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Purpose: Lurbinectedin suppresses the oncogenic transcription factor EWS-FLI1 through relocalization to the nucleolus, and delays tumor growth in mice bearing Ewing sarcoma xenografts. On the basis of this rationale, lurbinectedin was evaluated in patients with relapsed Ewing sarcoma. Patients and Methods: This open-label, single-arm, Basket phase II trial included a cohort of 28 treated adult patients with confirmed Ewing sarcoma, measurable disease as per Response Evaluation Criteria In Solid Tumors (RECIST) v.1.1, Eastern Cooperative Oncology Group performance status ≤2, adequate organ function, no central nervous system metastasis, and pretreated with ≤2 chemotherapy lines for metastatic/recurrent disease. Patients received lurbinectedin 3.2 mg/m2 as a 1-hour infusion every 3 weeks. Primary endpoint was overall response rate (ORR) as per RECIST v.1.1. Secondary endpoints included time-to-event parameters and safety profile. Results: ORR was 14.3% [95% confidence interval (CI), 4.0%–32.7%], with median duration of response of 4.2 months (95% CI, 2.9–5.5 months). Median progression-free survival was 2.7 months (95% CI, 1.4–4.3 months), clinical benefit rate was 39.3%, and disease control rate was 57.1%. With 39% censoring, median overall survival was 12.0 months (95% CI, 8.5–18.5 months). Most common grade 3/4 adverse events were neutropenia (57%), anemia, thrombocytopenia, and treatment-related febrile neutropenia (14% each). No deaths or discontinuations were due to toxicity. Conclusions: Lurbinectedin was active in the treatment of relapsed Ewing sarcoma and had a manageable safety profile. Lurbinectedin could represent a valuable addition to therapies for Ewing sarcoma, and is currently being evaluated in combination with irinotecan in advanced Ewing sarcoma in a phase Ib/II trial.

Supplementary Table from ARRY-382 in Combination with Pembrolizumab in Patients with Advanced Solid Tumors: Results from a Phase 1b/2 Study

PDF - 90K, Supplemental Table 1: Most Frequently Reported Adverse Events at Least Possibly Related to Pazopanib Supplemental Table 2: Steady-State Pazopanib Metabolite Pharmacokinetics Measured in All Patients at Week 3 (medians and ranges) Supplemental Table 3: Ratio of Metabolite AUC(0-6) to Pazopanib AUC(0-6) Measured at Steady-State in All Patients at Week 3 (medians and ranges) Supplemental Table 4: First-dose Pazopanib Metabolite Pharmacokinetics in Expanded Cohorts and the Maximum Tolerated Dose (medians and ranges)

Purpose: BNC105P inhibits tubulin polymerization, and preclinical studies suggest possible synergy with everolimus. In this phase I/II study, efficacy and safety of the combination were explored in patients with metastatic renal cell carcinoma (mRCC).Experimental Design: A phase I study in patients with clear cell mRCC and any prior number of therapies was conducted using a classical 3 + 3 design to evaluate standard doses of everolimus with increasing doses of BNC105P. At the recommended phase II dose (RP2D), patients with clear cell mRCC and one to two prior therapies (including ≥ 1 VEGF-TKI) were randomized to BNC105P with everolimus (arm A) or everolimus alone (arm B). The primary endpoint of the study was 6-month progression-free survival (6MPFS). Secondary endpoints included response rate, PFS, overall survival, and exploratory biomarker analyses.Results: In the phase I study (N = 15), a dose of BNC105P at 16 mg/m2 with everolimus at 10 mg daily was identified as the RP2D. In the phase II study, 139 patients were randomized, with 69 and 67 evaluable patients in arms A and B, respectively. 6MPFS was similar in the treatment arms (arm A: 33.82% vs. arm B: 30.30%, P = 0.66) and no difference in median PFS was observed (arm A: 4.7 mos vs. arm B: 4.1 mos; P = 0.49). Changes in matrix metalloproteinase-9, stem cell factor, sex hormone-binding globulin, and serum amyloid A protein were associated with clinical outcome with BNC105P.Conclusions: Although the primary endpoint was not met in an unselected population, correlative studies suggest several biomarkers that warrant further prospective evaluation. Clin Cancer Res; 21(15); 3420–7. ©2015 AACR.

Pharmacokinetic results at Day 29, by cohort (median [range])

Supplemental Table 1: Treatment-related AEs experienced by {greater than or equal to}10% of patients on any schedule, and treatmentrelated grade {greater than or equal to}3 AEs reported in at least 1 patient; Supplemental Table 2: Summary of hepatotoxicities reported with pevonedistat on each dosing schedule and overa ll

Supplementary Table 2. Drug-related treatment emergent adverse events by CTCAE grade ({greater than or equal to} Grade 2) seen in the phase I component of the study.

Purpose: Pazopanib is a potent, multitargeted receptor tyrosine kinase inhibitor; however, there is limited information regarding the effects of liver function on pazopanib metabolism and pharmacokinetics. The objective of this study was to establish the maximum-tolerated dose (MTD) and pharmacokinetic profile of pazopanib in patients with varying degrees of hepatic dysfunction.Experimental Design: Patients with any solid tumors or lymphoma were stratified into four groups based on the degree of hepatic dysfunction according to the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria. Pazopanib was given orally once a day on a 21-day cycle. A modified 3+3 design was used.Results: Ninety-eight patients were enrolled. Patients in the mild group tolerated 800 mg per day. The moderate and severe groups tolerated 200 mg per day. Pharmacokinetic data in the mild group were similar to the data in the normal group. Comparison of the median Cmax and area under the curve [AUC(0–24)] in the moderate or severe groups at 200 mg per day to the values in the normal and mild groups at 800 mg per day indicated less than dose–proportional systemic exposures in patients with moderate and severe hepatic impairment. This suggests that the lower maximum-tolerated dose in the moderate and severe group is not due to a decrease in drug clearance or alteration in the proportion of metabolites.Conclusions: In patients with mild liver dysfunction, pazopanib is well tolerated at the Food and Drug Administration (FDA)–approved dose of 800 mg per day. Patients with moderate and severe liver dysfunction tolerated 200 mg per day. Clin Cancer Res; 19(13); 3631–9. ©2013 AACR.

Purpose: To determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with advanced nonhematologic malignancies.Experimental Design: Pevonedistat was administered via 60-minute intravenous infusion on days 1 to 5 (schedule A, n = 12), or days 1, 3, and 5 (schedules B, n = 17, and C, n = 19) of 21-day cycles. Schedule B included oral dexamethasone 8 mg before each pevonedistat dose. Dose escalation proceeded using a Bayesian continual reassessment method. Tumor response was assessed by RECIST 1.0.Results: Schedule A MTD was 50 mg/m2; based on the severity of observed hepatotoxicity, this schedule was discontinued. Schedules B and C MTDs were 50 and 67 mg/m2, respectively. DLTs on both these schedules included hyperbilirubinemia and elevated aspartate aminotransferase. There were no grade ≥3 treatment-related serious adverse events reported on schedules B or C. Twenty-three (74%) evaluable patients on schedules B and C had stable disease. Intermittent dexamethasone use did not significantly influence pevonedistat pharmacokinetics. NAE inhibition by pevonedistat was demonstrated in multiple tumor types via IHC detection of pevonedistat-NEDD8 adduct and accumulation of Cullin-RING ligase substrates CDT1 and NRF2 in tumor biopsies.Conclusions: Pevonedistat was generally well tolerated on a day 1, 3, 5 schedule every 3 weeks with an MTD between 50 mg/m2 and 67 mg/m2. DLTs were predominantly hepatic enzyme elevations. Pharmacodynamic studies demonstrated that pevonedistat inhibited NAE in tumors. Clinical trials are ongoing. Clin Cancer Res; 22(4); 847–57. ©2015 AACR.

PDF - 36K, Structure of pazopanib and metabolites.

Purpose: This phase 1b dose-escalation study assessed safety, tolerability, and pharmacokinetics of ganitumab, a fully human monoclonal antibody against the insulin-like growth factor 1 (IGF1) receptor, combined with targeted agents or cytotoxic chemotherapy in patients with advanced solid tumors.Experimental Design: Patients with treatment-refractory advanced solid tumors were sequentially enrolled at 2 ganitumab dose levels (6 or 12 mg/kg i.v. every 2 weeks) combined with either sorafenib 400 mg twice daily, panitumumab 6 mg/kg every 2 weeks, erlotinib 150 mg once daily, or gemcitabine 1,000 mg/m2 on days 1, 8, and 15 of each 4-week cycle. The primary end points were safety and pharmacokinetics of ganitumab.Results: Ganitumab up to 12 mg/kg appeared well tolerated combined with sorafenib, panitumumab, erlotinib, or gemcitabine. Treatment-emergent adverse events were generally mild and included fatigue, nausea, vomiting, and chills. Three patients had dose-limiting toxicities: grade 3 hyperglycemia (ganitumab 6 mg/kg and panitumumab), grade 4 neutropenia (ganitumab 6 mg/kg and gemcitabine), and grade 4 thrombocytopenia (ganitumab 12 mg/kg and erlotinib). Ganitumab-binding and panitumumab-binding antibodies were detected in 5 and 2 patients, respectively; neutralizing antibodies were not detected. The pharmacokinetics of ganitumab and each cotherapy did not appear affected by coadministration. Circulating total IGF1 and IGF binding protein 3 increased from baseline following treatment. Four patients (9%) had partial responses.Conclusions: Ganitumab up to 12 mg/kg was well tolerated, without adverse effects on pharmacokinetics in combination with either sorafenib, panitumumab, erlotinib, or gemcitabine. Ganitumab is currently under investigation in combination with some of these and other agents. Clin Cancer Res; 18(12); 3414–27. ©2012 AACR.

PDF file - 97K, Reduction in glioma-associated oncogene homolog 1 in patients with available tumor and matching skin specimens.

Supplementary Figure 1. PFS in patients receiving BNC105P monotherapy after crossover.

PDF file - 29K, Chemical structures of sonidegib and cyclopamine.

LYC-55716 toxicology thermometer plot indicating a pharmacologically active exposure of 18.6μg·h/mL, based on the upregulation of target genes in mouse thymus

Baseline RORgt (RORC2) expression is variable from patient to patient.

Supplementary Figure from ARRY-382 in Combination with Pembrolizumab in Patients with Advanced Solid Tumors: Results from a Phase 1b/2 Study

PDF file - 71K, Supplementary data includes a table summarizing cohort enrollment and dose-limiting toxicities (Table S1) and a table showing the association between tumor response and Hh pathway activity in medulloblastoma and basal cell carcinoma (Table S2).

Purpose:Transcription factor retinoic acid receptor–related orphan receptor γ (RORγ) regulates type 17 effector T-cell differentiation and function and is key to immune cell regulation. Synthetic RORγ agonists modulate immune cell gene expression to increase effector T-cell activity and decrease immune suppression. A phase 1 study evaluated the safety and tolerability of LYC-55716 (cintirorgon), a first-in-class, oral, small-molecule RORγ agonist in adults with relapsed/refractory metastatic cancer.Patients and Methods:Patients received 28-day treatment cycles of oral LYC-55716; dose and dosing regimen were determined according to pharmacokinetic profile and safety. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective tumor response rate.Results:No dose-limiting toxicities occurred among the 32 enrolled patients who received LYC-55716 150 mg BID to 450 mg BID. Treatment-related adverse events (AE) were primarily grade 1–2 and included diarrhea (n = 11), fatigue (n = 7), anemia (n = 4), decreased appetite (n = 4), and nausea (n = 4). Grade 3 AEs were anemia (n = 2), elevated gamma-glutamyl transferase (n = 1), and hypophosphatemia (n = 1). Pharmacokinetic concentrations achieved levels expected for target gene regulation. Pharmacodynamic results indicated RORγ pathway engagement. Two patients (NSCLC and sarcomatoid breast cancer) had confirmed partial responses; 11 had disease stabilization for 2 to 12 months (6 received >4 months of treatment).Conclusions:These data support the safety and tolerability of LYC-55716 and selection of 450 mg BID dose for a phase 2a study assessing LYC-55716 clinical activity, safety, and biomarkers in patients with NSCLC, head and neck, gastroesophageal, renal cell, urothelial, and ovarian cancers.

PDF file - 79K, Mean sonidegib plasma concentration-time profiles after single oral administration on day 1 of the pharmacokinetic run-in period before initiation of continuous dosing.

Post-treatment changes in IL-17A and pharmacokinetic profiles for Cohort 4a (600 mg QD) and Cohort 4b (300 mg BID). D, day; PD, pharmacodynamics; PK, pharmacokinetics.

Purpose:Sabatolimab (MBG453) and spartalizumab are mAbs that bind T-cell immunoglobulin domain and mucin domain-3 (TIM-3) and programmed death-1 (PD-1), respectively. This phase I/II study evaluated the safety and efficacy of sabatolimab, with or without spartalizumab, in patients with advanced solid tumors.Patients and Methods:Primary objectives of the phase I/Ib part were to characterize the safety and estimate recommended phase II dose (RP2D) for future studies. Dose escalation was guided by a Bayesian (hierarchical) logistic regression model. Sabatolimab was administered intravenously, 20 to 1,200 mg, every 2 or 4 weeks (Q2W or Q4W). Spartalizumab was administered intravenously, 80 to 400 mg, Q2W or Q4W.Results:Enrolled patients (n = 219) had a range of cancers, most commonly ovarian (17%) and colorectal cancer (7%); patients received sabatolimab (n = 133) or sabatolimab plus spartalizumab (n = 86). The MTD was not reached. The most common adverse event suspected to be treatment-related was fatigue (9%, sabatolimab; 15%, combination). No responses were seen with sabatolimab. Five patients receiving combination treatment had partial responses (6%; lasting 12–27 months) in colorectal cancer (n = 2), non–small cell lung cancer (NSCLC), malignant perianal melanoma, and SCLC. Of the five, two patients had elevated expression of immune markers in baseline biopsies; another three had >10% TIM-3–positive staining, including one patient with NSCLC who received prior PD-1 therapy.Conclusions:Sabatolimab plus spartalizumab was well tolerated and showed preliminary signs of antitumor activity. The RP2D for sabatolimab was selected as 800 mg Q4W (alternatively Q3W or Q2W schedules, based on modeling), with or without 400 mg spartalizumab Q4W.

Supplementary Figure 2. CONSORT diagram reflecting patients that received monotherapy with BNC105P after progression on everolimus monotherapy.

Fold induction over Day 1 pre-dose.

Supplementary Materials

Purpose: This phase I trial was undertaken to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the novel smoothened inhibitor sonidegib (LDE225), a potent inhibitor of hedgehog signaling, in patients with advanced solid tumors.Experimental Design: Oral sonidegib was administered to 103 patients with advanced solid tumors, including medulloblastoma and basal cell carcinoma (BCC), at doses ranging from 100 to 3,000 mg daily and 250 to 750 mg twice daily, continuously, with a single-dose pharmacokinetics run-in period. Dose escalations were guided by a Bayesian logistic regression model. Safety, tolerability, efficacy, pharmacokinetics, and biomarkers in skin and tumor biopsies were assessed.Results: The MTDs of sonidegib were 800 mg daily and 250 mg twice daily. The main DLT of reversible grade 3/4 elevated serum creatine kinase (18% of patients) was observed at doses ≥ the MTD in an exposure-dependent manner. Common grade 1/2 adverse events included muscle spasm, myalgia, gastrointestinal toxicities, increased liver enzymes, fatigue, dysgeusia, and alopecia. Sonidegib exposure increased dose proportionally up to 400 mg daily, and displayed nonlinear pharmacokinetics at higher doses. Sonidegib exhibited exposure-dependent reduction in GLI1 mRNA expression. Tumor responses observed in patients with medulloblastoma and BCC were associated with evidence of hedgehog pathway activation.Conclusions: Sonidegib has an acceptable safety profile in patients with advanced solid tumors and exhibits antitumor activity in advanced BCC and relapsed medulloblastoma, both of which are strongly associated with activated hedgehog pathway, as determined by gene expression. Clin Cancer Res; 20(7); 1900–9. ©2014 AACR.

PDF file, 93KB, Supplemental Table 1. Study Drug Administration; Supplemental Table 2. Summary of Somatic Mutation Status and Tumor PTEN Expression Versus Best Result Change in Tumor Dimensions.

PDF file - 624K, Relationship between sonidegib area under the plasma concentration-time curve on day 15 and the incidence of grade 3/4 creatine kinase elevation.

Supplementary Table 1. List of 40 exploratory plasma biomarkers investigated.

PDF file, 86KB.

Individual dose-normalized exposures of pevonedistat (as assessed by Cmax and AUC24) obtained on Day 1 and Day 5 for schedule B (with dexamethasone) and schedule C (without dexamethasone).

Purpose: ARRY-382 (PF-07265804) is a selective inhibitor of colony-stimulating factor-1 receptor. We evaluated the safety and preliminary efficacy of ARRY-382 plus pembrolizumab in patients with advanced solid tumors. Patients and Methods: This was an open-label, multicenter, Phase 1b/2 study (NCT02880371) performed over September 1, 2016 to October 24, 2019. In the Phase 1b dose-escalation, patients with selected advanced solid tumors received ARRY-382 [starting dose 200 mg once daily (QD) orally] plus pembrolizumab [2 mg/kg intravenously (IV) every 3 weeks (Q3W)]. Phase 2 patients had: Pancreatic ductal adenocarcinoma (PDA); programmed cell death protein-1 (PD-1)/PD-ligand 1 (PD-L1) inhibitor-refractory (PD-1/PD-L1 IR) advanced solid tumors; or platinum-resistant ovarian cancer (prOVCA). Patients received ARRY-382 at the maximum tolerated dose (MTD) of 300 mg QD plus pembrolizumab 200 mg IV Q3W. Results: Primary endpoints of dose-limiting toxicities (DLT; Phase 1b) and objective response rate (Phase 2) were met. In Phase 1b, 19 patients received ARRY-382 200–400 mg. Three patients reported DLTs. The MTD of ARRY-382 (plus pembrolizumab) was 300 mg QD. In Phase 1b, 2 patients (10.5%) had confirmed partial response (PR): 1 with PDA and 1 with ovarian cancer, lasting 29.2 and 3.1 months, respectively. In Phase 2, there were 27, 19, and 11 patients in the PDA, PD-1/PD-L1 IR, and prOVCA cohorts, respectively. One patient (3.7%) with PDA had a PR lasting 2.4 months. The most frequent ARRY-382–related adverse events were increased transaminases (10.5%–83.3%) and increased creatine phosphokinase (18.2%–50.0%). Conclusions: Although limited clinical benefit was observed, ARRY-382 plus pembrolizumab was well tolerated.

This first-in-human (FIH), phase I, multicenter, open-label study was conducted to characterize the safety, tolerability, pharmacokinetics, and preliminary efficacy, and to establish the MTD/recommended dose for expansion (RDE) of PCA062 in patients with solid tumors. Adult patients with any solid tumor type and having a documented P-cadherin–positive tumor were enrolled; exceptions to P-cadherin positivity requirement were head and neck squamous cell carcinomas (HNSCC) and esophageal squamous cell carcinoma (ESCC). Dose escalation was guided by an adaptive Bayesian logistic regression model with escalation with overdose control to determine the MTD/RDE. Forty-seven patients were treated at 10 different dose levels of PCA062, ranging from 0.4 to 5.0 mg/kg every 2 weeks administered as a 1-hour intravenous infusion. All enrolled patients discontinued the treatment; primary reason for discontinuation was progressive disease (78.7%). All 47 patients experienced at least one AE, of which 32 patients had a grade ≥3 AE and 37 patients experienced AEs suspected to be study drug related. The MTD of PCA062 was 3.6 mg/kg every 2 weeks and thrombocytopenia was reported as a DLT that was attributed to the known toxicities of the DM1 payload with no P-cadherin–related toxicities. Pharmacokinetics was proportional, and no patients developed antidrug antibodies, suggesting adequate exposure at the doses tested. One patient of 47 achieved a partial response and there was no correlation between tumor P-cadherin expression and clinical efficacy. Because of limited antitumor activity at the MTD level, Novartis has terminated clinical development of PCA062 (NCT02375958).

BACKGROUND: In metastatic colorectal cancer (mCRC), regorafenib (RGF), a multi-kinase inhibitor with angiogenic inhibition has modest effects on survival. We reported that autophagy modulation using hydroxychloroquine (HCQ), enhances the anticancer activity of the histone deacetylase inhibitor, vorinostat (VOR), in mCRC, is well tolerated, and has comparable activity to RGF. Thus, we conducted a prospective study of VOR/HCQ versus RGF in mCRC. METHODS: This is a randomised, controlled trial of VOR 400 mg and HCQ 600 mg orally daily versus RGF 160 mg orally daily (3 weeks on/1 week off), every 4 weeks, in patients with mCRC. Primary endpoint: median progression-free survival (mPFS). Secondary endpoints: median overall survival (mOS); adverse events; pharmacodynamic analyses. RESULTS: From 2/2015-10/2017, 42 patients were randomised to VOR/HCQ and RGF. Median age was 58.4 years. mPFS on VOR/HCQ was 1.9 months versus 4.35 months with RGF (P = 0.032). There was no difference in mOS (P = 0.9). Treatment was tolerated in both arms. In both arms, there was improved anti-tumour immunity. CONCLUSIONS: VOR/HCQ had an inferior PFS when compared to RGF, although there was an increase in anti-tumour immunity in mCRC. VOR/HCQ has a favourable safety profile, and immune or tumour biomarkers may be used to identify clinical benefit of autophagy modulation in mCRC. CLINICAL TRIAL REGISTRATION: NCT02316340.

Background: The first interim analysis of the KEYNOTE-564 study showed improved disease-free survival with adjuvant pembrolizumab compared with placebo after surgery in patients with clear cell renal cell carcinoma at an increased risk of recurrence. The analysis reported here, with an additional 6 months of follow-up, was designed to assess longer-term efficacy and safety of pembrolizumab versus placebo, as well as additional secondary and exploratory endpoints. Methods: In the multicentre, randomised, double-blind, placebo-controlled, phase 3 KEYNOTE-564 trial, adults aged 18 years or older with clear cell renal cell carcinoma with an increased risk of recurrence were enrolled at 213 hospitals and cancer centres in North America, South America, Europe, Asia, and Australia. Eligible participants had an Eastern Cooperative Oncology Group performance status of 0 or 1, had undergone nephrectomy 12 weeks or less before randomisation, and had not received previous systemic therapy for advanced renal cell carcinoma. Participants were randomly assigned (1:1) via central permuted block randomisation (block size of four) to receive pembrolizumab 200 mg or placebo intravenously every 3 weeks for up to 17 cycles. Randomisation was stratified by metastatic disease status (M0 vs M1), and the M0 group was further stratified by ECOG performance status and geographical region. All participants and investigators involved in study treatment administration were masked to the treatment group assignment. The primary endpoint was disease-free survival by investigator assessment in the intention-to-treat population (all participants randomly assigned to a treatment). Safety was assessed in the safety population, comprising all participants who received at least one dose of pembrolizumab or placebo. As the primary endpoint was met at the first interim analysis, updated data are reported without p values. This study is ongoing, but no longer recruiting, and is registered with ClinicalTrials.gov, NCT03142334. Findings: Between June 30, 2017, and Sept 20, 2019, 994 participants were assigned to receive pembrolizumab (n=496) or placebo (n=498). Median follow-up, defined as the time from randomisation to data cutoff (June 14, 2021), was 30·1 months (IQR 25·7–36·7). Disease-free survival was better with pembrolizumab compared with placebo (HR 0·63 [95% CI 0·50–0·80]). Median disease-free survival was not reached in either group. The most common all-cause grade 3–4 adverse events were hypertension (in 14 [3%] of 496 participants) and increased alanine aminotransferase (in 11 [2%]) in the pembrolizumab group, and hypertension (in 13 [3%] of 498 participants) in the placebo group. Serious adverse events attributed to study treatment occurred in 59 (12%) participants in the pembrolizumab group and one (

PURPOSE Concurrent PIK3CA mutations and fibroblast growth factor receptor (FGFR) alterations occur in multiple cancer types, including estrogen receptor–positive breast cancer, bladder cancer, and endometrial cancer. In this first-in-human combination trial, we explored safety and preliminary efficacy of combining the PI3Kα selective inhibitor alpelisib with the FGFR1-4 selective inhibitor infigratinib. PATIENTS AND METHODS Patients with PIK3CA-mutant advanced solid tumors, with or without FGFR1-3 alterations, were enrolled in the dose escalation or one of three molecular-defined dose-expansion cohorts. The primary end point was the maximum tolerated dose. Secondary end points included safety, pharmacokinetics, and response. Archival tumor samples were sequenced to explore genomic correlates of response. RESULTS In combination, both agents were escalated to full, single-agent recommended doses (alpelisib, 300 mg per day continuously; infigratinib, 125 mg per day 3 weeks on followed by 1 week off). The toxicity profile of the combination was consistent with the established safety profile of each agent, although 71% of all patients required at least one treatment interruption or dose reduction. Molecularly selected dose expansions in breast cancer and other solid tumors harboring PIK3CA mutations, alone or in combination with FGFR alterations, identified sporadic responses, predominately in tumor types and genotypes previously defined to have sensitivity to these agents. CONCLUSION The combination of alpelisib and infigratinib can be administered at full single-agent doses, although the high rate of dose interruption or reduction suggests long-term tolerability may be challenging. In exploratory signal-seeking cohorts of patients harboring dual PIK3CA and FGFR1-3 alterations, no clear evidence of synergistic activity was observed.

Summary Background Few options exist for treatment of patients with small-cell lung cancer (SCLC) after failure of first-line therapy. Lurbinectedin is a selective inhibitor of oncogenic transcription. In this phase 2 study, we evaluated the acti and safety of lurbinectedin in patients with SCLC after failure of platinum-based chemotherapy. Methods In this single-arm, open-label, phase 2 basket trial, we recruited patients from 26 hospitals in six European countries and the USA. Adults (aged ≥18 years) with a pathologically proven diagnosis of SCLC, Eastern Cooperative Oncology Group performance status of 2 or lower, measurable disease as per Response Criteria in Solid Tumors (RECIST) version 1.1, absence of brain metastasis, adequate organ function, and pre-treated with only one previous chemotherapy-containing line of treatment (minimum 3 weeks before study initiation) were eligible. Treatment consisted of 3·2 mg/m2 lurbinectedin administered as a 1-h intravenous infusion every 3 weeks until disease progression or unacceptable toxicity. The primary outcome was the proportion of patients with an overall response (complete or partial response) as assessed by the investigators according to RECIST 1.1. All treated patients were analysed for activity and safety. This study is ongoing and is registered with ClinicalTrials.gov , NCT02454972 . Findings Between Oct 16, 2015, and Jan 15, 2019, 105 patients were enrolled and treated with lurbinectedin. Median follow-up was 17·1 months (IQR 6·5–25·3). Overall response by investigator assessment was seen in 37 patients (35·2%; 95% CI 26·2–45·2). The most common grade 3–4 adverse events (irrespective of causality) were haematological abnormalities—namely, anaemia (in nine [9%] patients), leucopenia (30 [29%]), neutropenia (48 [46%]), and thrombocytopenia (seven [7%]). Serious treatment-related adverse events occurred in 11 (10%) patients, of which neutropenia and febrile neutropenia were the most common (five [5%] patients for each). No treatment-related deaths were reported. Interpretation Lurbinectedin was active as second-line therapy for SCLC in terms of overall response and had an acceptable and manageable safety profile. Lurbinectedin could represent a potential new treatment for patients with SCLC, who have few options especially in the event of a relapse, and is being investigated in combination with doxorubicin as second-line therapy in a randomised phase 3 trial. Funding Pharma Mar.

Aim Preclinical evidence suggests that oxidized macrophage migration inhibitory factor (oxMIF) may be involved in carcinogenesis. This phase 1 study (NCT01765790) assessed the safety, tolerability, pharmacokinetics and antitumour activity of imalumab, an oxMIF inhibitor, in patients with advanced cancer using '3 + 3' dose escalation. Methods In Schedule 1, patients with solid tumours received doses from 1 to 50 mg/kg IV every 2 weeks. In Schedule 2, patients with metastatic colorectal adenocarcinoma, non-small-cell lung, or ovarian cancer received weekly doses of 10 or 25 mg/kg IV (1 cycle = 28 days). Treatment continued until disease progression, unacceptable toxicity, dose-limiting toxicity, or withdrawal of consent. Results Fifty of 68 enrolled patients received imalumab. The most common treatment-related adverse events (TRAEs) included fatigue (10%) and vomiting (6%); four grade 3 serious TRAEs (two patients) occurred. The dose-limiting toxicity was allergic alveolitis (one patient, 50 mg/kg every 2 weeks). The maximum tolerated and biologically active doses were 37.5 mg/kg every 2 weeks and 10 mg/kg weekly, respectively. Of 39 assessed patients, 13 had stable disease (≥4 months in 8 patients). Conclusions Imalumab had a maximum tolerated dose of 37.5 mg/kg every 2 weeks in patients with advanced solid tumours, with a biologically active dose of 10 mg/kg weekly. Further investigation will help define the role of oxMIF as a cancer treatment target.

Purpose:Sabatolimab (MBG453) and spartalizumab are mAbs that bind T-cell immunoglobulin domain and mucin domain-3 (TIM-3) and programmed death-1 (PD-1), respectively. This phase I/II study evaluated the safety and efficacy of sabatolimab, with or without spartalizumab, in patients with advanced solid tumors.Patients and Methods:Primary objectives of the phase I/Ib part were to characterize the safety and estimate recommended phase II dose (RP2D) for future studies. Dose escalation was guided by a Bayesian (hierarchical) logistic regression model. Sabatolimab was administered intravenously, 20 to 1,200 mg, every 2 or 4 weeks (Q2W or Q4W). Spartalizumab was administered intravenously, 80 to 400 mg, Q2W or Q4W.Results:Enrolled patients (n = 219) had a range of cancers, most commonly ovarian (17%) and colorectal cancer (7%); patients received sabatolimab (n = 133) or sabatolimab plus spartalizumab (n = 86). The MTD was not reached. The most common adverse event suspected to be treatment-related was fatigue (9%, sabatolimab; 15%, combination). No responses were seen with sabatolimab. Five patients receiving combination treatment had partial responses (6%; lasting 12–27 months) in colorectal cancer (n = 2), non–small cell lung cancer (NSCLC), malignant perianal melanoma, and SCLC. Of the five, two patients had elevated expression of immune markers in baseline biopsies; another three had >10% TIM-3–positive staining, including one patient with NSCLC who received prior PD-1 therapy.Conclusions:Sabatolimab plus spartalizumab was well tolerated and showed preliminary signs of antitumor activity. The RP2D for sabatolimab was selected as 800 mg Q4W (alternatively Q3W or Q2W schedules, based on modeling), with or without 400 mg spartalizumab Q4W.

Background The PI3K/AKT/mTOR (PAM) pathway is a key regulator of tumor therapy resistance. We investigated M2698, an oral p70S6K/AKT dual inhibitor, in patients with advanced cancer who failed standard therapies. Methods M2698 was administered as monotherapy (escalation, 15–380 mg daily; food effect cohort, 240–320 mg daily) and combined with trastuzumab or tamoxifen. Results Overall, 101 patients were treated (M2698, n = 62; M2698/trastuzumab, n = 13; M2698/tamoxifen, n = 26). Patients were predominantly aged KRAS, EGFR, AKT2) were 1.4 months and 2.8 months, respectively. Two patients with breast cancer (M2698/trastuzumab, n = 1; M2698/tamoxifen, n = 1) had partial response; their PFS durations were 31 months and 2.7 months, respectively. Conclusions M2698 was well tolerated. Combined with trastuzumab or tamoxifen, M2698 demonstrated antitumor activity in patients with advanced breast cancer resistant to multiple standard therapies, suggesting that it could overcome treatment resistance. Trial registration ClinicalTrials.gov, NCT01971515. Registered October 23, 2013.

TPS9595 Background: There is a need for novel immunotherapies to address the patient population that never or no longer responds to immune checkpoint inhibitors (CPI). VV1 is an oncolytic vesicular stomatitis virus engineered to express human interferon beta (IFNβ) to enhance cellular anti-tumor immune responses and tumor selectivity. Phase 1 studies demonstrated VV1 anti-tumor activity in several malignancies with or without a CPI. We are exploring ways to optimize VV1 efficacy in combination with cemiplimab, an anti-PD1 antibody approved for lung, basal and squamous cell skin cancers. Recent clinical data support a 5-fold higher dose of VV1 than was previously explored, and pre-clinical data show synergy between the oncolytic and an anti-CTLA4 antibody, in addition to cemiplimab, supporting exploration of a triplet. What was originally a five-arm study of intravenous (IV) VV1 in combination with IV cemiplimab has been amended to focus on 2 means of optimizing efficacy: use of a higher dose of VV1 and triplet combination in proof-of-concept populations. Methods: We are now enrolling pts with advanced melanoma (after progression on anti-PD1) and plan to include 1st-line NSCLC pts with PD-L1 expression ≥50%. The study is first exploring the preliminary anti-tumor activity, safety, and immunogenic activity of the combination of IV VV1 at a dose of 1.0 x 1011 TCID50 once on D1 followed by IV cemiplimab Q3W starting on D8, or the same regimen with an additional intratumoral injection of VV1 1.0 x 109 TCID50 once on D1 for pts with accessible lesions. Pts receive IV cemiplimab Q3W until confirmed disease progression or intolerable toxicity. Once at least 6 pts have been treated with acceptable safety across the 2 melanoma doublet cohorts using this higher dose of VV1, a 3rd melanoma cohort will open to add a single dose of ipilimumab 50 mg on D1 (all IV triplet). Once 6 melanoma pts have received the triplet safely, the 1st-line NSCLC cohort will open. All cohort decisions are guided by a Data Review Committee. Cohorts will be expanded based on a Simon 2-stage design using a type I error rate of 0.05 and power of 85%. Null ORR is 10% with a target of 35% for 2nd line melanoma and null ORR is 40% in 1st line NSCLC with a target of 70%. Each melanoma cohort will require a response in ≥2 of 10 pts in the 1st stage to add 11 more in the 2nd stage, while NSCLC will first need 5/9 evaluable pts to respond, then an additional 13 to complete the design. Response is assessed at week 7 then Q9W per RECIST v1.1. The study includes serial biopsies in ≥3/10 pts in Stage 1 of each of the IV melanoma cohorts (doublet and triplet therapy), all pts in Stage 2 of these IV melanoma cohorts, and all pts in both Stage 1 and Stage 2 of the IV/IT melanoma cohort, to permit a thorough investigation of the impact of the 3 immunotherapies under investigation. The study is currently ongoing in the USA. Clinical trial information: NCT04291105.

Background Expression of LAG-3, an inhibitory immunoreceptor, has been linked to reduced T-cell proliferation and cytokine production. LAG525 is a humanized IgG4 anti-LAG-3 antibody which inhibits LAG-3 binding to MHC class II. Spartalizumab is a humanized IgG4 anti-PD-1 mAb which inhibits PD-1 binding with its ligands PD-L1 and PD-L2. Preclinical data have shown promising antitumor activity when blocking LAG-3 and PD-1. Methods The Phase II part of the first-in-human study (NCT02460224) explored LAG525 + spartalizumab in patients with advanced/metastatic non-small cell lung cancer (NSCLC), cutaneous and non-cutaneous melanoma, renal cell carcinoma (RCC), mesothelioma, or triple-negative breast cancer (TNBC). The dose/schedule of LAG525 and spartalizumab was 400 mg IV Q3W and 300 mg IV Q3W, respectively. Half of patients with TNBC naive to anti-PD-1/PD-L1 received LAG525 at 600 mg IV Q4W and spartalizumab at 400 mg IV Q4W. The primary endpoint was overall response rate (ORR) using RECIST v1.1. Results As of June 1, 2020, 235 patients were enrolled in the Phase II part of the study, including patients with NSCLC (n=42), melanoma (n=42), RCC (n=38), mesothelioma (n=57), or TNBC (n=56). In total, 142 patients were naive to, and 93 patients were pretreated with, PD-1/PD-L1 inhibitors. Overall, 232 patients (99%) discontinued treatment, 76% due to progressive disease.ORR and disease control rate by indication and prior anti-PD-1/PD-L1 treatment are summarized below (table 1). Best overall response was 3 (1.3%) CR, 23 (9.8%) PR, 84 (35.7%) SD, 95 (40.4%) PD, and 30 (12.8%) unknown. For patients naive to anti-PD-1/PD-L1, median progression free survival (mPFS) in months (90% CI) was 3.9 (1.7–5.6) for NSCLC, 2.2 (1.6–5.6) for melanoma, 4.4 (2.1–11.1) for RCC, 5.5 (3.5–6.4) for mesothelioma, and 1.9 (1.6–2.6) for TNBC. For patients pretreated with anti-PD-1/PD-L1, mPFS in months (90% CI) was 3.5 (1.9–4.9) for NSCLC, 1.9 (1.8–3.7) for melanoma, 3.0 (1.6–3.9) for RCC, 3.4 (1.8–3.8) for mesothelioma, and 1.7 (1.3–3.4) for TNBC. Adverse events of any grade, regardless of cause, were reported in 233 (99%) patients; the most common (occurring in >20%) were nausea (25%), fatigue (23%), and dyspnea (21%). Conclusions LAG525 + spartalizumab exhibited antitumor activity across different indications, including patients with melanoma, RCC, and mesothelioma who had been pretreated with PD-1/-L1 inhibitors, suggesting that this combination may salvage prior PD-1/-L1 resistance. The combination was well tolerated, and no new safety signals were observed. Biomarker analysis is ongoing. Trial Registration NCT02460224 Ethics Approval This study was approved by an independent ethics committee or institutional review board at each site.

AIMS We evaluated the potential effect of sonidegib at an oral dose of 800 mg once daily (QD) on the pharmacokinetics (PK) of the probe drugs warfarin (CYP2C9) and bupropion (CYP2B6). METHODS This was a multicentre, open-label study to evaluate the effect of sonidegib on the PK of the probe drugs warfarin and bupropion in patients with advanced solid tumours. Cohort 1 patients received a single warfarin 15-mg dose on Day 1 of the run-in period and on Cycle 2 Day 22 (C2D22) of sonidegib administration. Cohort 2 patients received a single bupropion 75-mg dose on Day 1 of run-in period and on C2D22 of sonidegib administration. Sonidegib 800 mg QD oral dosing began on Cycle 1 Day 1 of a 28-day cycle after the run-in period in both cohorts. RESULTS The geometric means ratios [90% confidence interval] for (S)-warfarin with and without sonidegib were: area under the concentration-time curve from time 0 to infinity (AUCinf ) 1.15 [1.07, 1.24] and maximum plasma concentration (Cmax ) 0.88 [0.81, 0.97]; and for (R)-warfarin were: AUCinf 1.10 [0.98, 1.24] and Cmax 0.93 [0.87, 1.0]. The geometric means ratios [90% confidence interval] of bupropion with and without sonidegib were: AUCinf 1.10 [0.99, 1.23] and Cmax 1.16 [0.95, 1.42]. Sonidegib 800 mg had a safety profile that was similar to that of lower dose sonidegib 200 mg and was unaffected by single doses of the probe drugs. CONCLUSIONS Sonidegib dosed orally at 800 mg QD (higher than the Food and Drug Administration-approved dose) did not impact the PK or pharmacodynamics of warfarin (CYP2C9 probe substrate) or the PK of bupropion (CYP2B6 probe substrate).