cancer (PDAC) were treated daily with AM0010 alone (n = 24) or in combination with FOLFOX (5), capecitabine (5) or gemcitabine/nab-paclitaxel (6). Pts with colorectal cancer (n = 16) were treated with AM0010 alone. Tumor responses were monitored following irRC. Immune responses were monitored through analysis of serum cytokines, activation of blood derived T cells, immunosequencing for peripheral T cell clonality and immunohistochemistry for the infiltration of tumors by CD8 T cells. Results: In 24 PD...

3002Background: PF-05082566 (PF-2566) is a fully human IgG2 monoclonal antibody (mAb) that binds to human 4-1BB (CD137). Pembrolizumab is a humanized IgG4/kappa isotype mAb targeting PD-1. This Pha...

e14129Background: ASN001 is a novel non-steroidal CYP17 lyase inhibitor. In preclinical studies, ASN001 shows potent inhibition of CYP17 lyase with selective inhibition of testosterone synthesis ov...

2555Background: RX-3117 is an oral small-molecule antimetabolite, cyclopentyl pyrimidyl nucleoside that is activated by uridine cytidine kinase 2. RX-3117 has shown efficacy in xenograft models of ...

2502Background: FGFR2b-overexpressing gastric cancer is a distinct setting with poor prognosis. FPA144, a humanized monoclonal IgG1 antibody directed against FGFR2b, has been engineered for enhance...

751 Background: TAS-102 is a novel oral combination therapy of FTD plus tipiracil hydrochloride (TPI) with FTD:TPI molar and weight ratios of 1:0.5 and 1:0.471, respectively. FTD is a thymidine-based nucleoside analog that has shown antitumor effects in preclinical and clinical studies. TPI stabilizes orally administered FTD by inhibiting thymidine phosphorylase and TAS-102 has shown efficacy in refractory metastatic colorectal cancer. The objective of this study was to show that TPI, administered with FTD as TAS-102, increases exposure to FTD in patients with advanced solid tumors. Methods: This is a Phase 1, randomized, open-label, pharmacokinetic study of TAS-102 in patients with advanced solid tumors. On the morning of Day 1, one group received TAS-102 35 mg/m2 and the other group received FTD 35 mg/m2. Both groups received TAS-102 35 mg/m2 on the evening of Day 1, then twice daily on Days 2-5 and 8-12 in a 28-day cycle. Blood samples were collected to evaluate FTD AUC0-last and Cmax (primary endpoints). Results: Overall, 44 patients (50% male, mean age 57 years) were treated. After a single dose, the ratio of the geometric mean of FTD AUC0-last and Cmax were 38- and 22-fold higher, respectively (Table) following TAS-102 vs FTD alone. After multiple doses (Day 12 in Cycles 1, 2, or 3), FTD AUC and Cmax were ~3- and 2-fold higher, respectively, than after a single dose of TAS-102 (Day 1). For TPI, AUC and Cmax were similar after single and multiple doses of TAS-102. After Cycle 1, FTD did not accumulate with successive cycles of TAS-102 treatment. The most commonly reported treatment-related adverse events were nausea (47.7%), fatigue (31.8%), and anemia (27.3%), with Grade 3-4 events at 4.5%, 2.3%, and 18.2%, respectively. Grade ≥ 3 decreases in neutrophil counts were observed in 42.9% of the TAS-102 group. Conclusions: TPI, in combination with FTD, substantially increased exposure to FTD vs FTD alone. Clinical trial information: NCT01867866. [Table: see text]

140 Background: FPA144 is a humanized monoclonal IgG1 antibody directed against the 2b Isoform of thefibroblast growth factor receptor (FGFR2b) that has been glycoengineered to enhance ADCC. Amplification of FGFR2 is found in a number of tumors, including 3 – 9% of gastric cancer, and is associated with poor prognosis. FPA144-001 is a phase 1 study in two parts: Part 1 will evaluate the safety and pharmacokinetics (PK) of FPA144 in patients with solid tumors; Part 2 will evaluate efficacy in gastric cancer patients whose tumors overexpress FGFR2b, as determined by a proprietary test. Here we present early safety and PK results from solid tumor patients treated with FPA144. Methods: A standard 3+3 design was used to assess safety, tolerability and PK of escalating doses of FPA144 in patients with advanced solid tumors (Part 1A) or recurrent/metastatic gastric cancer (Part 1B). Tumor testing for FGFR2gene amplification or FGFR2b overexpression was conducted centrally by a proprietary assay consisting of both FISH and IHC. Results: At the time of data analysis, enrollment of FPA144-001 through the 6mg/kg q2w cohort had been completed. In Part 1A, 13 patients with 8 different tumor types have been enrolled. Patients have been treated for an average of 4 cycles (range 1 – 10, median 2) or 101 days (range 28 – 287, median 43). Nine patients have discontinued the study for progressive disease or lack of clinical benefit; all others continue on study treatment. No dose-limiting toxicities have been observed, and no patients have withdrawn due to an adverse drug reaction. Upper respiratory infection, alopecia and fatigue are the AEs reported in more than one patient; one SAE of dyspnea and pyrexia not related to drug has been reported. PK analysis demonstrates non-linear clearance in doses up to 3mg/kg, likely due to receptor-mediated clearance. Conclusions: FPA144 is a glycoengineered monoclonal antibody directed against FGFR2b that is being developed for the treatment of patients with tumors that overexpress FGFR2b. FPA144 has been safely administered at doses up to 6mg/kg q2w; dose escalation continues. Updated safety, PK and anti-tumor activity will be presented. Clinical trial information: NCT02318329.