A phase II evaluation of elesclomol sodium and weekly paclitaxel in the treatment of recurrent or persistent platinum-resistant ovarian, fallopian tube or primary peritoneal cancer: An NRG oncology/gynecologic oncology group study.

OBJECTIVE: Preclinical data suggest elesclomol increases oxidative stress and enhances sensitivity to cytotoxic agents. The objective of this prospective multicenter phase 2 trial was to estimate the activity of IV elesclomol plus weekly paclitaxel in patients with platinum-resistant recurrent ovarian, tubal or peritoneal cancer through the frequency of objective tumor responses (ORR). METHODS: Patients with measurable disease, acceptable organ function, performance status ≤ 2, and one prior platinum containing regimen were eligible. A two-stage design was utilized with a target sample size of 22 and 30 subjects, respectively. Prior Gynecologic Oncology Group studies within the same population involving single agent taxanes showed an ORR of approximately (20%) and served as a historical control for direct comparison. The present study was designed to determine if the regimen had an ORR of ≥40% with 90% power. RESULTS: Fifty-eight patients were enrolled, of whom 2 received no study treatment and were inevaluable. The median number of cycles was 3 (268 total cycles, range 1-18). The number of patients responding was 11 (19.6%; 90% CI 11.4% to 30.4%) with one complete response. The median progression-free survival and overall survival was 3.6 months and 13.3 months, respectively. The median ORR duration was 9.2 months. Percentages of subjects with grade 3 toxicity included: Neutropenia 9%; anemia 5%; metabolic 5%; nausea 4%; infection 4%; neurologic (mostly neuropathy) 4%; and vascular (mostly thromboembolism) 4%. There were no grade 4 toxicities reported. CONCLUSIONS: This combination was well tolerated but is unworthy of further investigation based on the proportion responding [ClinicalTrials.gov Identifier: NCT00888615].

Randomized phase II trial of bevacizumab plus everolimus versus bevacizumab alone for recurrent or persistent ovarian, fallopian tube or peritoneal carcinoma: An NRG oncology/gynecologic oncology group study.

PURPOSE: Bevacizumab (BV) monotherapy leads to compensatory upregulation of multiple signaling pathways, resulting in mTOR activation. We evaluated combining BV and everolimus (EV), an mTOR kinase inhibitor, to circumvent BV-resistance in women with recurrent or persistent ovarian, fallopian tube or primary peritoneal cancer (OC). PATIENTS AND METHODS: Eligible OC patients had measurable (RECIST1.1) or detectable disease, 1-3 prior regimens, performance status (PS) 0-2, and no prior m-TOR inhibitor. All patients received BV 10 mg/kg IV every 2wks. Patients were randomized (1:1) to oral EV (10 mg daily) or placebo stratified by platinum-free interval (PFI), measurable disease and prior BV. Primary endpoint was progression-free survival (PFS); secondary endpoints included safety and response. RESULTS: 150 patients were randomized to BV with (n = 75) and without (n = 75) EV. Arms were well-balanced for age (median 63: range 28-92), PS (0: 73%, 1-2: 27%), prior regimens (1: 37%, 2: 47%, 3: 16%), prior BV (11%), PFI (<6mos: 65%) and measurable disease (81%). The BV + EV vs BV median PFS was 5.9 vs 4.5 months (hazard ratio [HR] 0.95 (95% CI, 0.66-1.37, p = 0.39)). Median OS was 16.6 vs 17.3 months (HR 1.16 (95% CI, 0.72-1.87, p = 0.55). Objective measurable responses were higher with BV + EV (22% vs 12%). Study removal due to toxicity was higher with BV + EV (29% vs 12%). Toxicity (≥grade 3) from BV + EV were "other GI (mucositis)" (23 vs 1%) and "metabolic/nutrition" (19 vs. 7%); common ≥ grade 2 toxicities with BV + EV were cytopenia, nausea, fatigue and rash. CONCLUSION: The combination regimen (BV + EV) did not significantly reduce the hazard of progression or death relative to BV and was associated with higher rates of adverse events and study discontinuation when compared to BV alone.

A phase II evaluation of brivanib in the treatment of persistent or recurrent carcinoma of the cervix: An NRG Oncology/Gynecologic Oncology Group study.

BACKGROUND: Brivanib is an oral, tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR). We studied its efficacy and tolerability in persistent or recurrent cervical cancer patients. METHODS: Eligible patients had at least one prior cytotoxic regimen for recurrence and with measurable disease. Brivanib 800mg was administered orally every day (1cycle=28days) until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) >6months and objective tumor response. RESULTS: Of 28 eligible and evaluable women enrolled, 11 (39%) had primary surgery and 25 (89%) had prior radiation. Eighteen (64%) received one prior cytotoxic treatment and 10 (36%) had 2 prior regimens. Twelve (43%) had >2cycles of brivanib with 4 (14%) receiving >10cycles (range: 1-20). Seven (25%) patients had PFS >6months (90% CI: 7.3%-33.9%). Two (7%) (90% CI: 1.3%-20.8%) patients had partial tumor response with duration of 8 and 22months and 12 (43%) had stable disease. The median PFS was 3.2months (90% CI: 2.1-4.4). The median overall survival was 7.9months (90% CI: 6.1-11.7). More common grade 3 adverse events were hypertension, anemia, hyponatremia, hyperglycemia, elevated liver enzymes, nausea, headache, and colon hemorrhage. Grade 4 adverse events included sepsis and hypertension. CONCLUSIONS: Based on early results of this phase II trial, brivanib was well tolerated and demonstrated sufficient activity after first stage but trial was stopped due to lack of drug availability.

Ribonucleotide reductase inhibition restores platinum-sensitivity in platinum-resistant ovarian cancer: a Gynecologic Oncology Group Study.

BACKGROUND: The potent ribonucleotide reductase (RNR) inhibitor 3-aminopyridine-2-carboxyaldehyde-thiosemicarbazone (3-AP) was tested as a chemosensitizer for restored cisplatin-mediated cytotoxicity in platinum-resistant ovarian cancer. METHODS: Preclinical in vitro platinum-resistant ovarian cancer cell survival, RNR activity, and DNA damage assays were done after cisplatin or cisplatin plus 3-AP treatments. Six women with platinum-resistant ovarian cancer underwent four-day 3-AP (96 mg/m(2), day one to four) and cisplatin (25 mg/m(2), day two and three) infusions every 21 days until disease progression or adverse effects prohibited further therapy. Pre-therapy ovarian cancer tissues were analyzed by immunohistochemistry for RNR subunit expression as an indicator of cisplatin plus 3-AP treatment response. RESULTS: 3-AP preceding cisplatin exposure in platinum-resistant ovarian cancer cells was not as effective as sequencing cisplatin plus 3-AP together in cell survival assays. Platinum-mediated DNA damage (i.e., γH2AX foci) resolved quickly after cisplatin-alone or 3-AP preceding cisplatin exposure, but persisted after a cisplatin plus 3-AP sequence. On trial, 25 four-day overlapping 3-AP and cisplatin cycles were administered to six women (median 4.2 cycles per patient). 3-AP-related methemoglobinemia (range seven to 10%) occurred in two (33%) of six women, halting trial accrual. CONCLUSIONS: When sequenced cisplatin plus 3-AP, RNR inhibition restored platinum-sensitivity in platinum-resistant ovarian cancers. 3-AP (96 mg/m(2)) infusions produced modest methemoglobinemia, the expected consequence of ribonucleotide reductase inhibitors disrupting collateral proteins containing iron. TRIAL REGISTRY: ClinicalTrials.gov NCT00081276.

Phase II trial of nab-paclitaxel in the treatment of recurrent or persistent advanced cervix cancer: A gynecologic oncology group study.

BACKGROUND: Metastatic and recurrent, platinum resistant cervix cancer has an extremely poor prognosis. The Gynecologic Oncology Group has studied >20 cytotoxic drugs or drug combinations in the second-line, phase II setting of advanced, drug resistant cervix cancer. METHODS: Nanoparticle, albumin-bound paclitaxel (nab-paclitaxel) was administered at 125 mg/m(2) IV over 30 minutes on days 1, 8 and 15 of each 28 day cycle to 37 women with metastatic or recurrent cervix cancer that had progressed or relapsed following first-line cytotoxic drug treatment. A flexible, 2-stage accrual design that allowed stopping early for lack of treatment activity was utilized. Because of slow patient accrual, the second stage was not completed. RESULTS: Of 37 patients enrolled, 2 were ineligible due to no prior cytotoxic chemotherapy, which left 35 eligible patients evaluable for response and tolerability. All of the eligible patients had 1 prior chemotherapy regimen and 27 of them had prior radiation therapy with concomitant cisplatin. The median number of nab-paclitaxel cycles were 4 (range 1-15). Ten (28.6%; CI 14.6%-46.3%) of the 35 patients had a partial response and another 15 patients (42.9%) had stable disease. The median progression-free and overall survival were 5.0 and 9.4 months, respectively. The only NCI CTCAE grade 4 event was neutropenia in 2 patients (5.7%) which resolved following dose reduction. Grade 3 neurotoxicity was reported in 1 (2.9%) patient and resolved to grade 2 following dose discontinuation. CONCLUSIONS: Nab-paclitaxel has considerable activity and moderate toxicity in the treatment of drug resistant, metastatic and recurrent cervix cancer.

Docetaxel plus trabectedin appears active in recurrent or persistent ovarian and primary peritoneal cancer after up to three prior regimens: a phase II study of the Gynecologic Oncology Group.

OBJECTIVE: This study aims to estimate the activity of docetaxel 60mg/m(2) IV over 1h followed by trabectedin 1.1mg/m(2) over 3h with filgrastim, pegfilgrastim, or sargramostim every 3weeks (one cycle). METHODS: Patients with recurrent and measurable disease, acceptable organ function, PS≤2, and ≤3 prior regimens were eligible. A two-stage design was utilized with a target sample size of 35 subjects per stage. Another Gynecologic Oncology Group study within the same protocol queue involving a single agent taxane showed a response rate (RR) of (16%) (90% CI 8.6-28.5%) and served as a historical control for direct comparison. The present study was designed to determine if the current regimen had an RR of ≥36% with 90% power. RESULTS: Seventy-one patients were eligible and evaluable (prior regimens: 1=28%, 2=52%, 3=20%). The median number of cycles was 6 (438 total cycles, range 1-22). The number of patients responding was 21 (30%; 90% CI 21-40%). The odds ratio for responding was 2.2 (90% 1-sided CI 1.07-Infinity). The median progression-free survival and overall survival were 4.5months and 16.9months, respectively. The median response duration was 6.2months. Numbers of subjects with grade 3/4 toxicity included neutropenia 7/14; constitutional 8/0; GI (excluding nausea/vomiting) 11/0; metabolic 9/1; pain 6/0. There were no treatment-related deaths nor cases of liver failure. CONCLUSIONS: This combination was well tolerated and appears more active than the historical control of single agent taxane therapy in those with recurrent ovarian and peritoneal cancer after failing multiple lines of chemotherapy. Further study is warranted.

Evaluation of pemetrexed (Alimta, LY231514) as second line chemotherapy in persistent or recurrent carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group.

OBJECTIVE: To estimate the anti-tumor activity of pemetrexed in patients with advanced or recurrent carcinoma of the cervix that failed on higher priority treatment protocols and to determine the nature and degree of toxicity. METHODS: A multicenter Phase II trial was conducted by the Gynecologic Oncology Group (GOG). Patients must have had advanced or recurrent measurable carcinoma of the cervix, and failed one prior chemotherapy regimen. Pemetrexed at a dose of 900 mg/m(2) was to be administered as an IV infusion over 10 min every 21 days. RESULTS: From July 6, 2004 to April 3, 2006, twenty-nine patients were entered by ten member institutions of the GOG. Two patients did not receive treatment and thus were inevaluable. A total of 128 cycles were administered with 37% of patients receiving six or more cycles. The treatment was well tolerated overall. More serious toxicities (grade 3 and 4) included anemia in 41%, leukopenia in 30%, neutropenia in 26%, and infection in 26%. No treatment related deaths were reported. Four patients (15%) had partial responses with a median response duration of 4.4 months. The response rate for non-radiated or radiated disease sites was 25% and 7% respectively. Sixteen patients (59%) had stable disease and seven (26%) patients had increasing disease. Median progression free survival (PFS) was 3.1 months and overall survival (OS) was 7.4 months. CONCLUSION: Pemetrexed at this dose and schedule showed moderate activity against advanced or recurrent cervical cancer that has failed prior chemotherapy. Data from other tumor sites has suggested synergy between pemetrexed and cisplatin and should be considered for further study.

Randomised phase II study of docetaxel plus vandetanib versus docetaxel followed by vandetanib in patients with persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma: SWOG S0904.

BACKGROUND: Vandetanib is an oral tyrosine kinase inhibitor of VEGFR-2/3, EGFR and RET, which has demonstrated clinical activity as a single agent and in combination with taxanes. We explored the efficacy, safety and toxicity of docetaxel and vandetanib in women with recurrent ovarian cancer (OC). METHODS: Women with refractory or progressive OC were randomised 1:1 to docetaxel (75 mg/m(2), IV)+vandetanib (100mg daily, PO, D+V) or docetaxel (75 mg/m(2), D). Up to three additional cytotoxic regimens for recurrence and prior anti-angiogenic agents (as primary therapy) were allowed. The primary end-point was progression free survival (PFS). The study had 84% power to detect a PFS hazard ratio of 0.65, using a one-sided P of 0.1. This corresponds to an increase in median PFS from 3.6 months to 5.6 months. Patients progressing on D were allowed to receive single agent vandetanib (D → V). RESULTS: 131 Patients were enrolled; two were excluded. 16% had received prior anti-angiogenic therapy. The median PFS estimates were 3.0 mos (D+V) versus 3.5 (D); HR: 0.99 (80% CI: 0.79-1.26). 61 Patients on D+V were assessable for toxicity; 20(33%) had treatment-related Grade (G) 4 events, primarily haematologic. Similarly, 17 (27%) of 64 patients receiving D had G4 events, primarily haematologic. 27 Evaluable patients crossed-over to V. 1/27(4%) experienced a G4 event. G3 diarrhoea was observed in 4% D → V patients. Median OS was 14 mos (D+V) versus 18 mos (D → V); HR(OS): 1.25 (80% CI: 0.93-1.68). Crossover vandetanib response was 4% (1/27 evaluable patients). High plasma IL-8 levels were associated with response to D+V. CONCLUSIONS: Combination docetaxel+vandetanib did not prolong PFS relative to docetaxel alone in OC patients. No unexpected safety issues were identified.