GYNECOLOGIC COMMITTEE - SWOG

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Program Director/Principal Investigator (Last, First, Middle): Baker, Laurence H., D.O. Rationale Despite the high objective response rate to platinum-based chemotherapy, the majority of patients with advanced disease ultimately progress and die of complications of the malignancy. In this trial we have attempted to take advantage of the intraperitoneal route of anti-neoplastic drug delivery by administering regional treatment to patients with bulky Stage III and Stage IV disease who have achieved an initial response to primary systemic chemotherapy and have small volume residual disease after an interval surgical cytoreductive surgery. Objectives • To evaluate the overall survival and progression-free survival in Stage III or IV epithelial ovarian, fallopian tube or primary peritoneal carcinoma patients with bulky disease and/or malignant pleural effusions treated with neoadjuvant intravenous paclitaxel and carboplatin, cytoreductive surgery and intravenous/intraperitoneal paclitaxel and intraperitoneal carboplatin. • To estimate the percent of patients successfully cytoreduced to optimal disease (< 1 cm residual) following neoadjuvant chemotherapy. • To evaluate the toxicities associated with this therapy. • To explore the relationship between tumor p53 expression, cellular proliferation rate as measured by PCNA and apoptotic rate, and human tumor cloning assay results at time of debulking surgery with progression-free survival and overall survival in patients undergoing cytoreductive surgery. Statistical Endpoints This study was designed as a pilot Phase II trial to determine the potential of this approach to favorably impact survival in advanced ovarian cancer. Results Sixty-two patients were registered. Four were ineligible. Fifty-six were evaluated for neoadjuvant chemotherapy toxicities. One patient died of pneumonia. Five patients had grade 4 toxicity, including neutropenia (3), anemia, leucopenia, anorexia, fatigue, muscle weakness, respiratory infection, and cardiac ischemia. Thirty-six patients had debulking surgery. Two had grade 4 hemorrhage. Twenty-six patients received post-cytoreduction chemotherapy. Four had grade 4 neutropenia. At a median follow-up of 21 months, median PFS was found to be 21 months and median OS 32 months for all 58 patients. PFS and OS for the 26 patients who received IV/IP chemotherapy was 29 and 34 months respectively. Publication The abstract was presented as an oral presentation at ASCO and has been submitted for publication. Additionally, the Gynecologic Cancer Intergroup in Canada is currently developing a randomized phase III trial which incorporates the strategy and piloted this in a phase II study. GYNECOLOGIC COMMITTEE GYN- 7
Program Director/Principal Investigator (Last, First, Middle): Baker, Laurence H., D.O. To Be Activated S0821: A Phase II Trial of Axitinib for a Biochemical Recurrence (“Rising CA-125”) in Women with Epithelial Ovarian, Fallopian Tube, and Primary Peritoneal Cancers after First-Line Chemotherapy Rationale Most women with advanced ovarian cancer will be treated initially with cytoreductive surgery followed by platinum/taxane-based chemotherapy, and most (approximately75%) will achieve a complete response (CR). However, most of those who achieve a CR will eventually relapse and succumb to their disease, despite additional treatment with either surgery or chemotherapy. Further, most patients will be followed during and after first-line treatment using the tumor marker CA- 125. Many patients will be found to have a rising CA-125 level (biochemical recurrence) while they are asymptomatic, and virtually all of these will go on to develop objective evidence of measurable disease recurrence. The interval between recognition of a rising CA-125 and identification of (1, 2) measurable disease has been estimated at 3-6 months. Axitinib is a selective inhibitor of vascular endothelial growth factor receptor 1,2 and 3. Preclinical data suggest that axitinib has antitumor activity that results from its anti-angiogenic effect, which is reversible when discontinued. (3) In a Phase I study of 36 patients with advanced solid tumours who received axitinib doses ranging from 5 to 30 mg twice daily, the dose-limiting toxicities were hypertension and stomatitis. Other toxicities included diarrhea, fatigue, nausea, and vomiting. Axitinib was rapidly absorbed, with peak plasma concentration noted 2-6 hours after dosing. (4) Axitinib at a dose of 5 mg twice daily was reported to show clinical activity in a Phase II study of metastatic renalcell cancer patients, with mild, manageable toxicity. Objectives To evaluate the recurrence-free interval associated with using axitinib in patients who have achieved a complete response to first-line chemotherapy and develop a biochemical recurrence (rising CA-125) in the absence of other evidence of disease. Statistical Endpoints The goal of the study is to evaluate the recurrence-free survival in patients with ovarian cancer who have achieved a complete response to first-line chemotherapy, develop a rising CA-125, (biochemical recurrence) and use axitinib. For purposes of this study, we estimate that the median time from enrollment to documentation of recurrent disease by RECIST is 3 months. It is assumed that the agent (axitinib) will be of considerable interest for future testing if the median recurrence-free survival is increased by 50% or more (i.e. an RFS hazard ratio of ≥ 1.5). Fifty-six centrally reviewed eligible patients are targeted over two years. Upon accrual completion, patients will be followed for an additional six months before analysis. The power is approximately 0.90 for detecting a statistically significant, favorable recurrence-free survival compared to the estimated historical benchmark of a 3-month median RFS. This calculation assumes an exponential RFS distribution and parameter estimation. Assuming a 10% central review ineligibility rate, approximately 62 patients will be enrolled GYNECOLOGIC COMMITTEE GYN- 8
Page 1 and 2: GYNECOLOGIC COMMITTEE Maurie Markma
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GYNECOLOGIC COMMITTEE - SWOG

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