John F. Mahoney

Randomized, Double-Blind, Placebo-Controlled Phase III Trial Comparing Docetaxel and Prednisone With or Without Bevacizumab in Men With Metastatic Castration-Resistant Prostate Cancer: CALGB 90401

PURPOSE A randomized, placebo-controlled study based on preclinical and clinical data that supports the potential role of vascular endothelial growth factor in prostate cancer was performed to evaluate the addition of bevacizumab to standard docetaxel and prednisone therapy in patients with metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS Patients with chemotherapy-naive progressive mCRPC with Eastern Cooperative Oncology Group performance status ≤ 2 and adequate bone marrow, hepatic, and renal function were randomly assigned to receive docetaxel 75 mg/m(2) intravenously (IV) over 1 hour for 21 days plus prednisone 5 mg orally twice per day (DP) with either bevacizumab 15 mg/kg IV every 3 weeks (DP + B) or placebo. The primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), 50% decline in prostate-specific antigen, objective response (OR), and toxicity. RESULTS In total, 1,050 patients were randomly assigned. The median OS for patients given DP + B was 22.6 months compared with 21.5 months for patients treated with DP (hazard ratio, 0.91; 95% CI, 0.78 to 1.05; stratified log-rank P = .181). The median PFS time was superior in the DP + B arm (9.9 v 7.5 months, stratified log-rank P < .001) as was the proportion of patients with OR (49.4% v 35.5%; P = .0013). Grade 3 or greater treatment-related toxicity was more common with DP + B (75.4% v 56.2%; P ≤ .001), as was the number of treatment-related deaths (4.0% v 1.2%; P = .005). CONCLUSION Despite an improvement in PFS and OR, the addition of bevacizumab to docetaxel and prednisone did not improve OS in men with mCRPC and was associated with greater toxicity.

The effect of prior androgen synthesis inhibition on outcomes of subsequent therapy with docetaxel in patients with metastatic castrate-resistant prostate cancer: Results from a retrospective analysis of a randomized phase 3 clinical trial (CALGB 90401) (Alliance)

Preliminary data suggest a potential decreased benefit of docetaxel in patients with metastatic, castration‐resistant prostate cancer (mCRPC) who previously received abiraterone acetate, a novel androgen synthesis inhibitor (ASI). Cancer and Leukemia Group B (CALGB) trial 90401 (Alliance), a phase 3 trial in patients with mCRPC who received docetaxel‐based chemotherapy, offered the opportunity to evaluate effect of prior ketoconazole, an earlier generation ASI, on clinical outcomes after docetaxel.

Pharmacogenetic Discovery in CALGB (Alliance) 90401 and Mechanistic Validation of a VAC14 Polymorphism that Increases Risk of Docetaxel-Induced Neuropathy.

Purpose: Discovery of SNPs that predict a patients risk of docetaxel-induced neuropathy would enable treatment individualization to maximize efficacy and avoid unnecessary toxicity. The objectives of this analysis were to discover SNPs associated with docetaxel-induced neuropathy and mechanistically validate these associations in preclinical models of drug-induced neuropathy. Experimental Design: A genome-wide association study was conducted in metastatic castrate-resistant prostate cancer patients treated with docetaxel, prednisone and randomized to bevacizumab or placebo on CALGB 90401. SNPs were genotyped on the Illumina HumanHap610-Quad platform followed by rigorous quality control. The inference was conducted on the cumulative dose at occurrence of grade 3+ sensory neuropathy using a cause-specific hazard model that accounted for early treatment discontinuation. Genes with SNPs significantly associated with neuropathy were knocked down in cellular and mouse models of drug-induced neuropathy. Results: A total of 498,081 SNPs were analyzed in 623 Caucasian patients, 50 (8%) of whom experienced grade 3+ neuropathy. The 1,000 SNPs most associated with neuropathy clustered in relevant pathways including neuropathic pain and axonal guidance. An SNP in VAC14 (rs875858) surpassed genome-wide significance (P = 2.12 × 10−8, adjusted P = 5.88 × 10−7). siRNA knockdown of VAC14 in stem cell–derived peripheral neuronal cells increased docetaxel sensitivity as measured by decreased neurite processes (P = 0.0015) and branches (P < 0.0001). Prior to docetaxel treatment, VAC14 heterozygous mice had greater nociceptive sensitivity than wild-type litter mate controls (P = 0.001). Conclusions: VAC14 should be prioritized for further validation of its potential role as a predictor of docetaxel-induced neuropathy and biomarker for treatment individualization. Clin Cancer Res; 22(19); 4890–900. ©2016 AACR.

Bevacizumab and the risk of arterial and venous thromboembolism in patients with metastatic, castration‐resistant prostate cancer treated on Cancer and Leukemia Group B (CALGB) 90401 (Alliance)

Bevacizumab is associated with an increased risk of arterial thromboembolism (ATE); however, its effect on venous thromboembolism (VTE) remains controversial. Scant data exist on the factors that increase the risk of ATE/VTE in patients with prostate cancer. The authors investigated the association of bevacizumab treatment and clinical factors with ATE/VTE risk in patients who were treated on Cancer and Leukemia Group B (CALGB) trial 90401.

Phase I/II clinical trial of ALT-801, a T-cell receptor/IL-2 fusion protein, plus gemcitabine and cisplatin in urothelial cancer.

271 Background: ALT-801, a T-cell receptor/IL-2 fusion protein, activates NK and CD4+ lymphocytes to secrete IFN-gamma which re-polarizes tumor associated macrophages from M1 to M2 in various murine tumor models. CD8+ memory cells also acquire an innate immune phenotype and become expanded upon ALT-801 activation. Via this novel mechanism, ALT-801 mounted effective immune responses and maintained immunological memory against urothelial cancer in these models. Pretreatment chemotherapy eliminated myeloid-derived suppressive cells, potentiating the anti-tumor effects of ALT-801 (Wong, unpublished data). Previous clinical studies with ALT-801 (advanced malignancy; Fishman 2011 CCR 17:7765) and ALT-801 + cisplatin (melanoma; NCT01029873) showed anti-tumor activity in these settings. METHODS We evaluated co-administration of gemcitabine [G] (1000 mg/m2/dose, day 1 and 8) and cisplatin [C] (70 mg/m2/dose, day 1) with ALT-801 (escalating doses; days 3, 5, 8, 10) for three 21-day cycles, in patients with metastatic urothelial cancer. Those with at least stable disease after 3 courses could receive 4 additional weekly doses of ALT-801 alone. ALT-801 doses were planned at 0.04 to 0.12 mg/kg/dose in 5 cohorts with a 3+3 escalation design. RESULTS The dose-escalation is completed, with a recommended dose of ALT-801 of 0.06 mg/kg/dose. The best objective response rate (ORR, RECIST v1.1) among 5 chemo-naïve subjects was 100% (2 CR, 3 PR) and among 5 previously treated patients 60% (1 CR, 2 PR), for an overall total of 80% (3 CR, 5 PR, 1 SD, 1 PD). One of 2 patients who underwent radical cystectomy was confirmed pathologically free of tumor. Responding lesions included bulky and extensive liver and pulmonary metastases, and adenopathy. ALT-801 at the 0.06 mg/kg/dose level in this combination was adequately-tolerated. Grade 3/4 toxicities including neutropenia, thrombocytopenia and lymphopenia, appear consistent with known G, C, and ALT-801 effects. CONCLUSIONS ALT-801 is a novel and potentially active immunotherapy for urothelial cancer. More patients are in treatment on the open phase 2 expansion portion of the study (NCT01326871), and updated interim results are anticipated (CA097550). CLINICAL TRIAL INFORMATION NCT01326871.

Chemoradiation for organ preservation in the treatment of muscle-invasive bladder cancer

INTRODUCTION Standard therapy for muscle invasive bladder cancer includes neoadjuvant chemotherapy followed by radical cystectomy with urinary diversion. Three decades of interest in primary radiation and chemotherapy for bladder preservation have yielded mature that deserve closer examination. METHODS We reviewed the literature with an emphasis on outcomes from major clinical trials and prospective studies, while highlighting important aspects of effective treatment delivery and unanswered questions surrounding this approach. RESULTS There are no randomized trials comparing radical cystectomy to primary chemotherapy and radiation for bladder preservation, and future phase III comparisons are unlikely to be planned. Mature results from single institution protocols and phase II cooperative group trials demonstrate favorable disease-specific survival and bladder preservation rates. Here we review the results of relevant clinical trials, including cancer-related and patient functional outcomes. We outline multi-modal treatment specifics with respect to radiation delivery, incorporation of transurethral resection and chemotherapy selection, and future directions for optimizing results of non-operative strategies. CONCLUSIONS Combination chemotherapy and radiation can be used as an alternative to conserve the native bladder in appropriately selected patients, mirroring successful non-operative treatment paradigms used for organ-preservation for other cancer sites.

Bevacizumab and risk of arterial and venous thromboembolism in metastatic castration-resistant prostate cancer patients treated on Cancer and Leukemia Group B (CALGB) 90401 (Alliance)

Bevacizumab is associated with an increased risk of arterial thromboembolism (ATE); however, its effect on venous thromboembolism (VTE) remains controversial. Scant data exist on the factors that increase the risk of ATE/VTE in patients with prostate cancer. The authors investigated the association of bevacizumab treatment and clinical factors with ATE/VTE risk in patients who were treated on Cancer and Leukemia Group B (CALGB) trial 90401.

Abstract 2037: A discovery study to identify clinical and genetic risk factors for bevacizumab (BEV)-related gastrointestinal (GI) hemorrhage (HEM) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated on CALGB 90401 (Alliance)

Background: Treatment-related GI HEM is a major health concern with few known predictive risk factors. The objective of this analysis was to discover clinical and genetic factors that modulate GI HEM risk in a large randomized phase III study. Methods: Chemotherapy-naive mCRPC pts were randomized 1:1 to receive docetaxel and prednisone ± BEV once every 21 days for up to two years (N = 1008). Cause-specific time-to-event analysis using a Cox regression model was used to investigate the association between grade 2+ GI HEM (designated as at least “probably” related to therapy) and BEV, age, history (hx) of peptic ulcer disease (PUD), hx of HEM, antiplatelet/anticoagulant use, hx of smoking, and hemoglobin. Genetically-defined Caucasian pts who provided consent for the genomic companion study (CALGB 60404) were genotyped using the Illumina HumanHap610-Quad platform (N = 616). Log rank test was used to investigate the association of single nucleotide polymorphisms (SNPs) and GI HEM, and results were adjusted for significant clinical covariates. Results: The overall incidence of grade 2+ GI HEM was 9.5% (48/503) and 3.8% (19/505) in the BEV and placebo arms, respectively. Of the clinical covariates, only BEV (HR = 5.77; 95% CI 2.20-15.11; P Conclusion: BEV, age, and one putative intergenic SNP (rs1478947) were associated with cause-specific GI HEM risk in CALGB 90401. The effect of rs1478947 appears to be specific to pts receiving BEV. Although the mechanism by which rs1478947 increases GI HEM risk remains unclear, rs1478947 is in complete LD (r2 = 1) with rs1478948, variations of which may alter the binding motif for transcription factor hepatocyte nuclear factor-4 (HNF4). HNF4 exerts a major regulatory effect on clotting factor VII (fVII) expression and function. Altered binding of HNF4 to fVII promoter may result in reduced fVII function and an increased risk of bleeding. It is unclear how much weight each identified risk factor contributes to the overall incidence of GI HEM, which in absolute terms was not dramatically different between arms. Exploratory studies from large trials of BEV-treated pts are needed to better understand the genetic contribution to and biological basis of GI HEM. Support: U10CA180821 Citation Format: Jai N. Patel, Chen Jiang, Kouros Owzar, Daniel L. Hertz, Flora A. Mulkey, William K. Kelly, Susan Halabi, Yoichi Furukawa, Cameron Lassiter, Susan G. Dorsey, Paula N. Friedman, Eric J. Small, Michael A. Carducci, John F. Mahoney, Michael J. Kelley, Yusuke Nakamura, Michiaki Kubo, Mark J. Ratain, Michael J. Morris, Howard L. McLeod. A discovery study to identify clinical and genetic risk factors for bevacizumab (BEV)-related gastrointestinal (GI) hemorrhage (HEM) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated on CALGB 90401 (Alliance). [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 2037.

Castrate Resistant Prostate Cancer: Systemic Chemotherapy and a System Problem

Castrate resistant prostate cancer remains a significant problem, despite the introduction of many new anticancer agents in recent years. Of importance, establishing true castration resistance, confirmed biochemically, is a sine qua non of effective management. It should also be recognized that stage migration has occurred, with more patients being offered treatment for PSA-only castration-resistant disease, and with the increased radiological surveillance of patients after definitive local treatment, and the goal posts have widened due to increased emphasis on patient-reported outcomes and progression-free survival. That said, it is clear that, in addition to established cytotoxic agents, several new options of systemic therapy are active in castrate resistant prostate cancer, including ixabepilone, cabazitaxel, cabozantanib, and the current focus seems to be shifting somewhat from cytotoxic to targeted therapeutics.

Bevacizumab and the risk of arterial and venous thromboembolism in patients with metastatic, castration-resistant prostate cancer treated on Cancer and Leukemia Group B (CALGB) 90401 (Alliance): ATE/VTE Risk Factors in Prostate Cancer

Bevacizumab is associated with an increased risk of arterial thromboembolism (ATE); however, its effect on venous thromboembolism (VTE) remains controversial. Scant data exist on the factors that increase the risk of ATE/VTE in patients with prostate cancer. The authors investigated the association of bevacizumab treatment and clinical factors with ATE/VTE risk in patients who were treated on Cancer and Leukemia Group B (CALGB) trial 90401.