SS1P and Pentostatin Plus Cyclophosphamide for Mesothelioma

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 all kinds of
     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 safe and
     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 safety and 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.

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

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

• Mesothelioma

• Drug: Pentostatin
• Drug: Cyclophosphamide
• Drug: SS1P

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 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:

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

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:

  -  The first eleven 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)

  -  The next 10 evaluable patients will receive 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)

  -  Patients receiving Regimen A are 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

  -  Patients receiving regimen B will be treated with SS1(dsFv)PE38 on days 18, 20 and 22
     of the first cycle and days 6, 8, and 10 of each subsequent cycle

  -  In regimen A, the first cycle consisted of 30 days, and each subsequent cycle consisted
     of 21 days. Treatment cycles will be repeated for up to six 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 6)

  -  In regimen B, the first cycle will consist of 38 days, and each subsequent cycle will
     consist of 25 days. SS1(dsFv)PE38 will be given at a dose of 35 mcg/kg. Treatment
     cycles will be repeated for up to six 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 32 and 38 of
     Cycle 1, and Days 20 and 26 of Cycles 2 through 6)

  -  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

  -  Tumor biopsies will be performed before treatment, after 2 cycles, and after the last
     cycle or at  follow-up.

-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 90,000/ 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 45 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.