Soonmo Peter Kang

Efficacy and safety of the anti-PD-1 monoclonal antibody MK-3475 in 411 patients (pts) with melanoma (MEL).

LBA9000^ Background: The humanized monoclonal IgG4 anti-PD-1 antibody MK-3475 has demonstrated durable antitumor activity in MEL and NSCLC. We evaluated MK-3475 efficacy and safety in a pooled analysis of 411 MEL pts. METHODS A nonrandomized cohort of ipilimumab-naive (IPI-N) and IPI-treated (IPI-T) pts treated with MK-3475 10 mg/kg Q2W, 10 mg/kg Q3W, or 2 mg/kg Q3W and randomized cohorts of IPI-N and IPI-T pts treated with 2 Q3W or 10 Q3W were included. Response was assessed every 12 wk by RECIST 1.1 by independent central review and by immune-related response criteria (irRC) by investigator. RESULTS 162 pts were treated at 2 Q3W, 192 at 10 Q3W, and 57 at 10 Q2W. 190 pts were IPI-N and 221 were IPI-T. As of the 10/18/2013 cutoff, all pts had ≥6 mo follow-up and >75% had ≥9 mo follow-up. Among the 365 pts with measurable disease at baseline, ORR by RECIST was 40% (95% CI 32%-48%) in IPI-N and 28% (95% CI 22%-35%) in IPI-T pts. Responses were durable (88% ongoing at analysis). Median PFS by RECIST was 24 wk in IPI-N and 23 wk in IPI-T pts. Median OS was not reached, with 1-y OS of 71% in all pts. Benefit was observed by both RECIST and irRC at all doses and schedules in IPI-N and IPI-T pts (Table). MK-3475 demonstrated activity in all major subgroups irrespective of ECOG PS, LDH levels, BRAFmutation, M stage, and number and type of prior therapy. Overall, 12% of pts experienced drug-related grade 3/4 AEs and 4% discontinued due to a drug-related AE. There were no drug-related deaths. CONCLUSIONS MK-3475 showed durable responses and a manageable safety profile across dose and schedules in IPI-N and IPI-T MEL pts. The observed efficacy and safety suggest MK-3475 may be an appropriate treatment for all pts with MEL. CLINICAL TRIAL INFORMATION NCT01295827. [Table: see text].

Phase I Dose-Escalation Trial of Checkpoint Kinase 1 Inhibitor MK-8776 As Monotherapy and in Combination With Gemcitabine in Patients With Advanced Solid Tumors

PURPOSE We determined the safety, pharmacokinetics, pharmacodynamics, and recommended phase II dose of MK-8776 (SCH 900776), a potent, selective checkpoint kinase 1 (Chk1) inhibitor, as monotherapy and in combination with gemcitabine in a first-in-human phase I clinical trial in patients with advanced solid tumor malignancies. PATIENTS AND METHODS Forty-three patients were treated by intravenous infusion with MK-8776 at seven dose levels ranging from 10 to 150 mg/m(2) as monotherapy and then in combination with gemcitabine 800 mg/m(2) (part A, n = 26) or gemcitabine 1,000 mg/m(2) (part B, n = 17). Forty percent of patients had three or more prior treatment regimens, and one third of patients had previously received gemcitabine. RESULTS As monotherapy, MK-8776 was well tolerated, with QTc prolongation (19%), nausea (16%), fatigue (14%), and constipation (14%) as the most frequent adverse effects. Combination therapy demonstrated a higher frequency of adverse effects, predominantly fatigue (63%), nausea (44%), decreased appetite (37%), thrombocytopenia (32%), and neutropenia (24%), as well as dose-related, transient QTc prolongation (17%). The median number of doses of MK-8776 administered was five doses, with relative dose-intensity of 0.96. Bioactivity was assessed by γ-H2AX ex vivo assay. Of 30 patients evaluable for response, two showed partial response, and 13 exhibited stable disease. CONCLUSION MK-8776 was well tolerated as monotherapy and in combination with gemcitabine. Early evidence of clinical efficacy was observed. The recommended phase II dose is MK-8776 200 mg plus gemcitabine 1,000 mg/m(2) on days 1 and 8 of a 21-day cycle.

Inconsistent labeling of food effect for oral agents across therapeutic areas: differences between oncology and non-oncology products

Purpose: Several recent oral oncology drugs were labeled for administration in fasted states despite the fact that food increases their bioavailability. Because this was inconsistent with the principles of oral drug delivery, we hypothesized that there were inconsistencies across therapeutic areas. Experimental Design: Oral agents approved by the U.S. Food and Drug Administration from January 2000 to May 2009 were included in our study. Comparison of the food labeling patterns between oncology and non-oncology drugs was made using Fishers exact test. Results: Of the 99 drugs evaluated, 34 showed significant food effects on bioavailability. When food markedly enhanced bioavailability, eight out of nine non-oncology drugs were labeled “fed” to take advantage of the food-drug interaction, whereas all oncology drugs (n = 3) were labeled to be administered in “fasted” states (Fishers exact test, P = 0.01). Conclusions: Drug labeling patterns with respect to food-drug interactions observed with oncology drugs are in contradiction with fundamental pharmacologic principles, as exemplified in the labeling of non-oncology drugs. Clin Cancer Res; 16(17); 4446–51. ©2010 AACR.

First-In-Human Phase I Study of Lurbinectedin (PM01183) in Patients with Advanced Solid Tumors

Purpose: Lurbinectedin (PM01183) binds covalently to DNA and has broad activity against tumor cell lines. This first-in-human phase I study evaluated dose-limiting toxicities (DLT) and defined a phase II recommended dose for PM01183 as a 1-hour intravenous infusion every three weeks (q3wk). Experimental Design: Thirty-one patients with advanced solid tumors received escalating doses of PM01183 following an accelerated titration design. Results: PM01183 was safely escalated over 200-fold, from 0.02 to 5.0 mg/m2. Dose doubling was utilized, requiring 15 patients and nine dose levels to identify DLT. The recommended dose was 4.0 mg/m2, with one of 15 patients having DLT (grade 4 thrombocytopenia). Clearance was independent of body surface area; thus, a flat dose of 7.0 mg was used during expansion. Myelosuppression, mostly grade 4 neutropenia, occurred in 40% of patients but was transient and manageable, and none was febrile. All other toxicity was mild and fatigue, nausea and vomiting were the most common at the recommended dose. Pharmacokinetic parameters showed high interindividual variation, though linearity was observed. At or above the recommended dose, the myelosuppressive effect was significantly associated with the area under the concentration-time curve from time zero to infinity (white blood cells, P = 0.0007; absolute neutrophil count, P = 0.016). A partial response was observed in one patient with pancreatic adenocarcinoma at the recommended dose. Conclusion: A flat dose of 7.0 mg is the recommended dose for PM01183 as a 1-hour infusion q3wk. This dose is tolerated and active. Severe neutropenia occurred at this dose, although it was transient and with no clinical consequences in this study. Clin Cancer Res; 20(8); 2205–14. ©2014 AACR.

Evaluation of food effect on pharmacokinetics of vismodegib in advanced solid tumor patients

Purpose: Vismodegib, an orally bioavailable small-molecule Smoothened inhibitor, is approved for treatment of advanced basal cell carcinoma (BCC). We conducted a pharmacokinetic study of vismodegib in patients with advanced solid tumors to explore the effects of food on drug exposure. Experimental Design: In part I, patients were randomized to fasting overnight (FO), a high fat meal (HF), or a low fat meal (LF) before a single dose of vismodegib 150 mg. Plasma concentrations of vismodegib were determined by a validated liquid chromatography-tandem mass spectrometry assay. Primary endpoints were Cmax and area under the curve (AUC0–168). In part II, patients randomized to FO or HF in part I took vismodegib 150 mg daily after fasting; those randomized to LF took it after a meal. Primary endpoints after two weeks were Cmax and AUC0–24. Results: Sixty (22 FO, 20 HF, 18 LF) and 52 (25 fasting, 27 fed) patients were evaluable for primary endpoints in parts I and II, respectively. Mean Cmax and AUC0–168 after a single dose were higher in HF than FO patients [ratios of geometric means (90% CI) = 1.75 (1.30, 2.34) and 1.74 (1.25, 2.42), respectively]. There were no significant differences in Cmax or AUC0–24 between fasting and fed groups after daily dosing. The frequencies of drug-related toxicities were similar in both groups. Conclusions: A HF meal increases plasma exposure to a single dose of vismodegib, but there are no pharmacokinetic or safety differences between fasting and fed groups at steady-state. Vismodegib may be taken with or without food for daily dosing. Clin Cancer Res; 19(11); 3059–67. ©2013 AACR.

Estimation of Renal Cell Carcinoma Treatment Effects From Disease Progression Modeling

To improve future drug development efficiency in renal cell carcinoma (RCC), a disease‐progression model was developed with longitudinal tumor size data from a phase III trial of sorafenib in RCC. The best‐fit model was externally evaluated on 145 placebo‐treated patients in a phase III trial of pazopanib; the model incorporated baseline tumor size, a linear disease‐progression component, and an exponential drug effect (DE) parameter. With the model‐estimated effect of sorafenib on RCC growth, we calculated the power of randomized phase II trials between sorafenib and hypothetical comparators over a range of effects. A hypothetical comparator with 80% greater DE than sorafenib would have 82% power (one‐sided α = 0.1) with 50 patients per arm. Model‐based quantitation of treatment effect with computed tomography (CT) imaging offers a scaffold on which to develop new, more efficient, phase II trial end points and analytic strategies for RCC.

Clinical Outcome of Pancreatic Cancer Patients with Diabetes Mellitus: Is Diabetes a Poor Prognostic Factor?

Diabetes mellitus and its related factors such as hyperinsulinemia have been linked to various cancer risks and outcomes. Previous research has offered inconsistent results in terms of relationship between diabetes and pancreatic cancers. Establishing clear association between these two entities may guide us in improving clinical outcomes of pancreatic cancer patients. Two abstracts that examined the association between diabetes mellitus and pancreatic cancer are updated in this paper. Herein, the authors report updated information from the 2010 American Society of Clinical Oncology (ASCO) Annual Meeting in association between pancreatic cancer and diabetes mellitus. The present paper illustrates insufficient knowledge base to draw a conclusion in this topic. However, validation and understanding of the association could have significant clinical implications with respect to cancer prevention, early detection, and treatment. As such, further investigations are warranted to explore the link diabetes and pancreatic cancers.