Phase II Trial of Abiraterone Acetate Plus Prednisone in Black Men With Metastatic Prostate Cancer.

LESSONS LEARNED: The safety and activity findings of abiraterone acetate plus prednisone treatment in black men with mCRPC were similar to results from previously conducted studies with largely white populations.Poor trial accrual continues to be a challenge in black men with mCRPC and further efforts are needed to address such underrepresentation. BACKGROUND: Self-identified black men have higher incidence and mortality from prostate cancer in the United States compared with white men but are dramatically underrepresented in clinical trials exploring novel therapies for metastatic castration-resistant prostate cancer (mCRPC). METHODS: Black men with mCRPC were treated with abiraterone acetate (AA), 1,000 mg daily, and prednisone (P), 5 mg twice daily. The primary objective was to determine antitumor activity (defined by a ≥30% decline in prostate-specific antigen [PSA] level) and to correlate germline polymorphisms in androgen metabolism genes with antitumor activity. Secondary objectives included determining safety, post-treatment changes in measurable disease, and time to disease progression. RESULTS: From April 2013 to March 2016, a total of 11 black men were enrolled and received AA plus P (AA+P); 7 of 10 evaluable patients were docetaxel naive. Post-treatment declines in PSA level of ≥30% were achieved in 90% of patients. The side effect profile was consistent with prior clinical trials exploring AA+P in mCRPC. Due to poor accrual, the study was closed prematurely with insufficient sample size for the planned pharmacogenetic analyses. CONCLUSION: In this small prospective study terminated for poor accrual, the safety and activity of AA+P in black men with mCRPC was similar to that reported in prior studies exploring AA in largely white populations. Further efforts are needed to address underrepresentation of black men in mCRPC trials.

Phase Ib/II trial of gemcitabine, cisplatin, and lenalidomide as first-line therapy in patients with metastatic urothelial carcinoma.

BACKGROUND: Outcomes with current chemotherapy in metastatic urothelial carcinoma (MUC) remain poor. Lenalidomide, an antiangiogenic and immunomodulatory agent, enhances the effects of chemotherapy in preclinical studies. In this phase Ib/II study, we sought to determine a tolerable dose of lenalidomide in combination with gemcitabine and cisplatin (GCL) in patients with MUC and to explore the safety and activity of this regimen. METHODS: Patients with chemotherapy-naïve MUC received gemcitabine 1,000 mg/m(2) on days 1 and 8 and cisplatin 70 mg/m(2) on day 1 every 21 days. In phase Ib, there were four planned escalating dose levels of lenalidomide (10, 15, 20, and 25 mg) daily on days 1-14. RESULTS: Seven patients received GCL in phase Ib. The dose of lenalidomide was not escalated beyond 10 mg because of cytopenias requiring repeated dose delays and reductions. Two additional patients were enrolled in phase II, but the study was ultimately terminated due to poor tolerability and slow accrual. The most frequent grade ≥ 3 adverse events were cytopenias and diarrhea. Three of the nine patients experienced an objective response (one complete response, two partial responses). CONCLUSION: Chronic administration of the GCL regimen was poorly tolerated because of additive and cumulative myelosuppression.

Telemedicine-Enabled Clinical Trial of Metformin in Patients With Prostate Cancer.

PURPOSE: Clinical trials are critical to informing cancer care but often are hampered by slow accrual and lack of generalizability because of poor geographic accessibility. We tested the feasibility of replacing onsite study visits with telemedicine visits in a prospective clinical trial. METHODS: Castration-naïve patients with prostate cancer and a rising serum prostate-specific antigen after definitive local therapy were eligible. Patients were required to have a single onsite visit for enrollment. Study treatment consisted of oral metformin 850 mg daily for 1 month followed by 850 mg twice daily for 5 months. Telehealth video visits (televisits) were conducted monthly by using a Health Insurance Portability and Accountability Act-compliant smartphone application. The primary objective was to determine the feasibility of telemedicine-enabled study visits. Secondary objectives were defining safety, anticancer activity, quality of life, and patient satisfaction. RESULTS: Fifteen patients with a median age of 68 years (range, 57 to 83 years) and median one-way driving time to the study center of 71 minutes (range, 12 to 147 minutes) were enrolled. The patients completed 84 eligible televisits (completion rate, 100%; 95% CI, 0.80 to 1). Diarrhea was the most common adverse event but was limited to grade 1 in severity; a single patient experienced grade ≥ 3 adverse events. Seven patients (46.7%; 95% CI, 24.8% to 69.9%) had a ≤ 20% increase in prostate-specific antigen relative to baseline. Patients agreed or strongly agreed that they would participate in a telemedicine-enabled clinical trial in the future. CONCLUSION: To our knowledge, this interventional oncology clinical trial is the first to be conducted through telemedicine. Telemedicine-enabled trials are feasible and may overcome geographic barriers to trial participation. Metformin was generally well tolerated but associated with modest anticancer activity.

Phase 2 trial of the topoisomerase II inhibitor, amrubicin, as second-line therapy in patients with metastatic urothelial carcinoma.

PURPOSE: The purpose of this investigator-initiated multicenter phase II study was to determine the activity of the third-generation synthetic anthracycline, amrubicin, administered as second-line therapy in patients with advanced urothelial carcinoma. METHODS: Patients with progressive metastatic urothelial cancer despite first-line chemotherapy were eligible for enrollment. Amrubicin was initially administered at a dose of 40 mg/m(2)/day daily × 3 every 21 days, and the dose was subsequently reduced to 35 mg/m(2)/day daily × 3 every 21 days. Prophylactic granulocyte colony-stimulating factor was administered to all patients, and prophylactic antibiotics were administered to patients at high risk of febrile neutropenia. Treatment was administered for up to six cycles in the absence of intolerable toxicity or disease progression. The primary endpoint was the objective response rate. RESULTS: A total of 22 patients were enrolled. Among the first three patients enrolled, all developed grade 4 neutropenia and one patient died of neutropenic sepsis. The starting dose of amrubicin was subsequently reduced, there were no further episodes of febrile neutropenia, and only one patient required a subsequent dose reduction. The most common adverse events were hematologic; grade ≥3 neutropenia occurred in 27 %, and other grade ≥3 adverse events were uncommon. Partial responses were achieved in three patients [13.6, 95 % confidence interval (CI) 0-28 %), while stable disease was the best response in 12 patients (54.5, 95 % CI 33.7-75.3 %). The trial was closed prematurely due to a development decision by the funder. CONCLUSIONS: Amrubicin as second-line therapy in advanced urothelial carcinoma is associated with modest single-agent activity. While there remains a role for the introduction of novel cytotoxic agents in the management of metastatic urothelial cancer, optimal development of such therapies will likely require patient selection biomarkers.

Phase Ib study of dovitinib in combination with gemcitabine plus cisplatin or gemcitabine plus carboplatin in patients with advanced solid tumors.

PURPOSE: Dovitinib is a small molecule kinase inhibitor with activity against the fibroblast growth factor and vascular endothelial growth factor receptor families. The purpose of this phase Ib study was to define the recommended phase 2 dose of the combinations of gemcitabine and cisplatin or gemcitabine and carboplatin plus dovitinib. METHODS: Patients with advanced solid tumors were enrolled in two parallel dose escalation arms (cisplatin- or carboplatin-based regimens). Treatment was administered with gemcitabine (1,000 mg/m(2) on days 1 and 8), cisplatin (70 mg/m(2)), or carboplatin (AUC 5) on day 1, and dovitinib (orally on days 1-5, 8-12, and 15-19), every 21 days. The starting dose of dovitinib was 300 mg and was dose escalated in successive cohorts using 3 + 3 dose escalation rules. RESULTS: Fourteen patients with advanced solid tumors were enrolled, five to the cisplatin arm and nine to the carboplatin arm. Patients enrolled in the cisplatin arm received a median of two cycles of treatment (range 1-5), and patients enrolled in the carboplatin arm received a median of one cycle of treatment (range 1-4). There were no protocol-defined dose-limiting toxicities in the cisplatin arm. However, the cohort was closed due to the need for frequent dose delays and/or reductions and two patients experiencing severe thromboembolic events. There were two dose-limiting toxicities in the carboplatin arm at the starting dose level of dovitinib (both prolonged neutropenia), and the dose of dovitinib was de-escalated to 200 mg. Two additional dose-limiting toxicities (prolonged neutropenia and febrile neutropenia) occurred in the lower dose cohort, and the study was closed. No patients achieved an objective response to treatment. CONCLUSIONS: Dovitinib in combination with gemcitabine plus cisplatin or gemcitabine plus carboplatin was poorly tolerated due to myelosuppression.