Brett E. Houk

A Population Pharmacokinetic Meta-analysis of Sunitinib Malate (SU11248) and Its Primary Metabolite (SU12662) in Healthy Volunteers and Oncology Patients

Purpose: Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor approved for advanced renal cell carcinoma and imatinib-resistant or imatinib-intolerant gastrointestinal stromal tumor. Following administration, sunitinib is metabolized by cytochrome P450 3A4 to an active metabolite (SU12662). The objective of this analysis was to assess sunitinib and SU12662 pharmacokinetics and to identify covariates that might explain variability in exposure following oral administration. Experimental Design: Data from 590 subjects (73 volunteers and 517 patients) in 14 studies were analyzed. Plasma concentration-time data were analyzed using nonlinear mixed-effects modeling to estimate population pharmacokinetic parameters, as well as relationships between these parameters and gender, race, age, weight, creatinine clearance, Eastern Cooperative Oncology Group score, and tumor type. Simulations were done to determine the predicted effect of these covariates on exposure. Results: Separate models were developed for sunitinib and SU12662 (each a two-compartment model with first-order absorption and elimination). Sunitinib parameters were estimated as CL/F, 51.8 L/h and Vd/Fcentral, 2,030 liters. SU12662 parameters were estimated as CL/F, 29.6 L/h and Vd/Fcentral, 3,080 liters. Tumor type (except acute myeloid leukemia), Asian race, gender, body weight, and elevated Eastern Cooperative Oncology Group score described a portion of the variability in CL/F for sunitinib and metabolite; gender and body weight explained some of the variability in Vd/Fcentral for sunitinib and metabolite. Among patients, the predicted changes in sunitinib and metabolite AUC and Cmax as a result of the individual covariates ranged up to 17%. Conclusion: The magnitude of the predicted changes in exposure with the covariates studied minimizes the necessity for dose adjustment in any of these subpopulations.

A Phase II Study of Sunitinib in Japanese Patients with Metastatic Renal Cell Carcinoma: Insights into the Treatment, Efficacy and Safety

OBJECTIVE This study aims to assess the efficacy and safety of sunitinib in Japanese patients with metastatic renal cell carcinoma (RCC). METHODS Fifty-one Japanese patients with prior nephrectomy, 25 treatment-naive patients (first-line group) and 26 cytokine-refractory patients (pretreated group) were enrolled in this phase II trial. Patients received sunitinib 50 mg orally, once daily, in repeated 6-week cycles (4 weeks on treatment, 2 weeks off). The primary endpoint was RECIST-defined objective response rate (ORR) with tumour assessments every 6 weeks via computed tomography or magnetic resonance imaging. Toxicity was assessed regularly. In the primary efficacy analysis of the intent-to-treat (ITT) population, ORR and 95% confidence interval were calculated based on independent review. Secondary time-to-event endpoints, such as progression-free survival (PFS), were estimated using the Kaplan-Meier method. RESULTS In the ITT population, ORR was 48.0% in the first-line group (after a median 4 cycles), 46.2% in the pretreated group (5 cycles) and 47.1% overall, with median times to tumour response of 7.1, 10.7 and 10.0 weeks, respectively. Median PFS was 46.0, 33.6 and 46.0 weeks, respectively. The most common treatment-related grade 3/4 adverse events and laboratory abnormalities were fatigue (20%), hand-foot syndrome (14%) and hypertension (12%), decreased platelet count (55%), decreased neutrophil count (51%), increased lipase (39%) and decreased lymphocyte count (33%). CONCLUSIONS In Japanese patients with RCC, sunitinib is consistently effective and tolerable with similar risk/benefit as that in Western patients, though there was a trend toward greater antitumour efficacy and higher incidence of haematological adverse events in Japanese patients.

Overall Survival and Updated Results from a Phase II Study of Sunitinib in Japanese Patients with Metastatic Renal Cell Carcinoma

BACKGROUND In a phase II, open-label, multicentre Japanese study, sunitinib demonstrated antitumour activity and acceptable tolerability in metastatic renal cell carcinoma patients. Final survival analyses and updated results are reported. METHODS Fifty-one Japanese patients with a clear-cell component of metastatic renal cell carcinoma (25 treatment-naïve; 26 cytokine-refractory) received sunitinib 50 mg orally, once daily (Schedule 4/2). Overall and progression-free survivals were estimated by the Kaplan-Meier method. Objective response rate (per Response Evaluation Criteria in Solid Tumours) and safety were assessed with an updated follow-up. RESULTS First-line and pretreated patients received a median 6.0 and 9.5 treatment cycles, respectively. Investigator-assessed, end-of-study objective response rate was 52.0, 53.8 and 52.9% in first-line, pretreated and overall intent-to-treat populations, respectively. The median progression-free survival was 12.2 and 10.6 months in first-line and pretreated patients, respectively. Fourteen patients per group died (56 and 54%), and the median overall survival was 33.1 and 32.5 months, respectively. The most common treatment-related Grade 3 or 4 adverse events and laboratory abnormalities were fatigue (24%), hand-foot syndrome (18%), decreased platelet count (55%), decreased neutrophil count (53%) and increased lipase (49%). No Grade 5 treatment-related adverse events occurred. Forty patients (78%) required dose reduction, and 13 (25%) discontinued, due to treatment-related adverse events. CONCLUSIONS With the median overall survival benefit exceeding 2.5 years, and acceptable tolerability, in first-line and pretreated Japanese metastatic renal cell carcinoma patients with Eastern Cooperative Oncology Group performance status 0/1, sunitinib showed a favourable risk/benefit profile, similar to Western studies. However, there was a trend towards greater efficacy and more haematological adverse events in Japanese patients.

A Phase I Study of PF-04929113 (SNX-5422), an Orally Bioavailable Heat Shock Protein 90 Inhibitor, in Patients with Refractory Solid Tumor Malignancies and Lymphomas

Purpose: To determine the maximum tolerated dose (MTD), toxicities, and pharmacokinetic/pharmacodynamic profile of the Hsp90 inhibitor PF-04929113 (SNX-5422) in patients with advanced solid tumors and lymphomas. Methods: This was a single-institution, phase I, dose-escalation study of PF-04929113 administered twice weekly. Endpoints included determination of dose-limiting toxicities (DLT), MTD, the safety profile of PF-04929113, pharmacodynamic assessment of PF-04929113 on Hsp70 induction, pharmacokinetic analysis of PF-04928473 (SNX-2112) and its prodrug PF-04929113, and assessment of response. Results: Thirty-three patients with advanced malignancies were treated. Dose escalation was continued up to 177 mg/m2 administered orally twice a week. One DLT (nonseptic arthritis) was noted. No grade 4 drug-related adverse events were seen; grade 3 adverse events included diarrhea (9%), nonseptic arthritis (3%), aspartate aminotransferase elevation (3%), and thrombocytopenia (3%). No objective responses were seen in 32 evaluable patients. Fifteen patients (47%) had stable disease; 17 patients (53%) had progressive disease. Pharmacokinetic data revealed rapid absorption, hepatic, and extrahepatic clearance, extensive tissue binding, and almost linear pharmacokinetics of the active drug PF-04928473. Pharmacodynamic studies confirmed inhibition of Hsp90 and a linear correlation between pharmacokinetic parameters and Hsp70 induction. Conclusions: PF-04929113 administered orally twice a week is well tolerated and inhibits its intended target Hsp90. No objective responses were seen, but long-lasting stabilizations were obtained. Although no clinically significant drug-related ocular toxicity was seen in this study, the development of PF-04929113 has been discontinued because of ocular toxicity seen in animal models and in a separate phase I study. Clin Cancer Res; 17(21); 6831–9. ©2011 AACR.

PKPD Modeling of VEGF, sVEGFR‐2, sVEGFR‐3, and sKIT as Predictors of Tumor Dynamics and Overall Survival Following Sunitinib Treatment in GIST

The predictive value of longitudinal biomarker data (vascular endothelial growth factor (VEGF), soluble VEGF receptor (sVEGFR)‐2, sVEGFR‐3, and soluble stem cell factor receptor (sKIT)) for tumor response and survival was assessed based on data from 303 patients with imatinib‐resistant gastrointestinal stromal tumors (GIST) receiving sunitinib and/or placebo treatment. The longitudinal tumor size data were well characterized by a tumor growth inhibition model, which included, as significant descriptors of tumor size change, the model‐predicted relative changes from baseline over time for sKIT (most significant) and sVEGFR‐3, in addition to sunitinib exposure. Survival time was best described by a parametric time‐to‐event model with baseline tumor size and relative change in sVEGFR‐3 over time as predictive factors. Based on the proposed modeling framework to link longitudinal biomarker data with overall survival using pharmacokinetic–pharmacodynamic models, sVEGFR‐3 demonstrated the greatest predictive potential for overall survival following sunitinib treatment in GIST.

First-In-Human Study of PF-05212384 (PKI-587), a Small-Molecule, Intravenous, Dual Inhibitor of PI3K and mTOR In Patients With Advanced Cancer

Purpose: To evaluate safety (primary endpoint), tolerability, pharmacokinetics, pharmacodynamic profile, and preliminary activity of the intravenous, pan-class I isoform PI3K/mTOR inhibitor PF-05212384 in patients with advanced solid tumors. Experimental Design: Part 1 of this open-label phase I study was designed to estimate the maximum-tolerated dose (MTD) in patients with nonselected solid tumors, using a modified continual reassessment method to guide dose escalation. Objectives of part 2 were MTD confirmation and assessment of preliminary activity in patients with selected tumor types and PI3K pathway dysregulation. Results: Seventy-seven of the 78 enrolled patients received treatment. The MTD for PF-05212384, administered intravenously once weekly, was estimated to be 154 mg. The most common treatment-related adverse events (AE) were mucosal inflammation/stomatitis (58.4%), nausea (42.9%), hyperglycemia (26%), decreased appetite (24.7%), fatigue (24.7%), and vomiting (24.7%). The majority of patients treated at the MTD experienced only grade 1 treatment-related AEs. Grade 3 treatment-related AEs occurred in 23.8% of patients at the MTD. No treatment-related grade 4–5 AEs were reported at any dose level. Antitumor activity was noted in this heavily pretreated patient population, with two partial responses (PR) and an unconfirmed PR. Eight patients had long-lasting stable disease (>6 months). Pharmacokinetic analyses showed a biphasic concentration–time profile for PF-05212384 (half-life, 30–37 hours after multiple dosing). PF-05212384 inhibited downstream effectors of the PI3K pathway in paired tumor biopsies. Conclusions: These findings demonstrate the manageable safety profile and antitumor activity of the PI3K/mTOR inhibitor PF-05212384, supporting further clinical development for patients with advanced solid malignancies. Clin Cancer Res; 21(8); 1888–95. ©2015 AACR.

A randomized phase II non-comparative study of PF-04691502 and gedatolisib (PF-05212384) in patients with recurrent endometrial cancer.

OBJECTIVE PF-04691502 and gedatolisib (PF-05212384) are potent, dual PI3K/mTOR inhibitors. This phase II study (B1271004) was conducted in patients with recurrent endometrial cancer following platinum-containing chemotherapy. The primary endpoint was to assess clinical benefit response (complete or partial response, or stable disease for ≥16weeks) following treatment with PF-04691502 or gedatolisib. METHODS The main study consisted of four independent arms based on a Simon two-stage design. Patients were assigned to putative PI3K-basal (PF-04691502 or gedatolisib) or PI3K-activated (PF-04691502 or gedatolisib) arms based on stathmin-low or stathmin-high tumor expression, respectively. Japanese patients were also enrolled in a separate lead-in cohort. RESULTS In stage 1 (main study), eighteen patients were randomized to PF-04691502 and 40 to gedatolisib. The two PF-04691502 arms were discontinued early due to unacceptable toxicity, including pneumonia and pneumonitis. The most common treatment-related adverse events associated with gedatolisib were nausea (53%), mucosal inflammation (50%), decreased appetite (40%), diarrhea (38%), fatigue (35%), and dysgeusia and vomiting (each 30%). Clinical benefit response rate was 53% (10/19) in the gedatolisib/stathmin-low arm and 26% (5/19) in the gedatolisib/stathmin-high arm. Safety profile and pharmacokinetic characteristics of both drugs in the Japanese lead-in cohort were comparable to the Western population. CONCLUSIONS Gedatolisib administered by weekly intravenous infusion demonstrated acceptable tolerability and moderate activity in patients with recurrent endometrial cancer. PF-04691502 daily oral dosing was not well tolerated. Clinical benefit response criteria for proceeding to stage 2 were only met in the gedatolisib/stathmin-low arm. Stathmin-high expression did not correlate with greater treatment efficacy. ClinicalTrials.gov registration ID: NCT01420081.

Modeling and simulations relating overall survival to tumor growth inhibition in renal cell carcinoma patients

PurposeTo assess the link between tumor growth inhibition (TGI) and overall survival (OS) based on historical renal cell carcinoma (RCC) data. To illustrate how simulations can help to identify TGI thresholds based on target OS benefit [i.e., hazard ratio (HR) compared with standard of care] to support new drug development in RCC.MethodsTumor size (TS) data were modeled from 2552 patients with first-line or refractory RCC who received temsirolimus, interferon, sunitinib, sorafenib or axitinib in 10 Phase II or Phase III studies. Three model-based TGI metrics estimates [early tumor shrinkage (ETS) at week 8, 10 or 12, time to tumor growth (TTG) and growth rate] as well as baseline prognostic factors were tested in multivariate lognormal models of OS. Model performance was evaluated by posterior predictive check of the OS distributions and hazard ratio across treatments.ResultsTTG was the best TGI metric to predict OS. However, week 8 ETS had a satisfactory performance and was employed in order to maximize clinical utilization. The week 8 ETS to OS model was then used to simulate clinically relevant ETS thresholds for future Phase II studies with investigational treatments.ConclusionsThe published OS model and resultant simulations can be leveraged to support Phase II design and predict expected OS and HR (based on early observed TGI data obtained in Phase II or Phase III studies), thereby informing important mRCC development decisions, e.g., Go/No Go and dose regimen selection.

Standard Error of Empirical Bayes Estimate in NONMEM® VI

The pharmacokinetics/pharmacodynamics analysis software NONMEM® output provides model parameter estimates and associated standard errors. However, the standard error of empirical Bayes estimates of inter-subject variability is not available. A simple and direct method for estimating standard error of the empirical Bayes estimates of inter-subject variability using the NONMEM® VI internal matrix POSTV is developed and applied to several pharmacokinetic models using intensively or sparsely sampled data for demonstration and to evaluate performance. The computed standard error is in general similar to the results from other post-processing methods and the degree of difference, if any, depends on the employed estimation options.

Pharmacokinetics, Modeling, and Simulation in the Development of Sunitinib Malate: A Case Study

Pharmacokinetics, modeling, and simulation are integral components of the drug development process, with potential impact on the regulatory approval process and approval language, as well as the clinical use of the drug. The US Food and Drug Administration and other regulatory agencies recommend inclusion of such analyses as part of the regulatory submission process. The pharmacokinetics, modeling, and simulation studies performed for the anticancer agent sunitinib malate are presented here as a case study. Population based pharmacokinetic and pharmacokinetic−pharmacodynamic studies supported the sunitinib dosing schedule in the regulatory submission process and have provided insights into optimal use of the drug. Sunitinib also illustrates some of the practical difficulties of evaluating exposure−response relationships in clinical trials in oncology.