Pentostatin, Cyclophosphamide, and SS1(dsFv)-PE38 Immunotoxin in Treating Patients with Mesothelioma, Lung Cancer, or Pancreatic Cancer

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Basic Trial Information

PhaseTypeAgeTrial IDs
Phase IIBiomarker/Laboratory analysis, Treatment18 and over11-C-0160
NCI-2013-01490, 110160, P10761, 8980, NCT01362790

Trial Description

Summary

This pilot/phase II trial studies the side effects and how well pentostatin, cyclophosphamide, and SS1(dsFv)-PE38 immunotoxin work in treating patients with mesothelioma, lung cancer, or pancreatic cancer. Pentostatin may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Pentostatin and cyclophosphamide may also stop the patient’s immune system from rejecting cancer fighting antibodies. Immunotoxins, such as SS1(dsFv)-PE38 immunotoxin, can find certain tumor cells and kill them without harming normal cells. Giving pentostatin, cyclophosphamide, and SS1(dsFv)-PE38 immunotoxin may kill more tumor cells.

Further Study Information

PRIMARY OBJECTIVES:

I. To assess the safety, tolerability, and feasibility of a conditioning regimen of pentostatin and cyclophosphamide in combination with SS1(dsFv)PE38 (SS1[dsFv]-PE38 immunotoxin). (Mesothelioma Pilot)

II. To monitor antibody formation to SS1(dsFv)PE38 and to assess the impact of the conditioning regimen on the formation of these antibodies. (Mesothelioma Pilot)

III. 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. (Regimen A Mesothelin Positive Cancers Dose De-Escalation Pilot)

IV. To evaluate objective tumor response (partial response [PR] + complete response [CR]) in subjects with pleural mesothelioma and with peritoneal mesothelioma. (Phase II)

V. To evaluate objective tumor response (PR+CR) in subjects with pancreatic adenocarcinoma and lung adenocarcinoma using Regimen A of the study using drug lot FIL129J01. (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate the objective tumor response, duration of response, and progression-free survival. (Mesothelioma Pilot)

II. To investigate the potential of soluble mesothelin levels to predict any therapeutic response. (Mesothelioma Pilot)

III. To study the clinical pharmacology (pharmacokinetics) of SS1(dsFv)PE38. (Mesothelioma Pilot)

IV. To evaluate intra-tumoral immune response using tissue biopsies. (Mesothelioma Pilot)

V. To assess duration of response, progression free survival and overall survival in subjects with pleural and with peritoneal mesothelioma on Regimen A. (Phase II)

VI. To assess degree of tumor shrinkage by Response Evaluation Criteria in Solid Tumors (RECIST) criteria in subjects with adenocarcinoma of the lung. (Phase II)

VII. To evaluate response to post-study chemotherapy. (Phase II)

VIII. To evaluate intra-tumoral immune response using tissue biopsies. (Phase II)

IX. To study the clinical pharmacology (pharmacokinetics) of SS1(dsFv)PE38. (Phase II)

X. To investigate the potential of soluble mesothelin levels to predict any therapeutic response. (Phase II)

XI. To further characterize antibody formation to SS1(dsFv)PE38 and to assess the impact of the conditioning regimen on the formation of these antibodies. (Phase II)

OUTLINE: This is a dose-escalation study of pentostatin and a dose de-escalation study of SS1(dsFv)-PE38 immunotoxin. Patients are assigned to 1 of 2 treatment regimens.

REGIMEN A: (Mesothelioma pilot closed to accrual as of 6/18/15)

PILOT: Patients receive pentostatin intravenously (IV) over 30-60 minutes on days 1, 5, and 9, cyclophosphamide orally (PO) once daily (QD) on days 1-12, and SS1(dsFv)-PE38 immunotoxin IV over 30 minutes on days 10, 12, and 14 of course 1. During all subsequent courses, patients receive pentostatin IV over 30-60 minutes on day 1, cyclophosphamide PO QD on days 1-4, and SS1(dsFv)-PE38 immunotoxin IV over 30 minutes on days 2, 4, and 6. Treatment repeats every 21 days (30 days in course 1) for up to 4 courses in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients receive Regimen A as in Pilot for up to 4 courses in the absence of disease progression or unacceptable toxicity.

REGIMEN B: (Mesothelioma pilot closed to accrual as of 6/18/15)

Patients receive pentostatin IV over 30-60 minutes on days 1, 5, 9, 13, and 17, cyclophosphamide PO QD on days 1-20, and SS1(dsFv)-PE38 immunotoxin IV over 30 minutes on days 18, 20, and 22 of course 1. During all subsequent courses patients receive pentostatin IV over 30-60 minutes on days 1 and 5, cyclophosphamide PO QD on days 1-8, and SS1(dsFv)-PE38 immunotoxin IV over 30 minutes on days 6, 8, and 10. Treatment repeats every 25 days (38 days in course 1) for up to 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Eligibility Criteria

Inclusion Criteria:

LUNG ADENOCARCINOMA COHORT (COHORT 3 ONLY): Mesothelin expression in at least 5% of cells as assessed in archival tumor tissue samples, determined by the immunohistochemistry (IHC) assay performed at Laboratory of Pathology/CCR/NCI; archival samples must be available for eligibility

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; we ask that female patients who are participating in the study cease hormonal forms of birth control; patients must be off hormonal forms of birth control for at least 4 weeks prior to initiating the study

Platelets >= 90,000/mm^3

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 >= 50% sarcomatoid component will be excluded; the diagnosis will be confirmed by the Laboratory of Pathology/Center for Cancer Research (CCR)/National Cancer Institute (NCI)

PANCREATIC CANCER COHORT (COHORT 4 ONLY): Total bilirubin =< 2 x institutional upper limit of normal (ULN)

LUNG ADENOCARCINOMA COHORT (COHORT 3 ONLY): Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)

LUNG ADENOCARCINOMA COHORT (COHORT 3 ONLY): Patients must have had at least one prior therapy for advanced disease (platinum-containing chemotherapy or one of the approved targeted therapies [an approved epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for EGFR mutant tumors or crizotinib and ceritinib for anaplastic lymphoma receptor tyrosine kinase (ALK) translocated tumors]); there is no limit to the number of prior chemotherapy regimens received

Total bilirubin: see guidelines for individual cohorts

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

Creatinine =< 1.5 x institutional ULN or creatinine clearance >= 45 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal, obtained through calculated or measured creatinine clearance

Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN (5 x if liver function test [LFT] elevations due to liver metastases)

Hemoglobin >= 9 g/dL; patients may be transfused to obtain a hemoglobin of >= 9 g/Dl

Absolute neutrophil count >= 1,500/mm^3

Performance status (Eastern Cooperative Oncology Group [ECOG]) =< 1

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

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 computed tomography (CT) scan

PANCREATIC CANCER COHORT (COHORT 4 ONLY): Patients must have had at least one prior chemotherapy for advanced disease; there is no limit to the number of prior chemotherapy regimens received

PANCREATIC CANCER COHORT (COHORT 4 ONLY): Subjects with recurrent, locally advanced unresectable or metastatic adenocarcinoma of the pancreas; the diagnosis will be confirmed by the Laboratory of Pathology/CCR/NCI

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

MESOTHELIOMA COHORTS (COHORTS 1 AND 2 ONLY): Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)

MESOTHELIOMA COHORTS (COHORTS 1 AND 2 ONLY): Patients must have had at least one prior chemotherapy regimen, with the Food and Drug Administration (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

Leukocytes >= 3,000/mm^3

Exclusion Criteria:

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

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

Pregnant women are excluded from this study; breastfeeding women should be excluded; 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

Prior treatment with drugs of the immunotoxin class

History of another invasive malignancy in the last two years; adequately treated non-invasive, non-melanoma skin cancers as well as in situ carcinoma of the cervix will be allowed

Patients may not be receiving any other investigational agents

Serum neutralization antibody assay shows >= 75% neutralization of the SS1 (dsFv) PE38 activity at 200 ng/ml

Human immunodeficiency virus (HIV) positive patients will be excluded

Uncontrolled medical illness including, but not limited to, ongoing or uncontrolled, symptomatic congestive heart failure (American Heart Association [AHA] class II or worse), uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

Patients with symptomatic brain metastases should be excluded from this clinical trial; 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

Patients with hepatitis B and C will be excluded

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

National Cancer Institute

  • National Cancer Institute
Raffit Hassan, Principal Investigator

Trial Sites

U.S.A.

Maryland
Bethesda

Mark O Hatfield-Warren Grant Magnuson Clinical Center

Raffit Hassan
Ph: 301-451-8742
Email: hassanr@mail.nih.gov

Raffit Hassan
Principal Investigator

NCI Laboratory of Molecular Biology

Raffit Hassan
Ph: 301-451-8742
Email: hassanr@mail.nih.gov

Raffit Hassan
Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01362790

Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.