Clinical Trial: NCT01362790 - My Cancer Genome

NCT01362790

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. 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.

Related Conditions:

Lung Adenocarcinoma
Mesothelioma
Pancreatic Carcinoma

Recruiting Status:

Completed

Phase:

Phase 1/Phase 2

URL:

https://clinicaltrials.gov/show/NCT01362790

Trial Eligibility

Document

Title

Brief Title: SS1P and Pentostatin Plus Cyclophosphamide for Mesothelioma
Official Title: A Pilot/ Phase 2 Study of Pentostatin Plus Cyclophosphamide Immune Depletion to Decrease Immunogenicity of SS1P in Patients With Mesothelioma, Lung Cancer or Pancreatic Cancer

Clinical Trial IDs

ORG STUDY ID: 110160
SECONDARY ID: 11-C-0160
NCT ID: NCT01362790

Conditions

Mesothelioma
Adenocarcinoma of Lung
Pancreatic Neoplasms

Interventions

Drug	Synonyms	Arms
Pentostatin	Nipent	Mesothelioma Pilot Phase Regimen A
Cyclophosphamide	Cytoxan	Mesothelioma Pilot Phase Regimen A
SS1(dsFv)PE38 - lot 073I0809		Mesothelioma Pilot Phase Regimen A
SS1(dsFv)PE38 - lot FIL129J01		Mesothelioma Pilot Phase Regimen A

Purpose

Detailed Description

      BACKGROUND:

      Mesothelin is a cell surface glycoprotein present on normal mesothelial cells that is highly
      expressed in many human cancers including mesothelioma, lung and pancreatic 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:

      Mesothelioma Pilot Objective

      -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

      Mesothelioma Positive Cancers Dose De-escalation Pilot Objective

      -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

      Phase 2 and Lung and Pancreatic Adenocarcinoma Expansion Pilot Objective

      -To evaluate objective tumor response in subjects with pleural mesothelioma, peritoneal

      mesothelioma, lung and pancreatic adenocarcinoma using Regimen A

      ELIGIBILITY:

        -  Patients with one of the following histologically confirmed malignancies:

             -  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

             -  advanced (Stage IIIB/IV) lung adenocarcinoma who have had at least one prior
                chemotherapy for advanced disease. Patients who received an approved targeted
                therapy as first-line treatment should have also received chemotherapy prior to
                study entry.

             -  recurrent, locally advanced unresectable or metastatic adenocarcinoma of the
                pancreas.

        -  Measurable disease by modified Response Evaluation Criteria in Solid Tumors (RECIST)
           criteria for pleural mesothelioma or by RECIST criteria for peritoneal mesothelioma,
           lung adenocarcinoma and pancreatic adenocarcinoma

             -  Adequate renal, hepatic and hematopoietic function

             -  No major surgery, radiotherapy, chemotherapy or biologic therapy within 28 days of
                therapy

      DESIGN:

      -During the mesothelioma pilot phase of this study, the first eleven mesothelioma 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) while the
      next 8 mesothelioma patients received 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). SS1P was administered every other day for six days (3 doses) beginning on
      the day after the last pentostatin dose in each cycle for both regimens.

        -  In the mesothelin positive cancers dose de-escalation pilot study, a maximum of 12
           patients with mesothelioma or lung or pancreatic adenocarcinoma will be enrolled in a
           3+3 design to test up to 2 decreasing dose levels of SS1P administered in combination
           with cyclophosphamide and pentostatin on the Regimen A schedule for safety.

        -  In the phase 2 mesothelioma and pancreatic and lung adenocarcinoma pilot expansion
           portions of the study, a two-stage Minimax phase II trial design will be used to enroll
           up to 16 evaluable subjects with pleural mesothelioma (cohort 1), up to 10 evaluable
           subjects with peritoneal mesothelioma (cohort 2), up to 10 patients with lung
           adenocarcinoma (cohort 3)and up to 10 evaluable subjects with pancreatic adenocarcinoma
           (cohort 4) who will receive treatment on Regimen A.

        -  Treatment cycles will be repeated for up to four 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 4)

        -  Toxicity will be assessed by the Cancer Therapy Evaluation Program (CTEP) Version 4.0 of
           Common Terminology Criteria in Adverse Events (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.

Trial Arms

Name	Type	Description	Interventions
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.	Pentostatin Cyclophosphamide SS1(dsFv)PE38 - lot 073I0809 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.	Pentostatin Cyclophosphamide SS1(dsFv)PE38 - lot 073I0809 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.	Pentostatin Cyclophosphamide SS1(dsFv)PE38 - lot 073I0809 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.	Pentostatin Cyclophosphamide SS1(dsFv)PE38 - lot 073I0809 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.	Pentostatin Cyclophosphamide SS1(dsFv)PE38 - lot 073I0809 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.	Pentostatin Cyclophosphamide SS1(dsFv)PE38 - lot 073I0809 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.	Pentostatin Cyclophosphamide SS1(dsFv)PE38 - lot 073I0809 SS1(dsFv)PE38 - lot FIL129J01

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 / 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)

        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 [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)

        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 (Eastern Cooperative Oncology Group (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/mm^3

               -  absolute neutrophil count less than or equal to 1,500/mm^3

               -  hemoglobin less than or equal to 9 g/dL

               -  platelets less than or equal to 90,000/ mm^3

               -  total bilirubin See guidelines for individual cohorts in sections 3.1.1.3,
                  3.1.2.4 and 3.1.3.3

               -  Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase
                  (SGOT))/alanine aminotransferase (ALT)(serum glutamic-pyruvic transaminase
                  (SGPT)) less than or equal to 3 X institutional upper limit of normal (ULN) (5x
                  if liver function test (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 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 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 (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.

        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.

Maximum Eligible Age:	99 Years
Minimum Eligible Age:	18 Years
Eligible Gender:	All
Healthy Volunteers:	No

Primary Outcome Measures

Measure:	Response Assessment
Time Frame:	52 months and 4 days
Safety Issue:
Description:	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.

Secondary Outcome Measures

Measure:	Overall Survival
Time Frame:	36 months
Safety Issue:
Description:	The Kaplan-Meier was used to determine the probability of overall survival from on-study date until death or last follow-up (calculated from the date of study entry until the date of analysis).

Measure:	Progression-free Survival
Time Frame:	36 months
Safety Issue:
Description:	Defined as the time interval from the start of treatment to documented evidence of disease progression. Progressive disease is assessed by the European Organization for Research and Treatment of Cancer (EORTC) modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and is at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum on study LD (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. (Note: the appearance of one or more new lesions is also considered progression).

Measure:	Duration of Response
Time Frame:	up to 2.5 years
Safety Issue:
Description:	DOR is assessed by the European Organization for Research and Treatment of Cancer (EORTC) modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria and is measured from the time measurement criteria is met for complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Complete response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to<10mm. partial response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Progressive disease is at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum on study LD (this includes the baseline sum if that is the smallest on study).

Details

Phase:	Phase 1/Phase 2
Primary Purpose:	Interventional
Overall Status:	Completed
Lead Sponsor:	National Cancer Institute (NCI)

Trial Keywords

Immune Therapy
Immunotoxin
T-Cell Depletion
Mesothelioma

Last Updated

June 6, 2019

Clinical Trials /

SS1P and Pentostatin Plus Cyclophosphamide for Mesothelioma