A phase II trial of modified triple doublets for the treatment of advanced Müllerian malignancies

Abstract

5010 Background: Previously we reported the use of three sequential doublets (Triple Doublets) in the treatment of women with newly diagnosed and advanced stage mullerian malignancies (Matulonis et al. Gyn Onc 91:293, 2003). The surgically defined negative second look operation (SLO) rate to Triple Doublets was 38%. Modifications were made to this treatment regimen to reduce toxicity and increase efficacy. Methods: Open label two-cohort study. Patients (pts) with a new diagnosis of stage II-IV mullerian malignancy were eligible. After primary cytoreductive surgery, pts were treated with 3 sequential doublets including 3 initial cycles of carboplatin (d1) and gemcitabine (day 1 and 8; doublet 1), 3 cycles of carboplatin and Taxol (doublet 2), and 3 cycles of doxorubicin (d1) and topotecan (d3,4,5; doublet 3). Cycles 1–3 and 7–9 were supported with G-CSF. After therapy, all pts were clinically staged and evaluated at SLO if clinical staging was negative for residual disease. Primary endpoints were safety and negative SLO rate with rates of 60% and 40% defined apriori as encouraging in optimally cytoreduced (cohort 1) and suboptimally cytoreduced or stage IV (cohort 2), respectively. Results: 85 eligible pts were enrolled with a median age of 52. 76, 2, and 7 women had ovarian, tubal, and primary peritoneal carcinoma respectively. 47 and 38 pts were in cohorts 1 and 2, respectively. Over 700 cycles of chemotherapy were given with no toxic deaths. Only one pt has not yet completed therapy. Grade ¾ toxicities included neutropenia in 75% of patients and thrombocytopenia in 65% of pts during at least one cycle of therapy. Fever and neutropenia were seen in 13% of pts. All grade 3 and 4 non-hematologic toxicities were seen at a frequency of <10%. 5 pts were withdrawn from trial for toxicity (2 Taxol hypersensitivity, 3 for toxicity including toxic megacolon, 2 for culmulative hematologic toxicity). 8 additional pts withdrew consent and/ or refused SLO. 70 pts underwent SLO with a negative SLO rate of 53% with an additional 9% having microscopically positive procedures. Negative SLO rate was 74% in cohort 1 and 36% in Cohort 2. Conclusions: Treatment with the modified triple doublet regimen is tolerable with an encouraging pathologic CR rate. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly, GlaxoSmithKline Eli Lilly