Overall survival and updated progression-free survival outcomes in a randomized phase II study of combination cediranib and olaparib versus olaparib in relapsed platinum-sensitive ovarian cancer.

BACKGROUND: Olaparib is a poly(ADP-ribose) polymerase inhibitor and cediranib is an oral anti-angiogenic. In the primary analysis of this phase II study, combination cediranib/olaparib improved progression-free survival (PFS) compared with olaparib alone in relapsed platinum-sensitive ovarian cancer. This updated analysis was conducted to characterize overall survival (OS) and update PFS outcomes. PATIENTS AND METHODS: Ninety patients were enrolled to this randomized, open-label, phase II study between October 2011 and June 2013 across nine United States-based academic centers. Data cut-off was 21 December 2016, with a median follow-up of 46 months. Participants had relapsed platinum-sensitive ovarian cancer of high-grade serous or endometrioid histology or had a deleterious germline BRCA1/2 mutation (gBRCAm). Participants were randomized to receive olaparib capsules 400 mg twice daily or cediranib 30 mg daily and olaparib capsules 200 mg twice daily until disease progression. RESULTS: In this updated analysis, median PFS remained significantly longer with cediranib/olaparib compared with olaparib alone (16.5 versus 8.2 months, hazard ratio 0.50; P = 0.007). Subset analyses within stratum defined by BRCA status demonstrated statistically significant improvement in PFS (23.7 versus 5.7 months, P = 0.002) and OS (37.8 versus 23.0 months, P = 0.047) in gBRCA wild-type/unknown patients, although OS was not statistically different in the overall study population (44.2 versus 33.3 months, hazard ratio 0.64; P = 0.11). PFS and OS appeared similar between the two arms in gBRCAm patients. The most common CTCAE grade 3/4 adverse events with cediranib/olaparib remained fatigue, diarrhea, and hypertension. CONCLUSIONS: Combination cediranib/olaparib significantly extends PFS compared with olaparib alone in relapsed platinum-sensitive ovarian cancer. Subset analyses suggest this margin of benefit is driven by PFS prolongation in patients without gBRCAm. OS was also significantly increased by the cediranib/olaparib combination in this subset of patients. Additional studies of this combination are ongoing and should incorporate analyses based upon BRCA status. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT0111648.

A phase II trial of the epothilone B analog, BMS-247550, in patients with previously treated advanced colorectal cancer.

BACKGROUND: The epothilone B analog, BMS-247550, is a non-taxane microtubulin-stabilizing agent with preclinical activity in taxane-resistant cell lines and phase I activity in colorectal cancer. We conducted a phase II study of single-agent BMS-247550 in advanced colorectal cancer patients who had disease progression following treatment with irinotecan-5-fluorouracil-leucovorin (IFL). PATIENTS AND METHODS: Patients were required to have histologically or cytologically confirmed advanced or metastatic colorectal cancer; progressed on or after chemotherapy with IFL; Eastern Cooperative Oncology Group performance status < or =1; peripheral neuropathy grade < or =1; and adequate laboratory parameters. BMS-247550 40 mg/m(2) was administered intravenously over 3 h every 3 weeks. Patients were evaluated for response every 6 weeks. RESULTS: Twenty-five patients were enrolled; all were evaluable for toxicity and 23 were evaluable for response. There were no complete or partial responses. Thirteen patients (56%) had stable disease after two cycles of therapy; five patients (20%) received six or more cycles. The median time to progression was 11 weeks; median overall survival was 36 weeks. There was considerable grade 3/4 hematological toxicity, including neutropenia (48%) and leukopenia (36%). Grade 3/4 non-hematological toxicities included grade 3 hypersensitivity reaction (12%) and peripheral neuropathy (20%). CONCLUSIONS: Single-agent BMS-247550 (40 mg/m(2)) administered every 21 days demonstrated no activity in advanced colorectal cancer. Peripheral neuropathy was treatment-limiting.

Gemcitabine, paclitaxel, and trastuzumab in metastatic breast cancer.

A phase II trial evaluated the effectiveness and toxicity of combination paclitaxel (Taxol), gemcitabine (Gemzar), and trastuzumab (Herceptin) as first-line therapy for patients with newly diagnosed HER2-overexpressing metastatic breast cancer. To date, 27 patients have received paclitaxel at 175 mg/m2 over 3 hours on day 1, plus gemcitabine at 1,200 mg/m2 on days 1 and 8, plus trastuzumab at a 4-mg/kg loading dose on day 1, followed by 2 mg/kg weekly. Treatment cycles were repeated every 21 days. Responding or stable patients who had received six cycles of combination therapy continued single-agent trastuzumab weekly until disease progression. Treatment was generally well tolerated with grade 4 toxicity limited to myelosuppression. In all, 12 patients have achieved a partial remission and 1 patient had progressive disease; 14 patients continue treatment and have not yet been evaluated for response. Combination treatment with paclitaxel, gemcitabine, and trastuzumab is well tolerated and appears to be highly active. Accrual will continue to a total enrollment of 46 patients.

High-dose cimetidine for the treatment of metastatic renal cell carcinoma. A Hoosier Oncology Group study.

The Hoosier Oncology Group evaluated cimetidine in 42 patients with metastatic renal cell carcinoma. There were two complete remissions that lasted for 26 and 33+ months in 38 evaluable patients. There were no partial remissions. Toxicity was minimal. Patients with renal cell carcinoma can occasionally respond to cimetidine with long-term remission.