Pancreatic Neoplasms Clinical Trial
Official title:
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
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.
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.
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