Jeffrey D. Isaacson

Rociletinib in EGFR-mutated non-small-cell lung cancer.

BACKGROUND Non-small-cell lung cancer (NSCLC) with a mutation in the gene encoding epidermal growth factor receptor (EGFR) is sensitive to approved EGFR inhibitors, but resistance develops, mediated by the T790M EGFR mutation in most cases. Rociletinib (CO-1686) is an EGFR inhibitor active in preclinical models of EGFR-mutated NSCLC with or without T790M. METHODS In this phase 1-2 study, we administered rociletinib to patients with EGFR-mutated NSCLC who had disease progression during previous treatment with an existing EGFR inhibitor. In the expansion (phase 2) part of the study, patients with T790M-positive disease received rociletinib at a dose of 500 mg twice daily, 625 mg twice daily, or 750 mg twice daily. Key objectives were assessment of safety, side-effect profile, pharmacokinetics, and preliminary antitumor activity of rociletinib. Tumor biopsies to identify T790M were performed during screening. Treatment was administered in continuous 21-day cycles. RESULTS A total of 130 patients were enrolled. The first 57 patients to be enrolled received the free-base form of rociletinib (150 mg once daily to 900 mg twice daily). The remaining patients received the hydrogen bromide salt (HBr) form (500 mg twice daily to 1000 mg twice daily). A maximum tolerated dose (the highest dose associated with a rate of dose-limiting toxic effects of less than 33%) was not identified. The only common dose-limiting adverse event was hyperglycemia. In an efficacy analysis that included patients who received free-base rociletinib at a dose of 900 mg twice daily or the HBr form at any dose, the objective response rate among the 46 patients with T790M-positive disease who could be evaluated was 59% (95% confidence interval [CI], 45 to 73), and the rate among the 17 patients with T790M-negative disease who could be evaluated was 29% (95% CI, 8 to 51). CONCLUSIONS Rociletinib was active in patients with EGFR-mutated NSCLC associated with the T790M resistance mutation. (Funded by Clovis Oncology; ClinicalTrials.gov number, NCT01526928.).

A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer

The objective of this study was to evaluate the efficacy and safety of atrasentan (Xinlay), a selective endothelin‐A receptor antagonist, in patients with metastatic hormone‐refractory prostate cancer (HRPC).

Atrasentan, an Endothelin-Receptor Antagonist for Refractory Adenocarcinomas: Safety and Pharmacokinetics

PURPOSE Endothelin receptors, particularly the ET(A) receptor, have been shown to participate in the pathophysiology of prostate and other cancers. Atrasentan, an endothelin antagonist, binds selectively to the ET(A) receptor. This study evaluated the safety, pharmacokinetics, and maximum-tolerated dose of atrasentan in cancer patients. PATIENTS AND METHODS Patients who were 18 years or older and had histologically confirmed adenocarcinoma refractory to therapy enrolled in this 28-day, open-label, phase I study. Enrollment was planned for cohorts of three patients at doses escalating from 10 to 140 mg/d. When any patient had dose-limiting toxicity, that cohort was expanded. The primary outcome variable was safety; secondary outcome variables were pharmacokinetics, tumor response, and pain relief. RESULTS Thirty-one cancer patients (14 prostate) were treated at daily atrasentan doses of 10, 20, 30, 45, 60, and 75 mg (n = 3 to 8 per cohort). The most common adverse events, such as rhinitis, headache, asthenia, and peripheral edema, were reversible on drug discontinuation and responded to symptom-specific treatment. Reversible hemodilution was apparent in laboratory findings and weight gain. Clinically significant headache was the dose-limiting adverse event; the maximum-tolerated dose was 60 mg/d. Pharmacokinetics were dose-proportional across the 10- to 75-mg dose range. Atrasentan was rapidly absorbed; the time to maximum observed concentration was approximately 1.5 hours. The terminal elimination half-life was approximately 24 hours, and steady-state plasma concentrations were achieved within 7 days. Decreases in prostate-specific antigen and pain relief were noted in a patient subset. CONCLUSION Adverse events were consistent with atrasentans pharmacologic vasodilatory effect. Linear, dose-proportional pharmacokinetics suggest that atrasentan can be easily and consistently dosed.

Benefit of Atrasentan in Men with Hormone Refractory Prostate Cancer Metastatic to Bone

4687 Background: Bone alkaline phosphatase (BAP) predicts time to progression (TTP) and survival in patients with hormone refractory prostate cancer (HRPC). We tested 2 hypotheses: a) BAP at baseline is predictive of both TTP and survival in HRPC patients with bony metastases only and b) BAP predicts response to atrasentan therapy in these men. METHODS Data were analyzed from 474 men with HRPC metastastic only to bone from a randomized, double-blind, placebo-controlled phase 3 trial of atrasentan 10 mg QD. Kaplan-Meier and Cox proportional hazard methodologies were used to compare TTP (a composite of radiological and clinical outcomes) between treatments. Values from 451 patients with baseline BAP values were analyzed. Data from treatment arms were pooled and stratified by baseline BAP < and >/= the median value. TTP and survival and the effect of treatment within the 2 groups were compared using Kaplan-Meier methodology. RESULTS 253 patients received atrasentan, 221 received placebo; atrasentan resulted in a significant delay in TTP versus placebo (p=0.026). The median baseline BAP value was 31.5 ng/mL. Median TTP for patients whose baseline BAP < median was 168 days versus 85 days for patients with baseline BAP >/= median (p<0.001) and median time to death was 741 days vs 461 days for patients with BAP < median and >/= median, respectively (p<0.001). In patients with a baseline BAP >/= median, atrasentan significantly delayed TTP versus placebo, while in patients with baseline BAP < median, treatment effect did not reach significance (table). CONCLUSIONS These data confirm that high baseline BAP is predictive of early disease progression and reduced survival in HRPC patients with only bone metastases, independent of therapy. Atrasentan therapy significantly delayed TTP versus placebo in subjects with bone metastases only. It also significantly increased TTP in bony metastatic HRPC patients with a high baseline BAP. [Figure: see text] [Table: see text].

Relationship of bone alkaline phosphatase and quality of life in men with hormone refractory prostate cancer

4688 Background: Markers of osteoblastic activity, in particular bone alkaline phosphatase (BAP), increase in hormone refractory prostate cancer (HRPC) patients. BAP has been shown to be as valuable in predicting outcomes for men with HRPC as extent of bone disease, pain, or performance score. There are few data demonstrating prediction of quality of life (QOL) as a function of BAP. The relationship between BAP and QOL was explored in a study of atrasentan. METHODS Data from a randomized, double-blind, placebo-controlled phase 3 study of metastatic HRPC patients were analyzed (401 placebo, 408 atrasentan). Patients with a baseline BAP value and a baseline and final FACT-P score were analyzed and stratified according to baseline BAP value less than or equal to or greater than the median. Analysis of covariance (ANCOVA) was used to compare the mean change from baseline to final FACT-P assessment between baseline BAP stratified groups. In addition, ANCOVA was used to compare mean change from baseline to final BAP between treatment arms. RESULTS The median baseline BAP value was 25.2 ng/mL. Patients with baseline BAP level greater than the median experience a rapid clinically significant deterioration in disease-specific QOL compared to patients with baseline BAP level less than or equal to the median (table). The mean change from baseline to final is significantly smaller for atrasentan (13.19 ng/mL) versus placebo (33.86 ng/mL) (p=0.001). CONCLUSIONS HRPC patients with high BAP levels experience significant rapid deterioration in disease-specific QOL. Therapies such as atrasentan, which have significant effect on lowering BAP levels, may reduce the rapid decline in the QOL of HRPC patients. [Figure: see text] [Table: see text].

Prostate-specific antigen doubling time as a predictor of prostate cancer disease progression and survival

4554 Background: Prostate-specific antigen doubling time (PSADT) has been identified as a predictor of outcome in prostate cancer. Atrasentan, a potent, selective, oral endothelin A receptor antagonist, significantly decreased time to prostate-specific antigen (PSA) progression in a randomized, double-blind, placebo-controlled phase 2 trial in 271 men with metastatic HRPC. In that study, PSADT <4 mo was predictive of rapid disease progression and decreased survival in men with metastatic hormone-refractory prostate cancer (HRPC). Our objective was to confirm the utility of PSADT as a predictor of disease progression and survival in a larger population of subjects from combined phase 2 and 3 trials. METHODS Data from randomized, double-blind, placebo-controlled phase 2 and 3 trials of metastatic HRPC patients given either placebo or atrasentan (10 or 2.5 mg QD) were combined. Measurements from 982 patients with a minimum of 3 PSA values on treatment were analyzed. Data from all treatment arms were pooled and stratified by PSADT <4 mo vs ≥4 mo. Kaplan-Meier and Cox proportional hazard methodologies were used to compare time to disease progression (TTP) and survival between the PSADT <4 mo and PSADT ≥4 mo groups. RESULTS 982 patients were included in the analyses: 484 patients had a PSADT <4 mo and 498 had a PSADT ≥4 mo. Patients with a PSADT ≥4 mo showed a statistically significant longer median TTP (178 days), more than twofold greater than those with a PSADT <4 mo (85 days, log-rank p<0.001). Survival in patients with a PSADT <4 mo was significantly shorter than that in patients with a PSADT ≥4 mo (log-rank p<0.001). Median survival was 445 days for patients with PSADT <4 mo vs 746 days for patients with PSADT ≥4 mo. CONCLUSIONS These data confirm earlier findings that a PSADT <4 mo is predictive of early disease progression and reduced survival of men with metastatic HRPC, independent of therapy. [Table: see text].

Abstract CT339: Prospective molecular identification of ovarian cancer patients benefiting from PARP inhibitor (PARPi, rucaparib) maintenance therapy - reaching beyond germline BRCA mutations

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: PARP inhibitors are thought to be effective therapy for cancers with homologous recombination (HR) deficiency, best shown to date in patients (pts) with a germline BRCA (gBRCA) mutation. The Cancer Genome Atlas (TCGA) estimated ∼ 50% of high-grade serous ovarian carcinoma (OC) pts have an HR defect (HRD) due to a BRCA mutation (germline or somatic), other HR gene mutation, or another mechanism, e.g., BRCA1 promoter methylation. A randomized maintenance trial of olaparib in recurrent OC demonstrated a clinical benefit in both gBRCA-mutated and gBRCA-wild-type pts. Currently, the best molecular predictors of PARPi response (other than a BRCA mutation) are not known. Platinum sensitivity, often used as a surrogate predictive indicator for PARPi response, is inadequate. A better technique, such as molecular analysis of tumor tissue, could be a superior method for selection of pts for PARPi therapy. Methods: The rucaparib development plan in OC employs a unique strategy of conducting the key trials in parallel, allowing the Phase 2 (ARIEL2) to complete first so that a molecular HRD signature, associated with sub-groups most likely to benefit, can be prospectively applied to the final analysis of the Phase 3 pivotal trial (ARIEL3). ARIEL2 is an ongoing, single-arm, open-label biomarker study designed to refine the molecular signature associated with a response to rucaparib. Eligible pts (n=180) have relapsed, platinum-sensitive, high-grade OC and measurable disease. All pts undergo a pre-dose biopsy and provide archival tumor tissue. Tumor tissue HR status is assessed using Foundation Medicines next generation sequencing (NGS) platform and University of Washingtons BROCA-HR panel, with the current HRD algorithm developed using in vitro/in vivo and TCGA (and similar) bioinformatic data. The key efficacy analyses to be correlated with tumor HR status are response by RECIST v1.1, GCIG-defined CA-125 response, and PFS. The number of gBRCA pts is limited to maximize non-gBRCA response predictors. Exploratory biomarkers include assessment of tissue NHEJ competency (candidate predictive biomarker) and circulating tumor DNA (candidate efficacy surrogate). The optimized algorithm will then be tested prospectively in ARIEL3 (n=540), an international, randomized (2:1), double-blind, placebo-controlled maintenance trial in platinum-sensitive OC in remission after platinum-based therapy. The primary endpoint of ARIEL3 is PFS in molecularly-defined HRD subgroups as determined by NGS analysis of archival tumor tissue using the optimized algorithm, refined (as required) through ARIEL2.Conclusion: This pair of clinical trials seeks to determine prospectively the appropriate population, among all women with platinum-sensitive OC, who derive a meaningful benefit from PARPi treatment in the maintenance setting. Citation Format: Elizabeth Swisher, Iain McNeish, Robert L. Coleman, James D. Brenton, Scott H. Kaufmann, Andrew Allen, Mitch Raponi, Heidi Giordano, Lara Maloney, Jeffrey Isaacson, Jonathan A. Ledermann. Prospective molecular identification of ovarian cancer patients benefiting from PARP inhibitor (PARPi, rucaparib) maintenance therapy - reaching beyond germline BRCA mutations. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT339. doi:10.1158/1538-7445.AM2014-CT339

Bone alkaline phosphatase doubling time and outcome in metastatic hormone-refractory prostate cancer patients

4621 Background: Bone alkaline phosphatase (BAP) has been validated as a potential predictor of survival in hormone-refractory prostate cancer (HRPC) patients. Phase 2 results indicate that atrasentan, a potent, selective, oral endothelin A receptor antagonist, significantly attenuates BAP rise in HRPC patients. We tested the hypothesis that BAP response to treatment is predictive of time to disease progression (TTP) and survival. METHODS Data from a randomized, double-blind, placebo-controlled phase 3 trial of HRPC patients given either placebo or atrasentan 10 mg QD were combined. Values from 681 patients with at least 3 BAP values on treatment were analyzed. Data from treatment arms were pooled and stratified by the time over which BAP doubled (BAPDT) <12 mo vs ≥12 mo. Kaplan-Meier methodology was used to compare TTP (a composite of radiographic and clinical measures) and survival between the BAPDT <12 mo and ≥12 mo groups. In addition, frequency tables from the pooled data based on quartiles of time to BAP progression (TTBAP, ≥50% increase from nadir BAP value) vs quartiles of survival and TTP were analyzed, excluding subjects censored for both survival/TTP and TTBAP events. RESULTS 304 patients had BAPDT <12 mo; 377 had BAPDT ≥12 mo. Patients with BAPDT ≥12 mo had a significantly longer median TTP and a significantly longer time to death than those with BAPDT <12 mo (table). Frequency tables of TTBAP vs TTP and TTBAP vs survival also indicate that early TTBAP was associated with a faster TTP and a shorter survival duration. CONCLUSIONS These data show that a BAPDT <12 mo is predictive of early disease progression and reduced survival of HRPC patients, independent of therapy. This association warrants further exploration to determine whether BAP kinetics is a suitable surrogate endpoint for disease progression or survival. [Figure: see text] [Table: see text].