SS1P and Pentostatin Plus Cyclophosphamide for Mesothelioma

NCT01362790 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 11016011-C-0160
• Study Type: interventional
• Target: 55
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Mesothelioma; Adenocarcinoma of Lung; Pancreatic Neoplasms

Keywords

Immune Therapy; Immunotoxin; T-Cell Depletion; Mesothelioma

Outcome Measures

Primary Outcomes (4)

• Response Assessment

  Response was assessed by the European Organization for Research and Treatment of Cancer (EORTC) modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Complete response (CR) is complete disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions. Progressive disease (PD) disease is at least a 20% increase in the sum of the LD of target lesions. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.

  52 months and 4 days

• Count of Participants With SS1P Antibody Formation

  Development of antibodies following treatment with SS1P. The goal was to delay development of antibodies to SS1P so a patient could get a second cycle of therapy with SS1P.

  On last day of last dosing cycle, end of cycle 1 (day 30)

• Count of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) Who Were Administered SS1P and Pentostatin or Cyclophosphamide

  Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

  Date treatment consent signed to date off study, approximately 64 months and 26 days

• Recommended Phase 2 Dose (RP2D) in Drug Lot FIL129J01

  Should any 2 patients within the first 3 to 6 patients experience treatment limiting toxicity requiring cessation of treatment prior to the conclusion of the first cycle, the maximum tolerated dose will have been exceeded and patients will be enrolled to the next lower dose.

  Days 1, 3, and 5 of a 21 day cycle

Secondary Outcomes (3)

• Overall Survival

  36 months

• Progression-free Survival

  36 months

• Duration of Response

  up to 2.5 years

Other Outcomes (1)

• Count of Participants SS1P Cycles Received Following Onstudy

  Cycles 1-6, up to 180 days

Study Arms (7)

Mesothelioma Pilot Phase Regimen A

EXPERIMENTAL

Drug: Pentostatin Regimen A: Cycle 1: 4 mg/m\^2 on days 1, 5 and 9 of 30 day cycle Cycles 2-4: 4 mg/m\^2 on day 1 of 21 day cycle Other Names: • Nipent 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 Other Names: • Cytoxan Drug: SS1 (dsFv)PE38 Regimen A: Cycle 1: 35 mcg/kg days 10, 12, and 14. Cycles 2-4: Days 2, 4, and 6, for a maximum of six treatment cycles.

Drug: Pentostatin; Drug: Cyclophosphamide; Biological: SS1(dsFv)PE38 - lot 073I0809; Biological: SS1(dsFv)PE38 - lot FIL129J01

Mesothelioma Pilot Phase Regimen B

EXPERIMENTAL

Drug: Pentostatin Regimen B: Cycle 1: 4 mg/m\^2 or 2 mg/m\^2 on days 1, 5, 9, 13 and 17 of 38 day cycle Cycles 2-6: 4 mg/m\^2 on days 1 and 5 of 25 day cycle Regimen B: Cycle 1: 4 mg/m\^2 on days 1, 5, 9, 13 and 17 of 38 day cycle Cycles 2-6: 4 mg/m\^2 on days 1 and 5 of 25 day cycle Other Names: • Nipent Drug: Cyclophosphamide 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 Other Names: • Cytoxan Drug: SS1 (dsFv)PE38 Regimen B: Cycle 1: 35mcg/kg days 18, 20, and 22. Cycles 2-4: (Days 6, 8, and 10), for a maximum of six treatment cycles.

Drug: Pentostatin; Drug: Cyclophosphamide; Biological: SS1(dsFv)PE38 - lot 073I0809; Biological: SS1(dsFv)PE38 - lot FIL129J01

Phase 2 Peritoneal Mesothelioma Pilot Expansion Phase

EXPERIMENTAL

Drug: Pentostatin Regimen B: Cycle 1: 4 mg/m\^2 or 2 mg/m\^2 on days 1, 5 and 9 of 38 day cycle Cycles 2-6: 4 mg/m\^2 on day 1 and 5 of 25 day cycle Other Names: • Nipent Drug: Cyclophosphamide 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 Other Names: • Cytoxan Drug: SS1(dsFv)PE38 Regimen B: Cycle 1: 35 mcg/kg or 25 mcg/kg days 18, 20 and 22. Cycles 2-4: Days 6, 8, and 10, for a maximum of six treatment cycles.

Drug: Pentostatin; Drug: Cyclophosphamide; Biological: SS1(dsFv)PE38 - lot 073I0809; Biological: SS1(dsFv)PE38 - lot FIL129J01

Phase 2 Pleural Mesothelioma Pilot Expansion Phase

EXPERIMENTAL

Drug: Pentostatin Regimen A: Cycle 1: 4 mg/m\^2 on days 1, 5 and 9 of 30 day cycle Cycles 2-4: 4 mg/m\^2 on day 1 of 21 day cycle Other Names: • Nipent 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 Other Names: • Cytoxan Drug: SS1(dsFv)PE38 Regimen A: Cycle 1: 35 mcg/kg or 25 mcg/kg days 10, 12 and 14. Cycles 2-4: Days 2, 4, and 6, for a maximum of six treatment cycles.

Drug: Pentostatin; Drug: Cyclophosphamide; Biological: SS1(dsFv)PE38 - lot 073I0809; Biological: SS1(dsFv)PE38 - lot FIL129J01

Mesothelioma Positive Ca Dose De-escalation Pilot Regimen A

EXPERIMENTAL

Drug: Pentostatin Regimen A: Cycle 1: 4 mg/m\^2 on days 1, 5 and 9 of 30 day cycle Cycles 2-4: 4 mg/m\^2 on day 1 of 21 day cycle Other Names: • Nipent 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 Other Names: • Cytoxan Drug: SS1(dsFv)PE38 Regimen A: Cycle 1: 35 mcg/kg or 25 mcg/kg days 10, 12 and 14. Cycles 2-4: Days 2, 4, and 6, for a maximum of six treatment cycles.

Drug: Pentostatin; Drug: Cyclophosphamide; Biological: SS1(dsFv)PE38 - lot 073I0809; Biological: SS1(dsFv)PE38 - lot FIL129J01

Phase 2 Pancreatic Adenocarcinoma Pilot Phase Regimen A

EXPERIMENTAL

Drug: Pentostatin Regimen A: Cycle 1: 4 mg/m\^2 on days 1, 5 and 9 of 30 day cycle Cycles 2-4: 4 mg/m\^2 on day 1 of 21 day cycle Other Names: • Nipent 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 Other Names: • Cytoxan Drug: SS1(dsFv)PE38 Regimen A: Cycle 1: 35 mcg/kg or 25 mcg/kg days 10, 12 and 14. Cycles 2-4: Days 2, 4, and 6, for a maximum of six treatment cycles.

Drug: Pentostatin; Drug: Cyclophosphamide; Biological: SS1(dsFv)PE38 - lot 073I0809; Biological: SS1(dsFv)PE38 - lot FIL129J01

Phase 2 Lung Adenocarcinoma Pilot Expansion Phase Regimen A

EXPERIMENTAL

Drug: Pentostatin Regimen A: Cycle 1: 4 mg/m\^2 on days 1, 5 and 9 of 30 day cycle Cycles 2-4: 4 mg/m\^2 on day 1 of 21 day cycle Other Names: • Nipent 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 Other Names: • Cytoxan Drug: SS1(dsFv)PE38 Regimen A: Cycle 1: 35 mcg/kg or 25 mcg/kg days 10, 12 and 14. Cycles 2-4: Days 2, 4, and 6, for a maximum of six treatment cycles.

Drug: Pentostatin; Drug: Cyclophosphamide; Biological: SS1(dsFv)PE38 - lot 073I0809; Biological: SS1(dsFv)PE38 - lot FIL129J01

Interventions

Pentostatin DRUG

Regimen A: Cycle 1: 4 mg/m\^2 on days 1, 5 and 9 of 30 day cycle Cycles 2-4: 4 mg/m\^2 on day 1 of 21 day cycle Regimen B: Cycle 1: 4 mg/m\^2 or 2 mg/m\^2 on days 1, 5, 9, 13 and 17 of 38 day cycle Cycles 2-6: 4 mg/m\^2 on days 1 and 5 of 25 day cycle

Also known as: Nipent

Mesothelioma Pilot Phase Regimen A; Mesothelioma Pilot Phase Regimen B; Mesothelioma Positive Ca Dose De-escalation Pilot Regimen A; Phase 2 Lung Adenocarcinoma Pilot Expansion Phase Regimen A; Phase 2 Pancreatic Adenocarcinoma Pilot Phase Regimen A; Phase 2 Peritoneal Mesothelioma Pilot Expansion Phase; Phase 2 Pleural Mesothelioma Pilot Expansion Phase

Cyclophosphamide DRUG

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

Also known as: Cytoxan

Mesothelioma Pilot Phase Regimen A; Mesothelioma Pilot Phase Regimen B; Mesothelioma Positive Ca Dose De-escalation Pilot Regimen A; Phase 2 Lung Adenocarcinoma Pilot Expansion Phase Regimen A; Phase 2 Pancreatic Adenocarcinoma Pilot Phase Regimen A; Phase 2 Peritoneal Mesothelioma Pilot Expansion Phase; Phase 2 Pleural Mesothelioma Pilot Expansion Phase

SS1(dsFv)PE38 - lot 073I0809 BIOLOGICAL

Regimen A: Cycle 1: Cycle 1: 35mcg/kg days 10, 12 and 14 Cycles 2-4: Days 2, 4 and 6, for a maximum of six treatment cycles Regimen B: Cycle 1: 35mcg/kg days 18, 20 and 22 Cycles 2-4: (Days 6, 8 and 10), for a maximum of six treatment cycles

Mesothelioma Pilot Phase Regimen A; Mesothelioma Pilot Phase Regimen B; Mesothelioma Positive Ca Dose De-escalation Pilot Regimen A; Phase 2 Lung Adenocarcinoma Pilot Expansion Phase Regimen A; Phase 2 Pancreatic Adenocarcinoma Pilot Phase Regimen A; Phase 2 Peritoneal Mesothelioma Pilot Expansion Phase; Phase 2 Pleural Mesothelioma Pilot Expansion Phase

SS1(dsFv)PE38 - lot FIL129J01 BIOLOGICAL

Regimen A: Cycle 1: Cycle 1:35mcg/kg or 25 mcg/kg days 10, 12 and 14 Cycles 2-4: Days 2, 4 and 6, for a maximum of six treatment cycles

Mesothelioma Pilot Phase Regimen A; Mesothelioma Pilot Phase Regimen B; Mesothelioma Positive Ca Dose De-escalation Pilot Regimen A; Phase 2 Lung Adenocarcinoma Pilot Expansion Phase Regimen A; Phase 2 Pancreatic Adenocarcinoma Pilot Phase Regimen A; Phase 2 Peritoneal Mesothelioma Pilot Expansion Phase; Phase 2 Pleural Mesothelioma Pilot Expansion Phase

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 / Center for Cancer Research (CCR) / National Cancer Institute (NCI).
• 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.
• Total Bilirubin less than or equal to 1.5 X institutional upper limit of normal (ULN)
• 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 \[platinum containing chemotherapy or one of the approved targeted therapies (an approved estimated glomerular filtration rate (EGFR) tyrosine kinase inhibitor (TKI) for EGFR mutant tumors or crizotinib and ceritinib for ALK translocated tumors)\]. 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 immunohistochemistry (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)
• 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)
• 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 (Eastern Cooperative Oncology Group (ECOG)) less than or equal to 1
• Patients must have adequate organ and marrow function (as defined below).

You may not qualify if:

• 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 (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.
• Human immunodeficiency virus (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.
• 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.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Hassan R, Bullock S, Premkumar A, Kreitman RJ, Kindler H, Willingham MC, Pastan I. Phase I study of SS1P, a recombinant anti-mesothelin immunotoxin given as a bolus I.V. infusion to patients with mesothelin-expressing mesothelioma, ovarian, and pancreatic cancers. Clin Cancer Res. 2007 Sep 1;13(17):5144-9. doi: 10.1158/1078-0432.CCR-07-0869.

  PMID: 17785569 BACKGROUND

• Kay NE, Geyer SM, Call TG, Shanafelt TD, Zent CS, Jelinek DF, Tschumper R, Bone ND, Dewald GW, Lin TS, Heerema NA, Smith L, Grever MR, Byrd JC. Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia. Blood. 2007 Jan 15;109(2):405-11. doi: 10.1182/blood-2006-07-033274. Epub 2006 Sep 28.

  PMID: 17008537 BACKGROUND

• Zhang Y, Xiang L, Hassan R, Paik CH, Carrasquillo JA, Jang BS, Le N, Ho M, Pastan I. Synergistic antitumor activity of taxol and immunotoxin SS1P in tumor-bearing mice. Clin Cancer Res. 2006 Aug 1;12(15):4695-701. doi: 10.1158/1078-0432.CCR-06-0346.

  PMID: 16899620 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Mesothelioma; Adenocarcinoma of Lung; Pancreatic Neoplasms

Interventions

Pentostatin; Cyclophosphamide

Condition Hierarchy (Ancestors)

Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Mesothelial; Adenocarcinoma; Carcinoma; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Digestive System Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Coformycin; Formycins; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Results Point of Contact

• Title: Dr. Raffit Hassan
• Organization: National Cancer Institute

raffit_hassan@nih.gov

301-451-8742

Study Officials

• Raffit Hassan, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: May 27, 2011
• First Posted: May 30, 2011
• Study Start: May 11, 2011
• Primary Completion: August 3, 2016
• Study Completion: August 7, 2017
• Last Updated: June 6, 2019
• Results First Posted: June 6, 2019

Record last verified: 2019-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)