Laurel M. Adams

Phase II and Biomarker Study of the Dual MET/VEGFR2 Inhibitor Foretinib in Patients With Papillary Renal Cell Carcinoma

PURPOSE Foretinib is an oral multikinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors. Activating mutations or amplifications in MET have been described in patients with papillary renal cell carcinoma (PRCC). We aimed to evaluate the efficacy and safety of foretinib in patients with PRCC. PATIENTS AND METHODS Patients were enrolled onto the study in two cohorts with different dosing schedules of foretinib: cohort A, 240 mg once per day on days 1 through 5 every 14 days (intermittent arm); cohort B, 80 mg daily (daily dosing arm). Patients were stratified on the basis of MET pathway activation (germline or somatic MET mutation, MET [7q31] amplification, or gain of chromosome 7). The primary end point was overall response rate (ORR). RESULTS Overall, 74 patients were enrolled, with 37 in each dosing cohort. ORR by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 was 13.5%, median progression-free survival was 9.3 months, and median overall survival was not reached. The presence of a germline MET mutation was highly predictive of a response (five of 10 v five of 57 patients with and without germline MET mutations, respectively). The most frequent adverse events of any grade associated with foretinib were fatigue, hypertension, gastrointestinal toxicities, and nonfatal pulmonary emboli. CONCLUSION Foretinib demonstrated activity in patients with advanced PRCC with a manageable toxicity profile and a high response rate in patients with germline MET mutations.

Erratum to: A Phase 1 dose-escalation study of the safety and pharmacokinetics of once-daily oral foretinib, a multi-kinase inhibitor, in patients with solid tumors

Foretinib is an oral multi-kinase inhibitor targeting MET, vascular endothelial growth factor receptor (VEGFR)-2, RON, KIT, and AXL kinases. In this Phase 1, open-label, non-randomized study, foretinib was administered once daily at doses of 60 mg, 80 mg, 100 mg, or 120 mg for 28 days. The primary objectives were to determine the maximum tolerated dose (MTD) and assess the safety and tolerability of the daily oral administration schedule. Secondary objectives included pharmacokinetics, pharmacodynamics, and assessment of tumor response. Patients had histologically confirmed metastatic or unresectable solid tumors for which no standard treatments existed and all received oral foretinib once daily. Dose escalation was planned as a conventional “3 + 3” design with an expansion at the MTD for collection of additional safety and pharmacokinetic information. Thirty-seven patients were treated across four dose levels. The MTD was established as 80 mg foretinib. Dose-limiting toxicities were hypertension, dehydration, and diarrhea. The most common adverse events included fatigue, hypertension, nausea, and diarrhea. Twenty-three of 31 patients (74 %) had a best response of stable disease. No patient had a confirmed partial or complete response. At the MTD, steady state was achieved by approximately 2 weeks, with average post-dose time to maximum concentration, peak concentration, and trough concentration of 4 h, 46 ng/mL, and 24 ng/mL, respectively. In patients treated at the MTD, soluble MET and VEGF-A plasma levels significantly increased (P < 0.003) and soluble VEGFR2 plasma levels significantly decreased from baseline (P < 0.03). The MTD of foretinib bisphosphate salt was determined to be 80 mg once daily.

First-in-human Phase I Study of GSK2126458, an Oral Pan-Class I Phosphatidylinositol-3-kinase inhibitor, in Patients with Advanced Solid Tumor Malignancies

Purpose: GSK2126458 (GSK458) is a potent inhibitor of PI3K (α, β, γ, and δ), with preclinical studies demonstrating broad antitumor activity. We performed a first-in-human phase I study in patients with advanced solid tumors. Materials and Methods: Patients received oral GSK458 once or twice daily in a dose-escalation design to define the maximum tolerated dose (MTD). Expansion cohorts evaluated pharmacodynamics, pharmacokinetics, and clinical activity in histologically and molecularly defined cohorts. Results: One hundred and seventy patients received doses ranging from 0.1 to 3 mg once or twice daily. Dose-limiting toxicities (grade 3 diarrhea, n = 4; fatigue and rash, n = 1) occurred in 5 patients (n = 3 at 3 mg/day). The MTD was 2.5 mg/day (MTD with twice daily dosing undefined). The most common grade ≥3 treatment-related adverse events included diarrhea (8%) and skin rash (5%). Pharmacokinetic analyses demonstrated increased duration of drug exposure above target level with twice daily dosing. Fasting insulin and glucose levels increased with dose and exposure of GSK458. Durable objective responses (ORs) were observed across multiple tumor types (sarcoma, kidney, breast, endometrial, oropharyngeal, and bladder cancer). Responses were not associated with PIK3CA mutations (OR rate: 5% wild-type vs. 6% mutant). Conclusions: Although the MTD of GSK458 was 2.5 mg once daily, twice-daily dosing may increase duration of target inhibition. Fasting insulin and glucose levels served as pharmacodynamic markers of drug exposure. Select patients achieved durable responses; however, PIK3CA mutations were neither necessary nor predictive of response. Combination treatment strategies and novel biomarkers may be needed to optimally target PI3K. Clin Cancer Res; 22(8); 1932–9. ©2015 AACR.

A phase II and biomarker study (MET111644) of the dual Met/VEGFR-2 inhibitor foretinib in patients with sporadic and hereditary papillary renal cell carcinoma: Final efficacy, safety, and PD results.

355 Background: Foretinib is an oral multi-kinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors. Activating mutations and/or amplifications in MET have been described in patients (pts) with papillary renal cell carcinoma (PRC). The aim of this study was to evaluate the efficacy and safety of 2 dosing regimens of single agent foretinib bisphosphate (foretinib) in pts with PRC and to explore modulation of plasma proteins indicative of target inhibition. METHODS Pts were enrolled in 2 cohorts with different dosing schedules of foretinib: 240 mg/day on days 1-5 of every 14 days (intermittent arm) or 80 mg/day (daily dosing arm). The primary endpoint was overall response rate (ORR) targeting an ORR of at least 25%. Pts were stratified based on status of MET pathway activation (germline or somatic MET mutation, MET [7q31] amplification, chromosome 7 gain or none of these). Plasma markers reflecting potential target effects of MET and VEGFR inhibition were also analyzed. RESULTS Overall, 74 pts were enrolled with 37 in each dosing cohort. ORR was 13.5%, progression-free survival 9.3 months, 1 year overall survival (OS) was 70% and median OS was not reached. The median duration of response was 18.5 months. Of 68 pts with adequate tumor assessment data available, 50 experienced some reduction in the sum of the longest tumor diameters (SLD) ranging from -2% to -75%. The most frequent grade 3/4 adverse events related to foretinib were fatigue (6.8%), hypertension (50%), and diarrhea (6.8%). A high rate of non-fatal pulmonary embolism was observed (11%). There were no significant differences in efficacy or safety between the two cohorts. In both arms, plasma sMET and VEGF increased and sVEGFR2 decreased after 2 cycles indicating target inhibition, but these changes were not associated with response or PFS. Outcomes based on molecular characterization are presented separately at this meeting. CONCLUSIONS In the largest clinical trial devoted to papillary RCC, foretinib demonstrated anti-tumor activity in patients with PRC, modulation of several target indicator plasma proteins, and a manageable toxicity profile.

Correlation of germline MET mutation with response to the dual Met/VEGFR-2 inhibitor foretinib in patients with sporadic and hereditary papillary renal cell carcinoma: Results from a multicenter phase II study (MET111644).

372 Background: Activating mutations and/or amplifications in MET have been described in patients (pts) with papillary renal cell carcinoma (PRC). Foretinib, an oral multi-kinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors, was evaluated in a phase 2 study in pts with PRC. An important objective of this study was to evaluate whether activation of the MET receptor pathway by mutation, amplification, or gain of chromosome 7 was predictive for or correlated with clinical outcomes. METHODS Pts were stratified based on status of MET pathway activation. Blood samples were collected at screening for determination of germline MET mutational status. Archival tumor tissue samples were obtained for the analysis of somatic MET mutation, amplification of the MET locus (7q31), and gain of chromosome 7 using standardized assays. RESULTS A total of 74 pts were enrolled on the trial (37 each in intermittent and daily dosing arms); overall efficacy and safety data are reported separately at this meeting. Sixty-seven pts were evaluable for both mutation status and response. 5/10 pts (50%) with a germline MET mutation experienced a PR, while 5 pts (50%) had SD as their best response, including 4 pts who demonstrated tumor SLD reductions of > 10%, but did not achieve PR by RECIST 1.0. Responses were also seen in pts without germline MET mutation. However, the presence of a germline MET mutation was highly predictive of a response as only 5/57 pts (9%) without a mutation experienced a PR. Other measures of MET pathway activation did not appear to correlate with activity with only 1/5 pts (20%) with somatic MET mutation having a PR; furthermore, in the absence of a concomitant MET mutation, no responses were seen in patients with MET amplification (n=2) and only 1/18 (5%) pts with a gain of chromosome 7 experienced a PR. CONCLUSIONS The presence of germline MET mutations correlated strongly with activity of the MET inhibitor foretinib in pts with PRC. These data provide early proof of principle that MET may be a valid therapeutic target in a subset of patients with PRC.

A phase I study of a new nucleoside analogue, OSI-7836, using two administration schedules in patients with advanced solid malignancies

Purpose: To investigate the safety, tolerability, and pharmacokinetic profile of the novel nucleoside analogue OSI-7836 in patients with advanced solid malignancies. Experimental Design: OSI-7836 was initially given as a 60-minute i.v. infusion on day 1 every 21 days. In view of its dose-limiting toxicities, the administration time was amended to a 5-minute bolus, and subsequently, the schedule was amended to weekly for 4 weeks followed by a 2-week rest. Blood and urine samples were collected for pharmacokinetic studies. Analyses of cytokines and lymphocyte subsets were added later in the study to elucidate a mechanism for the severe fatigue and lymphocyte depletion observed in earlier patients. Results: Thirty patients received a total of 61 treatment cycles. Fatigue was the main dose-limiting toxicity. Maximum-tolerated dose was defined as 300 mg/m2 in the 60-minute infusion, (three times per week) schedule; 400 mg/m2 in the 5-minute bolus infusion, (three times per week) schedule; and 100 mg/m2 in the weekly schedule. Other common toxicities were nausea, vomiting, rash, fever, and a flu-like syndrome. There were no clinically significant hematologic toxicities. Following the initial dose, OSI-7836 was eliminated from plasma with a median (range) elimination half-life of 48.3 minutes (22.6-64.8 minutes). Lymphocyte subset analysis showed a significant drop in B cell counts, which persisted to day 14 and beyond. Cytokine analysis showed significant elevations of interleukin-6 and interleukin-10 in all patients who received ≥200 mg/m2 OSI-7836. Best response was disease stabilization in seven patients. Conclusion: OSI-7836 was associated with excessive fatigue, and despite changes in its schedule and duration of administration, we did not observe an improvement in its tolerability. Its potentially selective effect on B lymphocytes could be exploited in further studies in specific hematologic malignancies.

Population pharmacokinetics modeling and analysis of foretinib in adult patients with advanced solid tumors

Foretinib is a multikinase inhibitor that inhibits multiple receptor tyrosine kinases, including MET and VEGFR, with the potential for treatment of solid tumors. Hepatocellular carcinoma (HCC) pathogenesis is associated with overexpression of MET, and physiologic changes in the livers of HCC patients may decrease CYP3A isozyme‐mediated metabolism of foretinib. A population pharmacokinetic model of foretinib was developed to explore the effect of tumor type, formulation, and other covariates. Data from 1 HCC study in Asia and 3 non‐HCC studies in the United States with varying foretinib regimens and formulations were used for analysis. A 2‐compartment model with a linear first‐order absorption and elimination and lag time in absorption adequately described foretinib pharmacokinetics in 132 advanced non‐HCC and HCC patients and identified an effect of formulations on bioavailability. The bisphosphate salt capsules and freebase tablets had a relative bioavailability 37% and 20% higher, respectively, than the solution formulation. HCC patients had ≈19.6% lower mean clearance (70.14 L/h), ≈16% lower mean volume of distribution (1725.6 L), and higher dose‐normalized exposure compared with non‐HCC patients. This could be a result of differences in metabolism in HCC patients, body weight, or activity of CYP3A isozymes between Asian and Western cancer patients.

A pharmacokinetic, pharmacodynamic, and safety study of intravenous cyclophosphamide with an oral casopitant antiemetic regimen in cancer patients

Casopitant is a potent and selective neurokinin‐1 receptor antagonist formerly under development for a number of indications, including the treatment of chemotherapy‐induced nausea and vomiting. This study was an open‐label, randomized, multi‐center, two‐period crossover casopitant–cyclophosphamide interaction study. Subjects were cancer patients receiving cyclophosphamide based chemotherapy. The objectives of the study were to assess the effect of 3‐day, repeat‐dose, 150 mg oral casopitant on the pharmacokinetics (PK), safety, tolerability, and pharmacodynamics (white blood cell count) of single‐dose IV cyclophosphamide. PK data from 14 evaluable subjects showed the geometric least‐squares mean ratios (90% CI) for cyclophosphamide and the metabolite 4‐hydroxycyclophosphamide AUC (with:without casopitant) were 1.03 (0.975, 1.09) and 0.948 (0.835, 1.08), respectively. Administration of casopitant was well tolerated and did not impact the safety profile of the treatment regimen. Casopitant did not affect the expected bone marrow toxicity of cyclophosphamide. Co‐administration of 150 mg oral casopitant with single‐dose IV cyclophosphamide did not appear to result in a clinically relevant change in cyclophosphamide or 4‐hydroxycyclophosphamide exposure or safety.