SS1P and Pentostatin Plus Cyclophosphamide for Mesothelioma

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT01362790
First received: May 27, 2011
Last updated: March 20, 2015
Last verified: November 2014
  Purpose

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.

Condition Intervention Phase
Mesothelioma
Drug: Pentostatin
Drug: Cyclophosphamide
Biological: SS1(dsFv)PE38
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Pilot/ Phase 2 Study of Pentostatin Plus Cyclophosphamide Immune Depletion to Decrease Immunogenicity of SS1P in Patients With Mesothelioma

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

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 ]

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 ]

Estimated Enrollment: 75
Study Start Date: May 2011
Estimated Study Completion Date: June 2018
Estimated Primary Completion Date: April 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
Regimen A pilot (closed)
Drug: Pentostatin
Regimen A: Cycle 1: 4 mg/m2 on days 1, 5 and 9 of 30 day cycle Cycles 2-4: 4 mg/m2 on day 1 of 21 day cycle Regimen B: Cycle 1: 4 mg/m2 on days 1, 5, 9, 13 and 17 of 38 day cycle Cycles 2-6: 4 mg/m2 on days 1 and 5 of 25 day cycle
Drug: Cyclophosphamide
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
Biological: SS1(dsFv)PE38
Regimen A: Cycle 1: assigned dose level on days 10, 12 and 14 of 30 day cycle Cycles 2-4: assigned dose level on days 2, 4 and 6 of 21 day cycle Regimen B: Cycle 1: assigned dose level on days 18, 20 and 22 of 38 day cycle Cycles 2-4: assigned dose level on days 6, 8 and 10 of 25 day cycle
Experimental: 2
Regimen B pilot (closed)
Drug: Pentostatin
Regimen A: Cycle 1: 4 mg/m2 on days 1, 5 and 9 of 30 day cycle Cycles 2-4: 4 mg/m2 on day 1 of 21 day cycle Regimen B: Cycle 1: 4 mg/m2 on days 1, 5, 9, 13 and 17 of 38 day cycle Cycles 2-6: 4 mg/m2 on days 1 and 5 of 25 day cycle
Drug: Cyclophosphamide
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
Biological: SS1(dsFv)PE38
Regimen A: Cycle 1: assigned dose level on days 10, 12 and 14 of 30 day cycle Cycles 2-4: assigned dose level on days 2, 4 and 6 of 21 day cycle Regimen B: Cycle 1: assigned dose level on days 18, 20 and 22 of 38 day cycle Cycles 2-4: assigned dose level on days 6, 8 and 10 of 25 day cycle
Experimental: 3
Regimen A phase 2 peritoneal mesothelioma
Drug: Pentostatin
Regimen A: Cycle 1: 4 mg/m2 on days 1, 5 and 9 of 30 day cycle Cycles 2-4: 4 mg/m2 on day 1 of 21 day cycle Regimen B: Cycle 1: 4 mg/m2 on days 1, 5, 9, 13 and 17 of 38 day cycle Cycles 2-6: 4 mg/m2 on days 1 and 5 of 25 day cycle
Drug: Cyclophosphamide
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
Biological: SS1(dsFv)PE38
Regimen A: Cycle 1: assigned dose level on days 10, 12 and 14 of 30 day cycle Cycles 2-4: assigned dose level on days 2, 4 and 6 of 21 day cycle Regimen B: Cycle 1: assigned dose level on days 18, 20 and 22 of 38 day cycle Cycles 2-4: assigned dose level on days 6, 8 and 10 of 25 day cycle
Experimental: 4
Regimen A phase 2 pleural mesothelioma
Drug: Pentostatin
Regimen A: Cycle 1: 4 mg/m2 on days 1, 5 and 9 of 30 day cycle Cycles 2-4: 4 mg/m2 on day 1 of 21 day cycle Regimen B: Cycle 1: 4 mg/m2 on days 1, 5, 9, 13 and 17 of 38 day cycle Cycles 2-6: 4 mg/m2 on days 1 and 5 of 25 day cycle
Drug: Cyclophosphamide
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
Biological: SS1(dsFv)PE38
Regimen A: Cycle 1: assigned dose level on days 10, 12 and 14 of 30 day cycle Cycles 2-4: assigned dose level on days 2, 4 and 6 of 21 day cycle Regimen B: Cycle 1: assigned dose level on days 18, 20 and 22 of 38 day cycle Cycles 2-4: assigned dose level on days 6, 8 and 10 of 25 day cycle

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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)

INCLUSION CRITERIA: 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 the tumor tissue from fresh biopsy samples (Any mesothelin expressionis adequate ), determined by the IHC assay performed at Laboratory of Pathology / CCR / NCI.
  • Total Bilirubin less than or equal to 1.5 X institutional upper limit of normal (ULN)

INCLUSION CRITERIA: 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.
  • Patients must have had at least one prior chemotherapy for advanced disease. There is no limit to the number of prior chemotherapy regimens received.
  • Total Bilirubin less than or equal to 2 X institutional upper limit of normal (ULN)

INCLUSION CRITERIA: 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 See guidelines for individual cohorts in sections 3.1.1.3, 3.1.2.4 and 3.1.3.3
    • 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: (All Subjects)

  • 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.

INCLUSION CRITERIA: WOMEN AND MINORITIES

-Both men and women and members of all races and ethnic groups are eligible for this trial. Every effort will be made to recruit women and minorities in this study.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01362790

Contacts
Contact: Yvonne D Mallory, R.N. (301) 402-0255 malloryy@mail.nih.gov
Contact: Raffit Hassan, M.D. (301) 451-8742 rh276q@nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    (888) NCI-1937      
Sponsors and Collaborators
Investigators
Principal Investigator: Raffit Hassan, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT01362790     History of Changes
Other Study ID Numbers: 110160, 11-C-0160
Study First Received: May 27, 2011
Last Updated: March 20, 2015
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Immune Therapy
Immunotoxin
T-Cell Depletion
Mesothelioma

Additional relevant MeSH terms:
Mesothelioma
Adenoma
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Mesothelial
Cyclophosphamide
Pentostatin
Adenosine Deaminase Inhibitors
Alkylating Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Enzyme Inhibitors
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on April 30, 2015