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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 .

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.

LY3022859 is an anti-TGFβRII IgG1 monoclonal antibody that inhibits receptor-mediated signaling activation. The primary objective of this phase I study was to determine a phase II dose in patients with advanced solid tumors. Secondary objectives were to assess safety and pharmacokinetics (PK). LY3022859 was infused intravenously (IV) at 1.25 mg/kg over 1 h every 2 weeks (Q2W) (cohort 1A) and at flat doses of 12.5 mg (cohort 1B) and 25 mg (cohort 2) over 3 h Q2W. Fourteen patients were enrolled in cohorts 1A (n = 2), 1B (n = 5), and 2 (n = 7). DLTs were experienced by both patients in cohort 1A (infusion-related reaction) and 2 patients in cohort 2 (cytokine release syndrome and infusion-related reaction). No MTD was determined. At the 25 mg dose level (cohort 2), after fifth infusion, LY3022859 had a short t1/2 (4.37-7.80 h) and rapid clearance (CLss, 0.412 L/h). Exposure increased twofold (from 28.5 to 60.2 μg·h/mL) with increase in dose from 12.5 to 25 mg. No accumulation was observed after repeat administration. The MTD for LY3022859 was not determined. Dose escalation beyond 25 mg was considered unsafe due to worsening symptoms (uncontrolled cytokine release) despite prophylaxis (corticosteroids and antihistamines). clinicaltrials.gov Identifier: NCT01646203.

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...

2522 Background: Nesvacumab (N) is a selective, human Ang-2 MAb, that potently blocks Ang2 signaling through the Tie2 receptor. Ziv-aflibercept (Z) is a recombinant human fusion protein and a decoy...

TPS3110 Background: With the knowledge that Bcl-2 facilitates drug resistance and cell survival, a DNA interference (DNAi) strategy was applied to silence Bcl-2 in cancer cells and promote apoptosis. DNAi differs from cytoplasmic mRNA targeting (antisense, RNAi, and miRNA targets) as it targets genomic DNA, blocking transcription. PNT100, a first in class DNAi, is a novel single-stranded 24-base unmodified DNA designed to bind to an upstream region of the Bcl-2 promoter. The drug product (PNT2258) is PNT100 encapsulated in a specialized pH tunable liposome and is being assessed for safety and tolerability in a phase I trial. PNT2258 avoids the toxicities associated with modified oligonucleotides and double-stranded RNAs; since the liposome formulation is anionic and contains no surface spacers, vehicle toxicities are minimal. Xenograft experiments demonstrated marked single agent activity in a diffuse large cell lymphoma, and therapy potentiation when combined with either rituximab in Daudi-Burkitt’s Lymphoma or docetaxel in A375 melanoma. Methods: An open-label, single-arm, first-in-man phase I dose-escalation study of PNT2258 in patients with advanced solid tumors was designed to evaluate safety, tolerability, dose-limiting toxicities, pharmacokinetics, and pharmacodynamics of PNT2258 to recommend a dose for phase II studies. In this phase I study, pharmacodynamic effects of PNT2258 will be evaluated through analyses of soluble serum and plasma markers and peripheral blood mononuclear cells. Patients will receive PNT2258 as an intravenous infusion over 2 hours once daily for 5 consecutive days (days 1-5) of each 21-day treatment cycle (3 weeks). The starting dose of 1 mg/m2 with PNT2258 administered to one patient per cohort and dose-escalation will proceed by dose-doubling in each successive cohort until a dose level of 64 mg/m2 is attained, provided no dose-limiting toxicities are observed in cycle 1. Thereafter, dose escalations shall proceed at 33% increments of the previous cohort dose-level to 85, 113, and 150 mg/m2 with expansions of up to six patients per cohort as needed. The ten planned dose cohorts have been completed with all patients enrolled.

2555 Background: Tesetaxel (TST) has anticancer activity in patients (pts) with metastatic breast cancer (MBC) and gastric cancer when administered orally once every 3 weeks (Q3W). This drug is not a Pgp substrate, does not cause hypersensitivity reactions, and may be associated with less neurotoxicity. The maximally tolerated dose (MTD) on the Q3W schedule is 27 mg/m2, and neutropenia is dose-limiting. Since taxane activity may be schedule-dependent, we conducted a weekly, dose-ranging, and PK evaluation of TST. Methods: Eligibility: advanced solid tumors; ECOG PS 0-2; adequate organ function. TST was given once weekly for 3 weeks in a 28-day cycle, beginning at a total flat dose of 25 mg/cycle with progressive increases in total dose up to 75 mg/cycle. Subsequently, dosing was converted to a weight-based regimen at weekly doses of 12.5, 15, and 17.5 mg/m2 (i.e., total per cycle dose up to 52.5 mg/m2). Serial plasma samples were assayed by HPLC. Results: 26 pts were treated in 8 dose cohorts. The MTD was 15 mg/m2/wk (total cycle dose, 45 mg/m2). With repeated cycles, constitutional symptoms (fatigue and anorexia) rather than neutropenia proved dose-limiting at 17.5 mg/m2/wk. Only 1 pt (at 12.5 mg/m2/wk) developed grade 3 neutropenia; no other episodes of Grade 3-4 myelotoxicity were observed. One pt with MBC (who had progressed after 2 prior taxane regimens) achieved a PR; 1 pt with prostate cancer has maintained prolonged reduction of PSA (> 57%). PK analyses showed low but progressive increases in trough TST concentrations (0.4–4.6 nmol/mL) 7 days after each succeeding dose, which was consistent with the prolonged T½ of this drug (~180 hrs). There was no substantial drug accumulation over multiple cycles. Conclusions: Weekly oral TST is safe, provides long-term low-level drug exposure, and increases the total delivered dose over 12 wks by 25%. Interestingly, this regimen is not associated with significant myelosuppression. Thus, weekly TST dosing provides a highly convenient, “dose-dense”, taxane regimen that is not associated with neutropenia, which should facilitate its integration into multiple chemotherapy regimens. An ongoing study is evaluating efficacy of weekly TST dosing in MBC.