W. Jeffrey Edenfield

Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK), MET, and ROS1, is approved for treatment of patients with ALK-positive or ROS1-positive advanced non-small-cell lung cancer (NSCLC). However, ALK rearrangements are also implicated in other malignancies, including anaplastic large-cell lymphoma and inflammatory myofibroblastic tumors (IMTs). In this ongoing, multicenter, single-arm, open-label phase 1b study (PROFILE 1013; NCT01121588), patients with ALK-positive advanced malignancies other than NSCLC were to receive a starting dose of crizotinib 250 mg twice daily. Primary endpoints were safety and objective responses based on Response Evaluation Criteria in Solid Tumors version 1.1 or National Cancer Institute International Response Criteria. Forty-four patients were enrolled (lymphoma, n = 18; IMT, n = 9; other tumors, n = 17). The objective response rate was 53% (95% confidence interval [CI], 28-77) for lymphoma, with 8 complete responses (CRs) and 1 partial response (PR); 67% (95% CI, 30-93) for IMTs, with 1 CR and 5 PRs; and 12% (95% CI, 2-36) for other tumors, with 2 PRs in patients affected by colon carcinoma and medullary thyroid cancer, respectively. The median duration of treatment was almost 3 years for patients with lymphoma and IMTs, with 2-year progression-free survival of 63% and 67%, respectively. The most common treatment-related adverse events were diarrhea (45.5%) and vision disorders (45.5%), mostly grade 1. These findings indicate strong and durable activity of crizotinib in ALK-positive lymphomas and IMTs. The safety profile was consistent with the known safety profile of crizotinib even with long-term treatment.

PURPOSE: Phase Ib study evaluating the effect of apalutamide, at therapeutic exposure, on ventricular repolarization by applying time-matched pharmacokinetics and electrocardiography (ECG) in patients with castration-resistant prostate cancer. Safety of daily apalutamide was also assessed. METHODS: Patients received 240 mg oral apalutamide daily. Time-matched ECGs were collected via continuous 12-lead Holter recording before apalutamide (Day - 1) and on Days 1 and 57 (Cycle 3 Day 1). Pharmacokinetics of apalutamide were assessed on Days 1 and 57 at matched time points of ECG collection. QT interval was corrected for heart rate using Fridericia correction (QTcF). The primary endpoint was the maximum mean change in QTcF (ΔQTcF) from baseline to Cycle 3 Day 1 (steady state). Secondary endpoints were the effect of apalutamide on other ECG parameters, pharmacokinetics of apalutamide and its active metabolite, relationship between plasma concentrations of apalutamide and QTcF, and safety. RESULTS: Forty-five men were enrolled; 82% received treatment for ≥ 3 months. At steady state, the maximum ΔQTcF was 12.4 ms and the upper bound of its associated 90% CI was 16.0 ms. No clinically meaningful effects of apalutamide were reported for heart rate or other ECG parameters. A concentration-dependent increase in QTcF was observed for apalutamide. Most adverse events (AEs) (73%) were grade 1-2 in severity. No patients discontinued due to QTc prolongation or AEs. CONCLUSION: The effect of apalutamide on QTc prolongation was modest and does not produce a clinically meaningful effect on ventricular repolarization. The AE profile was consistent with other studies of apalutamide.

Emerging evidence suggests a small subset of late-stage colon cancer driven by HER2, a biomarker routinely evaluated in select breast and gastric cancers, may respond to HER2-targeted therapy. Herein, we describe a 49-year-old male with widely metastatic colon cancer originating in the sigmoid colon. After failing standard therapy, a biopsy specimen of the tumor was evaluated for novel biomarkers using molecular profiling. After identification of ERBB2 (HER2) amplification using in situ hybridization, the patient subsequently received a trial of trastuzumab monotherapy and experienced a dramatic and durable response. This report builds on our understanding of using precision oncology to improve survival in metastatic colon cancer.

Abstract Introduction: This phase 1, open-label, randomized, crossover study assessed the bioequivalence (BE) and safety of an investigational, ready-to-dilute, rapid infusion, low-volume solution of bendamustine hydrochloride (test product [T]) and the approved bendamustine lyophilized powder formulation (reference product [R]). [CT.gov ID NCT02162888] Methods: Eligible patients (Pts) were aged 18 years or older with relapsed or refractory solid tumors or hematologic malignancies excluding chronic lymphocytic leukemia. All Pts received bendamustine 120 mg/m2 intravenously as T (in 50 mL; 0.9% NaCl) over 10 min, and as R (in 500 mL; 0.9% NaCl) over 60 min on days 1 and 2 of two consecutive 28-day cycles. Patients were randomly assigned to 1 of 3 treatment sequences defining the first 3 doses of study drug: TRR, RTR, RRT. T was given to all Pts at cycle 2, day 2. For the first 3 doses, blood samples were collected prior to infusion; mid-infusion (T 5 min, R 30 min); at 5, 15, 30, and 45 min, and at 1, 1.5, 2, 3, 4, 5, and 8 h postinfusion; and 24 h from the start of infusion on day 1 of both cycles. The pharmacokinetic (PK) endpoints for BE were area under plasma concentration-vs-time curve (AUC) from time 0 to the last quantifiable sample collected (AUC0-t) and from time 0 to infinity (AUC0-oo), which were evaluated using a scaled average BE (SABE) method, appropriate for high variability drugs. Other PK endpoints were maximum plasma concentration (Cmax), time to Cmax (tmax), and elimination half-life (t1/2). Safety was assessed by reported adverse events (AEs), Eastern Cooperative Oncology Group performance status, physical examination, and laboratory values throughout the 56-day study period. Results: A total of 83 Pts were randomized to the 3 treatment sequences; 81 received at least one dose of study drug and comprised the safety population; 60 received 3 doses (required for BE analysis). BE analyses were conducted for AUC in this population, and for other patient subsets based on dosing and sample collections deemed evaluable and complete. Here, PK results are presented for the 38 Pts meeting all BE inclusion criteria (Table 1). The BE of T and R was assessed by Reference-SABE for AUC as intra-subject variability for R (SWR) was >0.3 (Table 2). Mean concentration-vs-time is presented in the Figure. The AUC and t1/2 were similar in Pts treated with T and R. Cmax was higher and tmax was shorter in Pts treated with T, consistent with the faster infusion of bendamustine. The overall safety profiles of T and R were similar (Table 3), with serious AEs (SAEs) in 28% of Pts and 6 deaths (all attributable to disease progression). AEs occurring within 24 h of treatment were similar in type and frequency; the only AEs occurring in ≥3% of Pts with either treatment during this period were nausea (R 11%, T 9%), fatigue (R 8%, T 9%), vomiting (R 3%, T 4%), and constipation (R 4%, T 3%). Conclusions: BE of the two bendamustine formulations was demonstrated for AUCs as the upper critical values were <0 and the point estimates of T/R geometric mean ratio fell within 0.80 to 1.25 inclusive. Differences in Cmax and tmax were anticipated from the different infusion rates for the T and R. The safety profile of the two drugs was comparable with no new safety signals. Reported AEs were either known effects of bendamustine or presumed to be related to underlying disease. Sponsor: Eagle Pharmaceuticals, Inc. Table 1. Summary of PK Parameters Parameter Tn = 38 Rn = 38 AUC0-t, ng·h/mL (% CV) 10339.21 (49.3) 10514.87 (55.9) AUC0-¥, ng·h/mL (% CV) 10369.74 (49.2) 10527.76 (55.8) tmax, h (range) 0.18 (0.1-0.4) 1.0 (0.5-1.3) Cmax, ng/mL (% CV) 19158.16 (33.5) 8868.42 (47.4) t1/2, h (% CV) 0.65 (37.3) 0.60 (30.3) CV: coefficient of variation Table 2. Bioequivalence Analyses Results (n = 38) AUC(ng·h/mL) GM1 Test (T) GM1 Reference (R) T/R 90%Confidence Intervals Swr Upper Critical Value AUC0-t 9143.72 9047.81 1.01 0.898-1.145 0.403 -0.09 AUC0--¥ 9173.01 9062.77 1.02 0.899-1.146 0.402 -0.09 GM: geometric mean, Swr: within-patient standard deviation of the reference product1 by SABE Table 3. Summary of AEs Patientsn (%) Tn = 73 Rn = 81 Totaln = 81 Overall AEs 49 (67) 60 (74) 76 (94) SAEs 12 (16) 12 (15) 23 (28) Deaths* 5 (7) 1 (1) 6 (7) Occurring within 24 h of infusion AEs 23 (32) 34 (42) 49 (61) SAEs 2 (3) 2 (3) 4 (5) Deaths 0 0 0 *All attributable to disease progression Figure 1. Mean (± SD) bendamustine plasma concentration versus time for rapid-infusion test (T) and reference (R) formulations Figure 1. Mean (± SD) bendamustine plasma concentration versus time for rapid-infusion test (T) and reference (R) formulations Disclosures Edenfield: Novartis, Astellas/Medivation: Speakers Bureau. Anthony:Eagle Pharmaceuticals, Inc.: Research Funding. Mutch:Eagle Pharmaceuticals, Inc.: Employment. Chanas:Eagle Pharmaceuticals, Inc.: Employment. Smith:Eagle Pharmaceuticals, Inc.: Employment.