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SS1(dsFV)PE38 Plus Pemetrexed and Cisplatin to Treat Malignant Pleural Mesothelioma

Primary Purpose

Mesothelioma

Status

Terminated

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Multicycle SS1P

Pemetrexed

Cisplatin

Single cycle SS1P

About this trial

This is an interventional treatment trial for Mesothelioma focused on measuring Recombinant Immunotoxin, Monoclonal Antibody, Pseudomonas Exotoxin, Targeted Therapy, Pleural Mesothelioma, Mesothelioma, Epithelial Pleural Mesothelioma

Eligibility Criteria

18 Years - 100 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

INCLUSION CRITERIA:

Subjects must meet all of the following criteria to be eligible to participate in the study:

Subjects must have histologically confirmed epithelial or biphasic pleural mesothelioma not amenable to potentially curative surgical resection. However, patients with biphasic tumors that have a predominantly sarcomatoid component will be excluded.

Measurable disease

Subjects must be greater than or equal to 18 years old

Karnofsky Performance Status (KPS) of greater than or equal to 70

Life expectancy of greater than 3 months, as assessed by the principal investigator.

Adequate organ function with:Hepatic function: serum transaminases (either ALT or AST) or bilirubin, less than or equal to Grade 1, unless due to cancer or Gilbert s disease; less than or equal to Grade 2, if due to cancer

Renal function: serum creatinine clearance greater than or equal to 60mL/min as estimated by Cockroft-Gault formula.

Bone marrow function: ANC of at least 1,500/mm (3), Platelet count at least 100,000/mm (3)

Pulmonary Function: FEV (1) greater than or equal to 50 percent of predicted value (post-pleural drainage and bronchodilation if these are indicated)

Must be able to understand and sign informed consent

Female and male subjects agree to use an approved method of contraception during the study

EXCLUSION CRITERIA:

Subjects must not be pregnant or breast feeding

Prior radiotherapy (except palliative extra-thoracic localized radiotherapy) or biologic therapy for malignant pleural mesothelioma within 4 weeks

Prior systemic chemotherapy for malignant pleural mesothelioma

Documented and ongoing central nervous system involvement with their malignant disease (history of CNS involvement is not an exclusion criterion but the CNS metastases should have been adequately treated (radiation or surgical resection) and subjects are free from symptoms for 3 months off steroids).

Clinically significant heart disease (New York Heart Association Class III or IV)

Active bacterial or fungal infection.

Baseline coagulopathy greater than or equal to Grade 3 unless due to anticoagulant therapy

Surgery or pleurodesis within 2 weeks

HIV positive serology (due to increased risk of severe infection and unknown interaction of SS1(dsFv)PE38 with antiretroviral drugs)

Hepatitis B surface antigen positivity

Subjects with other (non-mesothelioma) cancers who meet eligibility criteria and have had less than 5 years of disease-free survival will be considered on a case-by-case basis

Uncontrolled, symptomatic, intercurrent illness including but not limited to: infections requiring systemic antibiotics, unstable angina pectoris, cardiac arrhythmia, psychiatric illness, or social situations that would limit compliance with study requirements.

Sites / Locations

National Institutes of Health Clinical Center, 9000 Rockville Pike

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Arm Description

Multi-cycle cohort

Single cycle cohort

Outcomes

Primary Outcome Measures

Safety and MTD

list of adverse events and highest dose at which fewer than 2 subjects experienced DLT

Best overall response

proportion of subjects experiencing complete response, partial response or stable disease as a best overall response

Secondary Outcome Measures

Full Information

NCT ID

NCT01445392

First Posted

September 30, 2011

Last Updated

August 2, 2018

Sponsor

National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT01445392

Brief Title

SS1(dsFV)PE38 Plus Pemetrexed and Cisplatin to Treat Malignant Pleural Mesothelioma

Official Title

A Phase 1, Single Center, Dose-Escalation Study of SS1(dsFv)PE38 Administered Concurrently With Pemetrexed and Cisplatin in Subjects With Unresectable Malignant Epithelial Pleural Mesothelioma

Study Type

Interventional

2. Study Status

Record Verification Date

August 1, 2018

Overall Recruitment Status

Terminated

Study Start Date

November 14, 2007 (undefined)

Primary Completion Date

January 31, 2014 (Actual)

Study Completion Date

October 3, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

5. Study Description

Brief Summary

Background: Standard therapy for mesothelioma is a combination of the drugs pemetrexed and cisplatin. However, the benefits of this treatment are limited, and in most treated patients the disease continues to worsen. SS1(dsFV)PE38 is a genetically engineered drug. It contains an antibody that binds to a certain protein on mesothelioma cells and a toxin (type of poison) made from a product of a bacterium called Pseudomonas aeruginosa. It is hoped that the antibody will attach to the cancer cells, allowing the toxin to enter and kill the cells. Objectives: To find out if SS1(dsFV)PE38, together with pemetrexed and cisplatin is safe and tolerable in patients with mesothelioma. To determine the maximum tolerated dose of SS1(dsFV)PE38 (the highest dose that does not cause unacceptable side effects). To see if SS1(dsFV)PE38 given with pemetrexed and cisplatin has any effect on patients tumors. To learn how the body breaks down SS1(dsFV)PE38. Eligibility: Patients 18 years of age and older with epithelial pleural mesothelioma whose disease cannot be cured with surgery, and have not had prior treatment with chemotherapy. Design: Treatment with pemetrexed, cisplatin and SS1(dsFV)PE38 in two 21-day cycles as follows: Day 1 - Intravenous (through a vein) infusions of pemetrexed and cisplatin. Days 1 and 2 - Intravenous solution to prevent dehydration that might occur with SS1(dsFV)PE38. Days 1, 3 and 5 Intravenous infusion of SS1(dsFV)PE38. Small groups (3 to 6) of patients are given SS1(dsFV)PE38 at a certain dose level. If the first group experiences no significant side effects, the next group a higher dose. This continues in succeeding groups until the maximum tolerated study dose (highest dose that patients can be given safely) is determined. Continuing standard treatment with additional cycles of pemetrexed and cisplatin. Evaluations during the treatment period: Physical examination, including vital signs and body weight checks, and pregnancy test for women who can become pregnant. Questions about medications and side effects. Blood and urine tests. Disease evaluation with CT, chest X-ray, and possibly PET scans, lung function tests, pulse oximetry, performance of daily activities and quality-of-life questionnaires. Post-treatment evaluations: Clinic visits at months 1, 3, 6, 12, 15, 18 and 21 for physical examination and disease assessment. End-of-study visit for blood tests, vital signs and weight measurements, disease assessment, electrocardiogram, pregnancy test for women who can become pregnant

Detailed Description

Background: SS1P (dsFv) PE38, is a recombinant immunotoxin targeting the tumor antigen mesothelin that is highly expressed in malignant mesothelioma. The maximum tolerated dose (MTD) of SS1 dsFv has been established in a phase I study. Combination therapy with pemetrexed plus cisplatin is the standard first line therapy for malignant mesothelioma, but results in a median overall survival of only 12.1 months. Combination of SS1(dsFv)PE38 with pemetrexed plus cisplatin could result in improved outcomes for patients with mesothelioma. Objectives: To determine the MTD of SS1(dsFv)PE38 that can be safely administered in combination with pemetrexed plus cisplatin in patients with mesothelioma. To characterize the toxicity profile of SS1(dsFv)PE38. To study the pharmacokinetics of SS1(dsFv)PE388. To observe anti-tumor activity, if any of SS1(dsFv)PE38 in combination with pemetrexed plus cisplatin. Eligibility: Subjects with histologically confirmed epithelial pleural mesothelioma. No prior radiotherapy (except palliative localized radiotherapy),systemic chemotherapy or biologic therapy for pleural mesothelioma. Design: This is a phase I dose-escalation study of SS1(dsFv)PE38 in combination with pemetrexed plus cisplatin. The dose of pemetrexed plus cisplatin will be the standard dose approved for malignant mesothelioma. The dose of SS1(dsFv)PE38 will be escalated to find the safe dose in combination with pemetrexed plus cisplatin. SS1(dsFv)PE38 will be administered concurrently with pemetrexed plus cisplatin in cycles one and two, and subjects will receive additional cycles of pemetrexed and cisplatin as per standard practice. Patients will be assessed for response every 6 weeks. An additional Single Cycle of SS1(dsFv)PE38 Cohort will involve up to 16 patients who will receive SS1(dsFv)PE38 administered for four or five doses during the first cycle concurrently with pemetrexed and cisplatin; subjects in this cohort will receive additional cycles of pemetrexed and cisplatin as per standard practice

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Mesothelioma

Keywords

Recombinant Immunotoxin, Monoclonal Antibody, Pseudomonas Exotoxin, Targeted Therapy, Pleural Mesothelioma, Mesothelioma, Epithelial Pleural Mesothelioma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

24 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm Type

Experimental

Arm Description

Multi-cycle cohort

Arm Title

Arm Type

Experimental

Arm Description

Single cycle cohort

Intervention Type

Biological

Intervention Name(s)

Multicycle SS1P

Intervention Description

Assigned dose level of SS1(dsFv)PE38 on days 1, 3 & 5 of a 21 day cycle for 2 cycles

Intervention Type

Drug

Intervention Name(s)

Pemetrexed

Intervention Description

500 mg/m^2 on day 1 of each 21 day cycle until disease progression

Intervention Type

Drug

Intervention Name(s)

Cisplatin

Intervention Description

75 mg/m^2 on day 1 of each 21 day cycle until disease progression

Intervention Type

Biological

Intervention Name(s)

Single cycle SS1P

Intervention Description

Patients 1 - 3 of single cycle cohort. 45 mcg/kg of SS1(dsFv)PE38 on 4 or 5 days (depending on dose level) of cycle 1 only.

Primary Outcome Measure Information:

Title

Safety and MTD

Description

list of adverse events and highest dose at which fewer than 2 subjects experienced DLT

Time Frame

30 days after last dose

Title

Best overall response

Description

proportion of subjects experiencing complete response, partial response or stable disease as a best overall response

Time Frame

Assessed every 42 days until disease progression

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

100 Years

Accepts Healthy Volunteers

Eligibility Criteria

INCLUSION CRITERIA: Subjects must meet all of the following criteria to be eligible to participate in the study: Subjects must have histologically confirmed epithelial or biphasic pleural mesothelioma not amenable to potentially curative surgical resection. However, patients with biphasic tumors that have a predominantly sarcomatoid component will be excluded. Measurable disease Subjects must be greater than or equal to 18 years old Karnofsky Performance Status (KPS) of greater than or equal to 70 Life expectancy of greater than 3 months, as assessed by the principal investigator. Adequate organ function with:Hepatic function: serum transaminases (either ALT or AST) or bilirubin, less than or equal to Grade 1, unless due to cancer or Gilbert s disease; less than or equal to Grade 2, if due to cancer Renal function: serum creatinine clearance greater than or equal to 60mL/min as estimated by Cockroft-Gault formula. Bone marrow function: ANC of at least 1,500/mm (3), Platelet count at least 100,000/mm (3) Pulmonary Function: FEV (1) greater than or equal to 50 percent of predicted value (post-pleural drainage and bronchodilation if these are indicated) Must be able to understand and sign informed consent Female and male subjects agree to use an approved method of contraception during the study EXCLUSION CRITERIA: Subjects must not be pregnant or breast feeding Prior radiotherapy (except palliative extra-thoracic localized radiotherapy) or biologic therapy for malignant pleural mesothelioma within 4 weeks Prior systemic chemotherapy for malignant pleural mesothelioma Documented and ongoing central nervous system involvement with their malignant disease (history of CNS involvement is not an exclusion criterion but the CNS metastases should have been adequately treated (radiation or surgical resection) and subjects are free from symptoms for 3 months off steroids). Clinically significant heart disease (New York Heart Association Class III or IV) Active bacterial or fungal infection. Baseline coagulopathy greater than or equal to Grade 3 unless due to anticoagulant therapy Surgery or pleurodesis within 2 weeks HIV positive serology (due to increased risk of severe infection and unknown interaction of SS1(dsFv)PE38 with antiretroviral drugs) Hepatitis B surface antigen positivity Subjects with other (non-mesothelioma) cancers who meet eligibility criteria and have had less than 5 years of disease-free survival will be considered on a case-by-case basis Uncontrolled, symptomatic, intercurrent illness including but not limited to: infections requiring systemic antibiotics, unstable angina pectoris, cardiac arrhythmia, psychiatric illness, or social situations that would limit compliance with study requirements.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Raffit Hassan, M.D.

Organizational Affiliation

National Cancer Institute (NCI)

Official's Role

Principal Investigator

Facility Information:

Facility Name

National Institutes of Health Clinical Center, 9000 Rockville Pike

City

Bethesda

State/Province

Maryland

ZIP/Postal Code

20892

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

8552591

Citation

Chang K, Pastan I. Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas, and ovarian cancers. Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):136-40. doi: 10.1073/pnas.93.1.136.

Results Reference

background

PubMed Identifier

1244564

Citation

Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31-41. doi: 10.1159/000180580.

Results Reference

background

PubMed Identifier

16082249

Citation

Hassan R, Kreitman RJ, Pastan I, Willingham MC. Localization of mesothelin in epithelial ovarian cancer. Appl Immunohistochem Mol Morphol. 2005 Sep;13(3):243-7. doi: 10.1097/01.pai.00000141545.36485.d6.

Results Reference

background

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SS1(dsFV)PE38 Plus Pemetrexed and Cisplatin to Treat Malignant Pleural Mesothelioma

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