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Phase II trial of pemetrexed and carboplatin in platinum-sensitive recurrent ovarian, fallopian tube, and primary peritoneal cancer
Abstracts / Gynecologic Oncology 133 (2014) 2–207
After a median follow-up of 6 months, there have been 2 recurrences (13.3%) in the VG vs 4 recurrences (25%) in the CG (P = 0.65). Conclusions: The maximally administered dose was well tolerated. In contrast to other FOLR-α-directed cytotoxic agents, the E39 vaccine holds the promise of an immunologic response and memory against FOLR-α-expressing recurrences without toxicity.
doi:10.1016/j.ygyno.2014.03.118
99 - Featured Poster Effect of BRCA1 and XPG mutations on treatment response to trabectedin and pegylated liposomal doxorubicin in subjects with advanced ovarian cancer: Exploratory analysis of phase III OVA-301 study B.J. Monk1, P. Ghatage2, T. Parekh3, E. Henitz3, R. Knoblauch3, A. Soto Matos-Pita4, A. Nieto4, Y.C. Park3, D. Ricci3, A. Poveda5. 1University of Arizona Cancer Center, Phoenix, AZ, USA, 2Tom Baker Cancer Centre, Calgary, AB, Canada, 3Janssen Research & Development, Raritan, NJ, USA, 4PharmaMar SA, Madrid, Spain, 5Fundación Instituto Valenciano de Oncología, Valencia, Spain. Objectives: Both trabectedin (T) and pegylated liposomal doxorubicin (PLD) induce double-strand DNA breaks. Repair of this sublethal DNA damage is central to clinical drug resistance and involves both BRCA1 and XPG. We investigated the association of BRCA1/XPG mutations (mut) with response rate (RR), progression-free survival (PFS), and overall survival (OS) in a subset of subjects from a phase III clinical trial (OVA-301) comparing the efficacy and safety of T + PLD vs PLD alone in 672 subjects with recurrent ovarian cancer (ROC). Methods: A candidate gene array was designed to detect 59 functional mutations based on characterization in BIC database. Association of BRCA1/XPG mutation status with selected clinical endpoints was determined using 2-sided log rank test (PFS and OS) or Fisher's exact test (RR) at 0.05 significance. Germline DNA samples from 264 women who failed first-line platinum-based chemotherapy, randomized (1:1) to T + PLD or only PLD were used for analysis. Results: Overall, 41/264 subjects (16%) had BRCA1mut (T + PLD: n = 24 [18%]; PLD: n = 17 [13%]) and 17/264 (6%) had XPGmut (C/C) (T + PLD: n = 8 [6%]; PLD: n = 9 [7%]). Subjects with BRCA1mut had improved RR vs BRCA1wt (37% vs 19% assessed by independent radiologist [IR]). Among BRCA1mut subjects, T + PLD-treated had longer OS vs PLD-treated (median OS 27.3 vs 18.7 months, P = 0.0093). Among BRCA1wt subjects, OS was not statistically different (median OS 27.3 vs 23 months, P = 0.4966). Overall, BRCA1mut subjects had similar PFS to BRCA1wt subjects, but in BRCA1mut subjects, T + PLDtreated had longer PFS (P = 0.0002) by IR (13.4 months) vs PLDtreated (5.5 months). No significant differences were noted between any of the XPG genotypes (C/C vs G/–) and RR in total population or by treatment or by platinum sensitivity. Subjects with XPGmut had shorter OS than those with XPGwt (median OS 17.7 vs 20.0 months, P = 0.0363). There was no difference in OS of subjects with XPGmut between 2 groups. In XPGmut subjects, T + PLD-treated had shorter PFS vs XPGwt subjects (median PFS-IR 5.2 vs 6.4 months, P = 0.0207). Conclusions: BRCA1mut may predict improved outcome among T + PLD-treated subjects. Prospective evaluation of BRCA status is important in evaluation of DNA-damaging agents and may significantly affect the interpretation of clinical trials. XPG may be a biomarker of poor outcome in ROC.
doi:10.1016/j.ygyno.2014.03.119
41
100 — Featured Poster Phase II trial of pemetrexed and carboplatin in platinum-sensitive recurrent ovarian, fallopian tube, and primary peritoneal cancer A. Van Arsdale1, M.H. Einstein1, M.A. Brewer2, P.F. Timmins III3, J.D. Wright4, A.L. Leiser5, A.B. Astrow6, S. Cohen7, G.L. Goldberg1, D.Y.S. Kuo1. 1Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA, 2University of Connecticut Health Center, Farmington, CT, USA, 3Women's Cancer Care Associates, Albany, NY, USA, 4 Columbia University College of Physicians and Surgeons, New York, NY, USA, 5Beth Israel Medical Center, New York, NY, USA, 6Maimonides Medical Center, Brooklyn, NY, USA, 7Roosevelt Hospital, New York, NY, USA. Objectives: Despite improvements in median and overall survival (OS) using adjuvant platinum and paclitaxel-based therapy, recurrence of epithelial ovarian cancer (EOC) remains challenging. Pemetrexed is a new-generation antifolate that is a potent inhibitor of thymidylate synthase. Based on prior studies, pemetrexed is a promising agent for targeting ovarian cancer, which generally overexpresses folate receptors, and has shown synergistic preclinical efficacy in combination with platinum. Methods: In this prospective phase II trial, patients with platinumsensitive recurrent EOC, primary peritoneal, or fallopian tube cancer who had received at least one prior platinum and taxane-based regimen were treated with pemetrexed 600 mg/m2 intravenous (IV) and carboplatin AUC 5 IV every 21 days for 6 cycles or until evidence of disease progression or toxicity. Response was determined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria and confirmed every 9 weeks. This is the completed data analysis of the first stage of a Simon's two-stage phase II study (NCT01001910). Results: Of the 28 patients enrolled, 23 were evaluable for response. Of the 6 patients receiving ≤2 cycles, 5 had hypersensitivity reactions by strict protocol criteria. The median age was 64 years (range, 46– 86 years). Patients completed a median of 6 cycles (range, 2–12). Five patients had a complete response (CR) and 5 had a partial response (PR) for a 43.5% (10/23) overall response rate. In addition 9 patients had confirmed stable disease and 4 pts had progressive disease. In patients who had clinical benefit (CR + PR), the median time to response was 9.8 weeks (range, 8.0–19.6 weeks). A total of 145 cycles were administered. There were 62 (42.8%) grade 3/4 hematologic toxicities and 3 (2.1%) grade 3/4 nonhematologic toxicities. The most common nonhematologic toxicities were elevations in liver function tests (n = 3 cycles). There were 11 dose reductions and 18 dose delays due to toxicity. There were no treatment-related deaths. Conclusions: Pemetrexed/carboplatin is a well-tolerated regimen that is comparable to other regimens for platinum-sensitive recurrent EOC and should be considered in the treatment armamentarium. While hypersensitivity was defined strictly on this protocol, the higher-thanexpected rate of hypersensitivity reactions (5/28 [18%]) needs further exploration for pemetrexed and potentially for other folate receptortargeting therapies. doi:10.1016/j.ygyno.2014.03.120
101 – Featured Poster Evaluation of CA-125 response in the TRINOVA-1 study of weekly paclitaxel plus trebananib or placebo in women with recurrent ovarian cancer T.J. Herzog1, G.E. Richardson2, B.J. Monk3, B.Y. Karlan4, C. Marth5, L. Navale6, D.J. Warner6, A.M. Oza7. 1Columbia University College of Physicians and Surgeons, New York, NY, USA, 2Cabrini Hospital, Melbourne, Australia, 3University of Arizona Cancer Center, Phoenix, AZ, USA, 4Cedars-Sinai Medical Center, Los Angeles, CA, USA, 5Medical University Innsbruck, Innsbruck, Austria, 6Amgen Inc., Thousand Oaks, CA, USA, 7Princess Margaret Hospital, Toronto, ON, Canada.
After a median follow-up of 6 months, there have been 2 recurrences (13.3%) in the VG vs 4 recurrences (25%) in the CG (P = 0.65). Conclusions: The maximally administered dose was well tolerated. In contrast to other FOLR-α-directed cytotoxic agents, the E39 vaccine holds the promise of an immunologic response and memory against FOLR-α-expressing recurrences without toxicity.
doi:10.1016/j.ygyno.2014.03.118
99 - Featured Poster Effect of BRCA1 and XPG mutations on treatment response to trabectedin and pegylated liposomal doxorubicin in subjects with advanced ovarian cancer: Exploratory analysis of phase III OVA-301 study B.J. Monk1, P. Ghatage2, T. Parekh3, E. Henitz3, R. Knoblauch3, A. Soto Matos-Pita4, A. Nieto4, Y.C. Park3, D. Ricci3, A. Poveda5. 1University of Arizona Cancer Center, Phoenix, AZ, USA, 2Tom Baker Cancer Centre, Calgary, AB, Canada, 3Janssen Research & Development, Raritan, NJ, USA, 4PharmaMar SA, Madrid, Spain, 5Fundación Instituto Valenciano de Oncología, Valencia, Spain. Objectives: Both trabectedin (T) and pegylated liposomal doxorubicin (PLD) induce double-strand DNA breaks. Repair of this sublethal DNA damage is central to clinical drug resistance and involves both BRCA1 and XPG. We investigated the association of BRCA1/XPG mutations (mut) with response rate (RR), progression-free survival (PFS), and overall survival (OS) in a subset of subjects from a phase III clinical trial (OVA-301) comparing the efficacy and safety of T + PLD vs PLD alone in 672 subjects with recurrent ovarian cancer (ROC). Methods: A candidate gene array was designed to detect 59 functional mutations based on characterization in BIC database. Association of BRCA1/XPG mutation status with selected clinical endpoints was determined using 2-sided log rank test (PFS and OS) or Fisher's exact test (RR) at 0.05 significance. Germline DNA samples from 264 women who failed first-line platinum-based chemotherapy, randomized (1:1) to T + PLD or only PLD were used for analysis. Results: Overall, 41/264 subjects (16%) had BRCA1mut (T + PLD: n = 24 [18%]; PLD: n = 17 [13%]) and 17/264 (6%) had XPGmut (C/C) (T + PLD: n = 8 [6%]; PLD: n = 9 [7%]). Subjects with BRCA1mut had improved RR vs BRCA1wt (37% vs 19% assessed by independent radiologist [IR]). Among BRCA1mut subjects, T + PLD-treated had longer OS vs PLD-treated (median OS 27.3 vs 18.7 months, P = 0.0093). Among BRCA1wt subjects, OS was not statistically different (median OS 27.3 vs 23 months, P = 0.4966). Overall, BRCA1mut subjects had similar PFS to BRCA1wt subjects, but in BRCA1mut subjects, T + PLDtreated had longer PFS (P = 0.0002) by IR (13.4 months) vs PLDtreated (5.5 months). No significant differences were noted between any of the XPG genotypes (C/C vs G/–) and RR in total population or by treatment or by platinum sensitivity. Subjects with XPGmut had shorter OS than those with XPGwt (median OS 17.7 vs 20.0 months, P = 0.0363). There was no difference in OS of subjects with XPGmut between 2 groups. In XPGmut subjects, T + PLD-treated had shorter PFS vs XPGwt subjects (median PFS-IR 5.2 vs 6.4 months, P = 0.0207). Conclusions: BRCA1mut may predict improved outcome among T + PLD-treated subjects. Prospective evaluation of BRCA status is important in evaluation of DNA-damaging agents and may significantly affect the interpretation of clinical trials. XPG may be a biomarker of poor outcome in ROC.
doi:10.1016/j.ygyno.2014.03.119
41
100 — Featured Poster Phase II trial of pemetrexed and carboplatin in platinum-sensitive recurrent ovarian, fallopian tube, and primary peritoneal cancer A. Van Arsdale1, M.H. Einstein1, M.A. Brewer2, P.F. Timmins III3, J.D. Wright4, A.L. Leiser5, A.B. Astrow6, S. Cohen7, G.L. Goldberg1, D.Y.S. Kuo1. 1Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA, 2University of Connecticut Health Center, Farmington, CT, USA, 3Women's Cancer Care Associates, Albany, NY, USA, 4 Columbia University College of Physicians and Surgeons, New York, NY, USA, 5Beth Israel Medical Center, New York, NY, USA, 6Maimonides Medical Center, Brooklyn, NY, USA, 7Roosevelt Hospital, New York, NY, USA. Objectives: Despite improvements in median and overall survival (OS) using adjuvant platinum and paclitaxel-based therapy, recurrence of epithelial ovarian cancer (EOC) remains challenging. Pemetrexed is a new-generation antifolate that is a potent inhibitor of thymidylate synthase. Based on prior studies, pemetrexed is a promising agent for targeting ovarian cancer, which generally overexpresses folate receptors, and has shown synergistic preclinical efficacy in combination with platinum. Methods: In this prospective phase II trial, patients with platinumsensitive recurrent EOC, primary peritoneal, or fallopian tube cancer who had received at least one prior platinum and taxane-based regimen were treated with pemetrexed 600 mg/m2 intravenous (IV) and carboplatin AUC 5 IV every 21 days for 6 cycles or until evidence of disease progression or toxicity. Response was determined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria and confirmed every 9 weeks. This is the completed data analysis of the first stage of a Simon's two-stage phase II study (NCT01001910). Results: Of the 28 patients enrolled, 23 were evaluable for response. Of the 6 patients receiving ≤2 cycles, 5 had hypersensitivity reactions by strict protocol criteria. The median age was 64 years (range, 46– 86 years). Patients completed a median of 6 cycles (range, 2–12). Five patients had a complete response (CR) and 5 had a partial response (PR) for a 43.5% (10/23) overall response rate. In addition 9 patients had confirmed stable disease and 4 pts had progressive disease. In patients who had clinical benefit (CR + PR), the median time to response was 9.8 weeks (range, 8.0–19.6 weeks). A total of 145 cycles were administered. There were 62 (42.8%) grade 3/4 hematologic toxicities and 3 (2.1%) grade 3/4 nonhematologic toxicities. The most common nonhematologic toxicities were elevations in liver function tests (n = 3 cycles). There were 11 dose reductions and 18 dose delays due to toxicity. There were no treatment-related deaths. Conclusions: Pemetrexed/carboplatin is a well-tolerated regimen that is comparable to other regimens for platinum-sensitive recurrent EOC and should be considered in the treatment armamentarium. While hypersensitivity was defined strictly on this protocol, the higher-thanexpected rate of hypersensitivity reactions (5/28 [18%]) needs further exploration for pemetrexed and potentially for other folate receptortargeting therapies. doi:10.1016/j.ygyno.2014.03.120
101 – Featured Poster Evaluation of CA-125 response in the TRINOVA-1 study of weekly paclitaxel plus trebananib or placebo in women with recurrent ovarian cancer T.J. Herzog1, G.E. Richardson2, B.J. Monk3, B.Y. Karlan4, C. Marth5, L. Navale6, D.J. Warner6, A.M. Oza7. 1Columbia University College of Physicians and Surgeons, New York, NY, USA, 2Cabrini Hospital, Melbourne, Australia, 3University of Arizona Cancer Center, Phoenix, AZ, USA, 4Cedars-Sinai Medical Center, Los Angeles, CA, USA, 5Medical University Innsbruck, Innsbruck, Austria, 6Amgen Inc., Thousand Oaks, CA, USA, 7Princess Margaret Hospital, Toronto, ON, Canada.