SS1P and Pentostatin Plus Cyclophosphamide for Mesothelioma
Condition: Mesothelioma; Adenocarcinoma of Lung; Pancreatic Neoplasms
MeSH terms: Mesothelioma; Mesothelioma, Malignant; Pancreatic Neoplasms; Adenocarcinoma of Lung
Study type: Interventional
Phase: Phase 1/Phase 2

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.
    

Intervention name(s): Pentostatin; Cyclophosphamide; SS1(dsFv)PE38 - lot 073I0809; SS1(dsFv)PE38 - lot FIL129J01
Intervention type(s): Drug; Drug; Biological; Biological
Intervention description(s): 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; 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; 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; 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
Other intervention name(s): Nipent; Cytoxan
Intervention MeSH terms: Cyclophosphamide; Pentostatin; Antibodies, Monoclonal
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Immune Therapy; Immunotoxin; T-Cell Depletion; Mesothelioma