Manash Shankar Chatterjee

The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: A phase 1 dose-escalation trial

BACKGROUND Poly(ADP-ribose) polymerase (PARP) is implicated in DNA repair and transcription regulation. Niraparib (MK4827) is an oral potent, selective PARP-1 and PARP-2 inhibitor that induces synthetic lethality in preclinical tumour models with loss of BRCA and PTEN function. We investigated the safety, tolerability, maximum tolerated dose, pharmacokinetic and pharmacodynamic profiles, and preliminary antitumour activity of niraparib. METHODS In a phase 1 dose-escalation study, we enrolled patients with advanced solid tumours at one site in the UK and two sites in the USA. Eligible patients were aged at least 18 years; had a life expectancy of at least 12 weeks; had an Eastern Cooperative Oncology Group performance status of 2 or less; had assessable disease; were not suitable to receive any established treatments; had adequate organ function; and had discontinued any previous anticancer treatments at least 4 weeks previously. In part A, cohorts of three to six patients, enriched for BRCA1 and BRCA2 mutation carriers, received niraparib daily at ten escalating doses from 30 mg to 400 mg in a 21-day cycle to establish the maximum tolerated dose. Dose expansion at the maximum tolerated dose was pursued in 15 patients to confirm tolerability. In part B, we further investigated the maximum tolerated dose in patients with sporadic platinum-resistant high-grade serous ovarian cancer and sporadic prostate cancer. We obtained blood, circulating tumour cells, and optional paired tumour biopsies for pharmacokinetic and pharmacodynamic assessments. Toxic effects were assessed by common toxicity criteria and tumour responses ascribed by Response Evaluation Criteria in Solid Tumors (RECIST). Circulating tumour cells and archival tumour tissue in prostate patients were analysed for exploratory putative predictive biomarkers, such as loss of PTEN expression and ETS rearrangements. This trial is registered with ClinicalTrials.gov, NCT00749502. FINDINGS Between Sept 15, 2008, and Jan 14, 2011, we enrolled 100 patients: 60 in part A and 40 in part B. 300 mg/day was established as the maximum tolerated dose. Dose-limiting toxic effects reported in the first cycle were grade 3 fatigue (one patient given 30 mg/day), grade 3 pneumonitis (one given 60 mg/day), and grade 4 thrombocytopenia (two given 400 mg/day). Common treatment-related toxic effects were anaemia (48 patients [48%]), nausea (42 [42%]), fatigue (42 [42%]), thrombocytopenia (35 [35%]), anorexia (26 [26%]), neutropenia (24 [24%]), constipation (23 [23%]), and vomiting (20 [20%]), and were predominantly grade 1 or 2. Pharmacokinetics were dose proportional and the mean terminal elimination half-life was 36·4 h (range 32·8-46·0). Pharmacodynamic analyses confirmed PARP inhibition exceeded 50% at doses greater than 80 mg/day and antitumour activity was documented beyond doses of 60 mg/day. Eight (40% [95% CI 19-64]) of 20 BRCA1 or BRCA2 mutation carriers with ovarian cancer had RECIST partial responses, as did two (50% [7-93]) of four mutation carriers with breast cancer. Antitumour activity was also reported in sporadic high-grade serous ovarian cancer, non-small-cell lung cancer, and prostate cancer. We recorded no correlation between loss of PTEN expression or ETS rearrangements and measures of antitumour activity in patients with prostate cancer. INTERPRETATION A recommended phase 2 dose of 300 mg/day niraparib is well tolerated. Niraparib should be further assessed in inherited and sporadic cancers with homologous recombination DNA repair defects and to target PARP-mediated transcription in cancer. FUNDING Merck Sharp and Dohme.

Systematic evaluation of pembrolizumab dosing in patients with advanced non-small-cell lung cancer

BACKGROUND In the phase I KEYNOTE-001 study, pembrolizumab demonstrated durable antitumor activity in patients with advanced non-small-cell lung cancer (NSCLC). We sought to characterize the relationship between pembrolizumab dose, exposure, and response to define an effective dose for these patients. PATIENTS AND METHODS Patients received pembrolizumab 2 mg/kg every 3 weeks (Q3W) (n = 55), 10 mg/kg Q3W (n = 238), or 10 mg/kg Q2W (n = 156). Response (RECIST v1.1) was assessed every 9 weeks. The relationship between the estimated pembrolizumab area under the concentration-time curve at steady state over 6 weeks (AUCss-6weeks) and the longitudinal change in tumor size (sum of longest diameters) was analyzed by regression and non-linear mixed effects modeling. This model was simultaneously fit to all tumor size data, then used to simulate response rates, normalizing the trial data across dose for prognostic covariates (tumor PD-L1 expression and EGFR mutation status). The exposure-safety relationship was assessed by logistic regression of pembrolizumab AUCss-6weeks versus occurrence of adverse events (AEs) of interest based on their immune etiology. RESULTS Overall response rates were 15% [95% confidence interval (CI) 7%-28%] at 2 mg/kg Q3W, 25% (18%-33%) at 10 mg/kg Q3W, and 21% (95% CI 14%-30%) at 10 mg/kg Q2W. Regression analyses of percentage change from baseline in tumor size versus AUCss-6weeks indicated a flat relationship (regression slope P > 0.05). Simulations showed the exposure-response relationship to be similarly flat, thus indicating that the lowest evaluated dose of 2 mg/kg Q3W to likely be at or near the efficacy plateau. Exposure-safety analysis showed the AE incidence to be similar among the clinically tested doses. CONCLUSIONS No significant exposure dependency on efficacy or safety was identified for pembrolizumab across doses of 2-10 mg/kg. These results support the use of a 2 mg/kg Q3W dosage in patients with previously treated, advanced NSCLC. CLINICALTRIALSGOV REGISTRY NCT01295827.

Lipids, safety parameters, and drug concentrations after an additional 2 years of treatment with Anacetrapib in the DEFINE study

Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor that has previously been shown to reduce low-density lipoprotein cholesterol (LDL-C) and raise high-density lipoprotein cholesterol (HDL-C) in patients with or at high risk of coronary heart disease in the 76-week, placebo-controlled, Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib (DEFINE) trial. Here, we report the results of the 2-year extension to the DEFINE study where patients (n = 803) continued on the same assigned treatment as in the original 76-week study. Treatment with anacetrapib during the 2-year extension was well tolerated with a safety profile similar to patients on placebo. No clinically important abnormalities in liver enzymes, blood pressure, electrolytes, or adverse experiences were observed during the extension. At the end of the extension study, relative to the original baseline value, anacetrapib reduced Friedewald-calculated LDL-C by 39.9% and increased HDL-C by 153.3%, compared to placebo. The apparent steady state mean plasma trough concentration of anacetrapib was ∼640 nmol/L. Geometric mean plasma concentrations of anacetrapib did not appear to increase beyond week 40 of the 2-year extension of the 76-week DEFINE base study. In conclusion, an additional 2 years of treatment with anacetrapib were well tolerated with durable lipid-modifying effects on LDL-C and HDL-C.

Pembrolizumab: Role of Modeling and Simulation in Bringing a Novel Immunotherapy to Patients With Melanoma

Recently, immunotherapy has yielded promising results in several cancer types. Contrary to the established classical chemotherapy‐dosing paradigm, a maximum tolerated dose approach does not always produce better clinical outcomes for novel targeted therapies, as their efficacy is frequently robust at pharmacologically active doses below the maximum tolerated dose. Integrated safety and efficacy assessments are needed to inform clinical dose and trial design, and to support an early identification of potentially safe and efficacious combination treatments.

Preclinical and translational evaluation of coagulation factor IXa as a novel therapeutic target

The benefits of novel oral anticoagulants are hampered by bleeding. Since coagulation factor IX (fIX) lies upstream of fX in the coagulation cascade, and intermediate levels have been associated with reduced incidence of thrombotic events, we evaluated the viability of fIXa as an antithrombotic target. We applied translational pharmacokinetics/pharmacodynamics (PK/PD) principles to predict the therapeutic window (TW) associated with a selective small molecule inhibitor (SMi) of fIXa, compound 1 (CPD1, rat fIXa inhibition constant (Ki, 21 nmol/L) relative to clinically relevant exposures of apixaban (rat fXa Ki 4.3 nmol/L). Concentrations encompassing the minimal clinical plasma concentration (Cmin) of the 5 mg twice daily (BID) dose of apixaban were tested in rat arteriovenous shunt (AVS/thrombosis) and cuticle bleeding time (CBT) models. An Imax and a linear model were used to fit clot weight (CW) and CBT. The following differences in biology were observed: (1) antithrombotic activity and bleeding increased in parallel for apixaban, but to a lesser extent for CPD1 and (2) antithrombotic activity occurred at high (>99%) enzyme occupancy (EO) for fXa or moderate (>65% EO) for fIXa. translational PK/PD analysis indicated that noninferiority was observed for concentrations of CPD1 that provided between 86% and 96% EO and that superior TW existed between 86% and 90% EO. These findings were confirmed in a study comparing short interfering (si)RNA‐mediated knockdown (KD) modulation of fIX and fX mRNA. In summary, using principles of translational biology to relate preclinical markers of efficacy and safety to clinical doses of apixaban, we found that modulation of fIXa can be superior to apixaban.

Leveraging model-informed approaches for drug discovery and development in the cardiovascular space

Cardiovascular disease remains a significant global health burden, and development of cardiovascular drugs in the current regulatory environment often demands large and expensive cardiovascular outcome trials. Thus, the use of quantitative pharmacometric approaches which can help enable early Go/No Go decision making, ensure appropriate dose selection, and increase the likelihood of successful clinical trials, have become increasingly important to help reduce the risk of failed cardiovascular outcomes studies. In addition, cardiovascular safety is an important consideration for many drug development programs, whether or not the drug is designed to treat cardiovascular disease; modeling and simulation approaches also have utility in assessing risk in this area. Herein, examples of modeling and simulation applied at various stages of drug development, spanning from the discovery stage through late-stage clinical development, for cardiovascular programs are presented. Examples of how modeling approaches have been utilized in early development programs across various therapeutic areas to help inform strategies to mitigate the risk of cardiovascular-related adverse events, such as QTc prolongation and changes in blood pressure, are also presented. These examples demonstrate how more informed drug development decisions can be enabled by modeling and simulation approaches in the cardiovascular area.

Abstract CT112: Exposure-response analysis of pembrolizumab in patients with advanced melanoma and non-small cell lung cancer enrolled in KEYNOTE-001, -002, and -006

Background: The anti-PD-1 monoclonal antibody pembrolizumab has demonstrated durable antitumor activity against several advanced malignancies and is generally well tolerated. In the KEYNOTE-001, -002, and -006 trials, patients with advanced/metastatic melanoma and non-small cell lung cancer (NSCLC) were given pembrolizumab doses ranging from 2 mg/kg Q3W to 10 mg/kg Q2W. The objective of this current analysis was to explore the relationship between exposure to pembrolizumab and safety/efficacy in patients with advanced melanoma or NSCLC to help select an appropriate therapeutic dose. Methods: Exposure-response analyses (using graphical exploration and nonlinear mixed effects modeling) of tumor size data were used to characterize the relationship between pembrolizumab exposure and tumor size reduction. Data for these analyses were derived from 1366 patients with melanoma and 496 with NSCLC; exposure-response analyses were performed separately for each indication. Tumor size, defined as the sum of longest dimensions (SLD) of target lesions, was the response readout and individual steady-state area under the curve (AUC) estimates from a population PK model were used as an integrated exposure measure across all concentration data for each patient. Additionally, exposure-adverse event (AE) logistic regression was performed on the integrated dataset, focusing on AEs of special interest (AEOSIs), defined as a broad category of potentially immune-related AEs. Results: The graphical analysis for both melanoma (stratified by IPI pretreatment status) and NSCLC (stratified by PD-L1 expression status) identified an almost flat relationship between exposure and change in tumor size from baseline at 24 wk (melanoma) or 18 wk (NSCLC), with substantial overlap in confidence intervals. In agreement with the exploratory graphical analyses, individual pembrolizumab exposures showed a small and statistically insignificant influence on the final model estimated tumor decay parameter for both melanoma (slope = 0.131, P = 0.20 for IPI-naive; and slope = 0.1, P = 0.25 for IPI-experienced), and NSCLC (slope = 0.196, P = 0.54) patients. Clinical trial simulations, using the tumor size model to normalize for covariates, predicted little variation and considerable overlap in the confidence intervals for response across the dose regimens studied for both populations, confirming lack of clinically meaningful differences between 2 mg/kg and 10 mg/kg. The exposure-AEOSI analysis did not identify exposure to pembrolizumab as a significant predictor of the occurrence of AEOSIs. Conclusions: The exposure range associated with 2 mg/kg Q3W dose provides near maximal efficacy with acceptable tolerability, and thus there is no clear benefit to higher dosing. The findings of this analysis support a common regimen of 2 mg/kg Q3W for pembrolizumab in melanoma and NSCLC. Citation Format: Manash S. Chatterjee, David C. Turner, Malidi Ahamadi, Rik de Greef, Tomoko Freshwater, Kapil Mayawala, David Dong, Julie Stone, Dinesh de Alwis, Anna Kondic. Exposure-response analysis of pembrolizumab in patients with advanced melanoma and non-small cell lung cancer enrolled in KEYNOTE-001, -002, and -006. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT112.

EFFECTS OF LONGER-TERM TREATMENT WITH ANACETRAPIB ON SAFETY PARAMETERS, LIPIDS, AND PLASMA DRUG CONCENTRATIONS IN THE DEFINE TRIAL

Anacetrapib is a cholesteryl ester transfer protein inhibitor that has previously been shown to be well tolerated, reduce low-density lipoprotein cholesterol (LDL-C) and raise high-density lipoprotein cholesterol (HDL-C) in patients with or at high risk for coronary heart disease in the DEFINE base