SS1P and Pentostatin Plus Cyclophosphamide for Mesothelioma

Primary Outcome Measures

• Objective response rate stratified by tumor type [ Time Frame: At disease progression ] [ Designated as safety issue: No ]
• SS1P antibody formation [ Time Frame: On last day of last dosing cycle (maximum ~ 3 months) ] [ Designated as safety issue: No ]
• Grade and description of adverse events [ Time Frame: 30 days after last dose of treatment (maximum ~ 4 months) ] [ Designated as safety issue: Yes ]
• determine RP2D in drug lot FIL129J01 [ Time Frame: at end of first treatment cycle (30 days) ] [ Designated as safety issue: Yes ]

• Secondary Outcome Measures

  • Overall survival [ Time Frame: At death ] [ Designated as safety issue: No ]
  • Progression-free survival [ Time Frame: At disease progression ] [ Designated as safety issue: No ]
  • Duration of response [ Time Frame: At disease progression ] [ Designated as safety issue: No ]
  • Detailed Description:

    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.

    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.

    Eligibility

    Criteria

    Inclusion Criteria

    Mesothelioma Cohorts (Cohorts 1 and 2 Only)

    Subjects must have histologically confirmed epithelial or biphasic mesothelioma not amenable to potentially curative surgical resection. However, patients with biphasic tumors that have a less than or equal to 50% sarcomatoid component will be excluded. The diagnosis will be confirmed by the Laboratory of Pathology / CCR / NCI.

    Patients must have had at least one prior chemotherapy regimen, with the FDAapproved 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.

    Total Bilirubin less than or equal to 1.5 X institutional upper limit of normal (ULN).

    Lung Adenocarcinoma Cohort (Cohort 3) Only

    Subjects must have histologically confirmed advanced (Stage IIIB/IV) lung adenocarcinoma. The diagnosis will be confirmed by the Laboratory of Pathology/CCR/NCI.

    Patients must have had at least one prior therapy for advanced disease [platinumcontaining chemotherapy or one of the approved targeted therapies (an approved EGFR TKI for EGFR mutant tumors or crizotinib and ceritinib for ALK translocated tumors)]. There is no limit to the number of prior chemotherapy regimens received.

    Mesothelin expression in at least 5% of cells as assessed in archival tumor tissue samples, determined by the IHC assay performed at Laboratory of Pathology / CCR / NCI. Archival samples must be available for eligibility.

    Total Bilirubin less than or equal to 1.5 X institutional upper limit of normal (ULN).

    All Subjects

    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.

    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.

    Age greater than or equal to 18 years. Since the study diseases are extremely rare in children they are excluded from this study.

    Performance status (ECOG) less than or equal to 1.

    Patients must have adequate organ and marrow function (as defined below).

    • leukocytes less than or equal to 3,000/mm3
    • absolute neutrophil count less than or equal to 1,500/mm3
    • hemoglobin less than or equal to 9 g/dL
    • platelets less than or equal to 90,000/ mm3
    • total bilirubin
    • AST(SGOT)/ALT(SGPT) less than or equal to 3 X institutional ULN (5x if LFT elevations due to liver metastases)
    • creatinine less than or equal to 1.5 X institutional ULN

    OR creatinine clearance greater than or equal to 45 mL/min/1.73 m2 for patients with creatinine levels above institutional normal, obtained through calculated or measured Creatinine Clearance

    Patients may be transfused to obtain a hemoglobin of less than or equal to 9 g/Dl

    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

    Ability to comply with intravenous administration schedule, and the ability to understand and the willingness to sign a written informed consent document.

    Exclusion Criteria

    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.

    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.

    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.

    Patients with Hepatitis B and C will be excluded.

    Serum neutralization antibody assay shows greater than or equal to 75% neutralization of the SS1 (dsFv) PE38 activity at 200 ng/ml.

    Patients may not be receiving any other investigational agents.

    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.

    Prior treatment with drugs of the immunotoxin class.

    Patients with tumor amenable to potentially curative therapy as assessed by the investigator.

    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.

    History of allergic reactions attributed to compounds of similar chemical or biologic composition to SS1(dsFv)PE38.