NCT01362790

SS1P and Pentostatin Plus Cyclophosphamide for Mesothelioma

A Pilot/ Phase 2 Study of Pentostatin Plus Cyclophosphamide Immune Depletion to Decrease Immunogenicity of SS1P in Patients With Mesothelioma, Lung Cancer or Pancreatic Cancer

• Status: Completed
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 55 (actual)
• Sponsor: National Cancer Institute (NCI) · NIH
• Sex: All
• Age: 18 Years – 99 Years
• Healthy volunteers: Not accepted

Summary

Background: * Malignant mesothelioma is a form of cancer that develops on the protective lining that covers the body's internal organs. It most often occurs on the lining of the lungs and chest wall or the lining of the abdomen. There is no known cure for malignant mesothelioma, so researchers are searching for new ways to treat it. * Mesothelin is a protein that is found in mesothelioma and other types of cancer cells. An experimental cancer drug called SS1P is designed to attack cells that have mesothelin while leaving healthy cells alone. Researchers want to test how effective SS1P is when it is given with pentostatin and cyclophosphamide. These drugs help suppress the immune system and may make the SS1P more effective. Objectives: \- To study the effectiveness of SS1P plus two drugs that suppress the immune system to treat malignant mesothelioma. Eligibility: \- Individuals at least 18 years of age who have malignant mesothelioma in the chest or abdomen. Design: * Participants will be screened with a physical exam, medical history, and blood tests. They will also have imaging studies. * The first treatment cycle will last 30 days. Up to three 21-day cycles of treatment will follow. * In the first cycle, participants will have pentostatin on days 1, 5, and 9. They will have cyclophosphamide on days 1 through 12. They will have SS1P on days 10, 12, and 14. * On the next three cycles, participants will have pentostatin on day 1.They will have cyclophosphamide on days 1 through 4. They will have SS1P on days 2, 4, and 6. * Participants will have frequent blood tests and other studies. They will receive all four cycles of treatment as long as there are no severe side effects. * Participants will have regular followup visits as directed by the study doctors.

Detailed description

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.

Conditions

• Mesothelioma
• Adenocarcinoma of Lung
• Pancreatic Neoplasms

Interventions

Type	Name	Description
DRUG	Pentostatin	Regimen A: Cycle 1: 4 mg/m\^2 on days 1, 5 and 9 of 30 day cycle Cycles 2-4: 4 mg/m\^2 on day 1 of 21 day cycle Regimen B: Cycle 1: 4 mg/m\^2 or 2 mg/m\^2 on days 1, 5, 9, 13 and 17 of 38 day cycle Cycles 2-6: 4 mg/m\^2 on days 1 and 5 of 25 day cycle
DRUG	Cyclophosphamide	Regimen A:Cycle 1: 200 mg/day on days 1-12 of 30 day cycle Cycles 2-4: 200 mg/day on days 1-4 of 21 day cycle Regimen B:Cycle 1: 200 mg/day on days 1-20 of 38 day cycle Cycles 2-4: 200 mg/day on days 1-8 of 25 day cycle
BIOLOGICAL	SS1(dsFv)PE38 - lot 073I0809	Regimen A: Cycle 1: Cycle 1: 35mcg/kg days 10, 12 and 14 Cycles 2-4: Days 2, 4 and 6, for a maximum of six treatment cycles Regimen B: Cycle 1: 35mcg/kg days 18, 20 and 22 Cycles 2-4: (Days 6, 8 and 10), for a maximum of six treatment cycles
BIOLOGICAL	SS1(dsFv)PE38 - lot FIL129J01	Regimen A: Cycle 1: Cycle 1:35mcg/kg or 25 mcg/kg days 10, 12 and 14 Cycles 2-4: Days 2, 4 and 6, for a maximum of six treatment cycles

Timeline

• Start date: 2011-05-11
• Primary completion: 2016-08-03
• Completion: 2017-08-07
• First posted: 2011-05-30
• Last updated: 2019-06-06
• Results posted: 2019-06-06

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study