SS1P and Pentostatin Plus Cyclophosphamide for Mesothelioma

Primary Outcome Measures:

• Determining safety, tolerability, and feasibility of a conditioning regimen of pentostatin and cyclophosphamide in combination with SS1(dsFv)PE38
• Monitoring antibody formation to SS1(dsFv)PE38 and assessing the impact of the conditioning regimen

Secondary Outcome Measures:

• To evaluate the objective tumor response, duration of response and progression-free survival
• To investigate the potential of soluble mesothelin levels to predict any therapeutic response

Detailed Description:

Background:

Platinum-based chemotherapy is the standard of care for advanced unresectable malignant mesothelioma. New options for treatment are necessary in patients with advanced disease that have progressed on platinum-based therapy. Mesothelin is a cell surface glycoprotein present on normal mesothelial cells that is highly expressed in many human cancers including lung adenocarcinoma. SS1 (dsFv) PE38 is a recombinant anti-mesothelin immunotoxin that has undergone phase I testing and is currently in clinical trials in combination with pemetrexed and cisplatin for treatment of malignant pleural mesothelioma However, it is highly immunogenic, and it can only be administered for a maximum of two cycles, even with combination chemotherapy. 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:

Primary Objectives:

• 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

Secondary Objectives:

• To evaluate the objective tumor response, duration of response, and progression-free survival
• To investigate the potential of soluble mesothelin levels to predict any therapeutic response
• To study the clinical pharmacology (pharmacokinetics) of SS1(dsFv)PE38

Eligibility:

• Patients with histologically confirmed 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
• Measurable disease by modified RECIST criteria for pleural mesothelioma or by RECIST criteria for peritoneal mesothelioma
• Adequate renal, hepatic and hematopoietic function
• No major surgery, radiotherapy, chemotherapy or biologic therapy within 28 days of therapy

Design:

• Patients will receive conditioning regimen of pentostatin on days 1, 5 and 9 of the first cycle and day 1 of the second and third cycles in combination with cyclophosphamide on days 1 through 12 of the first cycle and days 1 through 4 of subsequent cycles
• Patients will be treated with SS1(dsFv)PE38 on days 10, 12 and 14 of the first cycle and days 2, 4, and 6 of each subsequent cycle
• The first cycle will consist of 30 days, and each subsequent cycle will consist of 21 days. Treatment cycles will be repeated for up to three 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 and 3)
• Toxicity will be assessed by the CTEP Version 4.0 of CTCAE
• Tumor response assessments will be performed at the end of 2 cycles and at the end of treatment

Criteria

Inclusion Criteria:

1. Subjects must have histologically confirmed epithelial or biphasic mesothelioma not amenable to potentially curative surgical resection. However, patients with biphasic tumors that have a greater than or equal to 50 percent sarcomatoid component will be excluded. The diagnosis will be confirmed by the Laboratory of Pathology / CCR / NCI.
2. Patients must have had at least one prior chemotherapy regimen, with the FDA-approved regimen of a platinum-based therapy in combination with pemetrexed being preferred unless there was a specific contraindication for an individual patient. There is no limit to the number of prior chemotherapy regimens received.
3. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as > 20 mm with conventional techniques or as > 10 mm with spiral CT scan. See Section 11 for the evaluation of measurable disease.
4. Patients must not have had major surgery, radiation therapy, chemotherapy, biologic therapy (including any investigational agents), or hormonal therapy (other than replacement), within 4 weeks prior to entering the study and must have evidence of stable or progressive disease to be eligible.
5. Age greater than or equal to 18 years. Since mesothelioma is extremely rare in children, they are excluded from this study.
6. Life expectancy of greater than 3 months.
7. Performance status (ECOG) less than or equal to 1 (Appendix A).
8. Patients must have adequate organ and marrow function (as defined below).
   • leukocytes greater than or equal to 3,000/mm(3)
   • absolute neutrophil count greater than or equal to 1,500/mm(3)
   • hemoglobin greater than or equal to 9 g/dL
   • platelets greater than or equal to 100,000/ mm(3)
   • total bilirubin less than or equal to 1.5 times institutional upper limit of normal (ULN)
   • AST(SGOT)/ALT(SGPT) less than or equal to 3 times institutional ULN (5 times if LFT elevations due to liver metastases)
   • creatinine less than or equal to 1.5 times institutional ULN

   OR

   • creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients with creatinine levels above institutional normal, obtained through calculated or measured Creatinine Clearance
   • Patients may be transfused to obtain a hemoglobin of greater than or equal to 9 g/Dl.
9. The effects of SS1(dsFv)PE38, pentostatin, and cyclophosphamide on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (barrier method of birth control; abstinence) for the duration of study therapy and for 3 months after the last dose of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. While hormonal methods of birth control are effective, we ask that female patients who are participating in the study cease hormonal forms of birth control, as these methods of birth control (birth control pills, injections, or implants) may affect the study drug. Patients must be off hormonal forms of birth control for at least 4 weeks prior to initiating the study.
10. Ability to comply with intravenous administration schedule, and the ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Patients with symptomatic brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. However, patients who have had treatment for their brain metastases and whose brain metastatic disease status has remained stable for at least 4-6 weeks without steroids may be enrolled at the discretion of the principal investigator.
2. Uncontrolled medical illness including, but not limited to, ongoing or uncontrolled, symptomatic congestive heart failure (AHA Class II or worse), uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
3. HIV positive patients will be excluded due to a theoretical concern that the degree of immune suppression associated with the treatment may result in progression of HIV infection.
4. Patients with Hepatitis B and C will be excluded.
5. Serum neutralization antibody assay shows greater than or equal to 75 percent neutralization of the SS1 (dsFv) PE38 activity at 200 ng/ml.
6. Patients may not be receiving any other investigational agents.
7. History of another invasive malignancy in the last two years. Adequately treated noninvasive, non-melanoma skin cancers as well as in situ carcinoma of the cervix will be allowed.
8. Prior treatment with drugs of the immunotoxin class.
9. Patients with tumor amenable to potentially curative therapy as assessed by the investigator. In patients with peritoneal mesothelioma who have had no prior surgery, a surgical consultation will be obtained to see if the patient is a candidate for debulking surgery.
10. Pregnant women are excluded from this study because SS1(dsFv)PE38, pentostatin, and cyclophosphamide have the potential for teratogenic or abortifacient effects. The agents in the trial may also potentially be secreted in milk and therefore breastfeeding women should be excluded. Because of the potential of teratogenic or abortifacient effects women of childbearing potential and men must agree to use adequate contraception (barrier methods) before, during the study and for a period of 3 months after the last dose of the investigational agent.
11. History of allergic reactions attributed to compounds of similar chemical or biologic composition to SS1(dsFv)PE38.