SS1P and Pentostatin Plus Cyclophosphamide for Mesothelioma

BACKGROUND: Mesothelin is a cell surface glycoprotein present on normal mesothelial cells that is highly expressed in many human cancers including mesothelioma, lung and pancreatic adenocarcinoma. SS1 (dsFv) PE38 is a recombinant anti-mesothelin immunotoxin that has undergone phase I testing and has been evaluated in combination with pemetrexed and cisplatin for treatment of malignant pleural mesothelioma. SS1 (dsFv)PE38 is highly immunogenic and the majority of patients develop antibodies to it at end of one cycle. Pre-clinical studies demonstrate that SS1(dsFv)PE38 may be administered multiple times in combination with an immune-depleting regimen consisting of pentostatin and cyclophosphamide. OBJECTIVES: Mesothelioma Pilot Objective -To assess the safety, tolerability, and feasibility of a conditioning regimen of pentostatin and cyclophosphamide in combination with SS1(dsFv)PE38 -To monitor antibody formation to SS1(dsFv)PE38 and to assess the impact of the conditioning regimen on the formation of these antibodies Mesothelioma Positive Cancers Dose De-escalation Pilot Objective -To determine the safety profile and recommended phase 2 dose of SS1P (dsFv)PE38 in drug lot FIL129J01 using dosing regimen A in patients with mesothelioma, lung and pancreatic adenocarcinoma Phase 2 and Lung and Pancreatic Adenocarcinoma Expansion Pilot Objective -To evaluate objective tumor response in subjects with pleural mesothelioma, peritoneal mesothelioma, lung and pancreatic adenocarcinoma using Regimen A ELIGIBILITY: * Patients with one of the following histologically confirmed malignancies: * malignant pleural or peritoneal mesothelioma with epithelial or biphasic tumors having less than a 50% sarcomatoid component who have previously been treated on at least one platinum-containing chemotherapy regimen with progressive disease documented prior to study entry * advanced (Stage IIIB/IV) lung adenocarcinoma who have had at least one prior chemotherapy for advanced disease. Patients who received an approved targeted therapy as first-line treatment should have also received chemotherapy prior to study entry. * recurrent, locally advanced unresectable or metastatic adenocarcinoma of the pancreas. * Measurable disease by modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria for pleural mesothelioma or by RECIST criteria for peritoneal mesothelioma, lung adenocarcinoma and pancreatic adenocarcinoma * Adequate renal, hepatic and hematopoietic function * No major surgery, radiotherapy, chemotherapy or biologic therapy within 28 days of therapy DESIGN: -During the mesothelioma pilot phase of this study, the first eleven mesothelioma patients enrolled in this study received a conditioning regimen of pentostatin on days 1, 5 and 9 of the first cycle and day 1 of subsequent cycles in combination with cyclophosphamide on days 1 through 12 of the first cycle and days 1 through 4 of subsequent cycles (Regimen A) while the next 8 mesothelioma patients received conditioning regimen of pentostatin on days 1, 5, 9, 13 and 17 of the first cycle and day 1 and 5 of subsequent cycles in combination with cyclophosphamide on days 1 through 20 of the first cycle and days 1 through 8 of subsequent cycles (Regimen B). SS1P was administered every other day for six days (3 doses) beginning on the day after the last pentostatin dose in each cycle for both regimens. * In the mesothelin positive cancers dose de-escalation pilot study, a maximum of 12 patients with mesothelioma or lung or pancreatic adenocarcinoma will be enrolled in a 3+3 design to test up to 2 decreasing dose levels of SS1P administered in combination with cyclophosphamide and pentostatin on the Regimen A schedule for safety. * In the phase 2 mesothelioma and pancreatic and lung adenocarcinoma pilot expansion portions of the study, a two-stage Minimax phase II trial design will be used to enroll up to 16 evaluable subjects with pleural mesothelioma (cohort 1), up to 10 evaluable subjects with peritoneal mesothelioma (cohort 2), up to 10 patients with lung adenocarcinoma (cohort 3)and up to 10 evaluable subjects with pancreatic adenocarcinoma (cohort 4) who will receive treatment on Regimen A. * Treatment cycles will be repeated for up to four cycles if patients do not develop neutralizing antibodies, which will be assessed by a biological assay 14 and 20 days (+/- 2 days) following the first dose of SS1P in each cycle (corresponding to Days 24 and 30 of Cycle 1, and Days 16 and 22 of Cycles 2 through 4) * Toxicity will be assessed by the Cancer Therapy Evaluation Program (CTEP) Version 4.0 of Common Terminology Criteria in Adverse Events (CTCAE) * Tumor response assessments will be performed at the end of 2 cycles and at the end of treatment * Tumor biopsies will be performed before treatment, after 2 cycles, and after the last cycle or at follow-up.