Holly Brown

A Phase I Pharmacokinetic and Pharmacodynamic Study of Dalotuzumab (MK-0646), an Anti-Insulin-like Growth Factor-1 Receptor Monoclonal Antibody, in Patients with Advanced Solid Tumors

Purpose: Insulin-like growth factor-1 receptor (IGF-1R) mediates cellular processes in cancer and has been proposed as a therapeutic target. Dalotuzumab (MK-0646) is a humanized IgG1 monoclonal antibody that binds to IGF-1R preventing receptor activation. This study was designed to evaluate the safety and tolerability of dalotuzumab, determine the pharmacokinetic (PK) and pharmacodynamic (PD) profiles, and identify a recommended phase II dose. Experimental Design: Patients with tumors expressing IGF-1R protein were allocated to dose-escalating cohorts of three or more patients each and received intravenous dalotuzumab weekly, every 2 or 3 weeks. Plasma was collected for PK analysis. Paired baseline and on-treatment skin and tumor biopsy samples were collected for PD analyses. Results: Eighty patients with chemotherapy-refractory solid tumors were enrolled. One dose-limiting toxicity was noted, but a maximum-tolerated dose was not identified. Grade 1 to 3 hyperglycemia, responsive to metformin, occurred in 15 (19%) patients. At dose levels or more than 5 mg/kg, dalotuzumab mean terminal half-life was 95 hours or more, mean Cmin was more than 25 μg/mL, clearance was constant, and serum exposures were approximately dose proportional. Decreases in tumor IGF-1R, downstream receptor signaling, and Ki67 expression were observed. 18F-Fluorodeoxy-glucose positron emission tomography metabolic responses occurred in three patients. One patient with Ewings sarcoma showed a mixed radiologic response. The recommended phase II doses were 10, 20, and 30 mg/kg for the weekly, every other week, and every third week schedules, respectively. Conclusions: Dalotuzumab was generally well-tolerated, exhibited dose-proportional PK, inhibited IGF-1R pathway signaling and cell proliferation in treated tumors, and showed clinical activity. The low clearance rate and long terminal half-life support more extended dosing intervals. Clin Cancer Res; 17(19); 6304–12. ©2011 AACR.

Abstract OT2-6-15: Efficacy and safety of vintafolide alone and vintafolide plus paclitaxel vs paclitaxel alone in advanced triple negative breast cancer subjects using etarfolatide subject selection

Background: Vintafolide (V) is a folic acid-vinca alkaloid small molecule drug conjugate that targets tumors that over-express the folate receptor (FR). 99mTc-etarfolatide (EC20) is a folate-targeted molecular imaging agent being developed to identify FR-positive tumors. Data suggest that triple negative breast cancers (TNBCs) expressing high levels of FR are likely to benefit from treatment with vintafolide. Trial design/Patient eligibility: This is a multicenter, randomized, open-label, Phase IIa trial in subjects with advanced TNBC. Patients will be evaluated for tumor specific expression of the FR using a EC20 SPECT/CT scan and classified as FR(100%) if 100% of RECIST 1.1 target lesions are FR-positive. Only FR(100%) patients are eligible for treatment and will be randomized in a 1:1:1 ratio to V alone, V + paclitaxel (P) or P alone. V will be administered at 2.5 mg IV 3x/week for 2 weeks on Days 1, 3, 5, 15, 17 and 19 of a 28-day cycle. P will be administered at 80 mg/m2 IV on Days 1, 8, 15, and 22. Specific aims: The primary endpoint for the trial is centrally assessed progression free survival (PFS). Secondary objectives include: assess the frequency of target tumors expressing FR(100%) vs FR(20-80%) vs FR(0%) in subjects with TNBC using EC20 SPECT scans; compare the clinical activity in subjects with advanced TNBC of V alone vs P and V + P vs P alone as measured by objective response rate (ORR), (complete response [CR] + partial response [PR]), clinical benefit rate (CBR; CR + PR + stable disease for ≥6 months), and overall survival; and assess the safety and tolerability of V alone vs P alone and V + P vs P alone in subjects with advanced TNBC. Statistical methods and target accrual: PFS and overall survival will be assessed in the intention to treat population using a stratified Cox model with Efron9s tie handling method, and Kaplan-Meier method for PFS and OS curve estimation, respectively, in each treatment group. Inferential comparisons between the arms will be tested using the stratified log-rank test at one sided alpha level of 5%. This study will randomize 34 subjects into each treatment group with total study duration of ∼16-17 months. The study has 80% power to demonstrate that either patients treated with V or patients treated with V + P combination have a higher median time to an event of PFS than subjects treated with P at an unadjusted one-sided, 5% alpha-level, if the underlying constant hazard ratio between treatment groups is 0.5 and median survival time of 2.6 months. First patient enrollment is targeted for October. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-15.