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

RATIONALE: Immunotoxins can find tumor cells and kill them without harming normal cells.

Drugs used in chemotherapy, such as pemetrexed and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing.

Giving more than one drug (combination chemotherapy) together with immunotoxin therapy may kill more malignant mesothelioma cells.

PURPOSE: This phase I trial is studying the side effects and best dose of immunotoxin therapy when given together with pemetrexed and cisplatin in treating patients with malignant pleural mesothelioma that cannot be removed by surgery.

Study Type: Interventional

Study Design: Treatment, Non-Randomized, Open Label, Active Control

Study Primary Completion Date: June 2009

OBJECTIVES:

Primary - To estimate the maximum tolerated dose (MTD) of SS1(dsFv)-PE38 immunotoxin when administered with pemetrexed disodium and cisplatin and to establish a safe dose, based on the MTD for subsequent clinical testing (phase II recommended dose) in patients with unresectable malignant epithelial pleural mesothelioma. - To characterize the toxicity profile of SS1(dsFv)-PE38 immunotoxin. - To study the clinical pharmacology (i.e., pharmacokinetics) which may dictate modification of SS1(dsFv)-PE38 immunotoxin schedule and administration in future studies. - To observe antitumor activity, if any, especially in patients who receive SS1(dsFv)-PE38 immunotoxin at or near the MTD (or phase II recommended dose).

Secondary - To monitor antibody formation to SS1(dsFv)-PE38 immunotoxin and to assess the impact of these antibodies on SS1(dsFv)-PE38 immunotoxin pharmacokinetics (PKs). - To investigate the potential of soluble mesothelin levels to predict PKs or any therapeutic or toxic response. - To perform a pilot assessment of a validated quality of life instrument.

OUTLINE: This is a dose-escalation study of SS1(dsFv)-PE38 immunotoxin.

Patients receive SS1(dsFv)-PE38 immunotoxin IV over 30 minutes on days 1, 3, and 5, pemetrexed disodium IV over 10 minutes on day 1, and cisplatin IV over 2 hours on day 1 in courses 1 and 2. Beginning in course 3 and all subsequent courses, patients receive pemetrexed disodium IV over 10 minutes and cisplatin IV over 2 hours on day 1. Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity.

Patients undergo blood sample collection at baseline, prior to course 2, and day 21 of course 2 for laboratory and pharmacokinetic studies. Samples are analyzed for the presence of anti-SS1(dsFv)-PE38 immunotoxin antibodies using a study drug-specific immunoassay and for concentrations of circulating mesothelin using enzyme-linked immunosorbent assay. Tumor cells from archival paraffin block biopsy specimens are analyzed for expression of mesothelin via immunohistochemistry.

Patients complete a quality of life questionnaire (i.e., LCSS-MESO) at baseline, after course 2, and subsequently after every even course to assess symptoms including appetite loss, fatigue, cough, dyspnea, and pain.

After completion of study treatment, patients are followed at 1, 3, 6, 12, 15, 18, 21, and 24 months.

Intervention(s) in this Clinical Trial

• Drug: SS1(dsFv)-PE38 immunotoxin
• Drug: cisplatin
• Drug: pemetrexed disodium
• Procedure: immunoenzyme technique
• Procedure: immunohistochemistry staining method
• Procedure: pharmacological study
• Procedure: quality-of-life assessment

Primary Measures

• Maximum tolerated dose of SS1(dsFv)-PE38 immunotoxin
  • Safety Issue?: Yes
• Pharmacokinetics of SS1(dsFv)-PE38 immunotoxin
  • Safety Issue?: No
• Antitumor response
  • Safety Issue?: No

Secondary Measures

• Measurement of antibody formation to drug and impact on pharmacokinetics
  • Safety Issue?: No

DISEASE CHARACTERISTICS:

• Histologically confirmed epithelial pleural mesothelioma not amenable to potentially curative surgical resection
• Unresectable disease, defined as any 1 of the following:
• Metastatic disease
• Patient found at surgery not to be amenable to resection
• Not to benefit from surgery due to extensive local disease or not a surgical candidate due to comorbid medical conditions as deemed by a qualified oncologist
• Measurable disease
• No documented and ongoing CNS involvement with malignant disease (history of CNS involvement is not an exclusion criterion)

PATIENT CHARACTERISTICS:

Inclusion criteria:

• Karnofsky performance status 70-100%
• Life expectancy > 3 months (assessed by the principal investigator)
• ALT, AST, or bilirubin ≤ grade 1 (unless due to cancer or Gilbert disease) OR ≤ grade 2 (if due to cancer)
• Serum creatinine clearance ≥ 60 mL/min
• ANC ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• FEV_1 ≥ 50% of predicted value (post-pleural drainage and bronchodilation if these are indicated)
• Must be able to understand and sign informed consent
• Other (non-mesothelioma) cancers that meet eligibility criteria and have had less than 5 years of disease-free survival are considered on a case by case basis
• May only be enrolled in this study once (i.e., no second time or later cohort re-enrollment)

Exclusion criteria:

• Clinically significant heart disease (New York Heart Association class III or IV)
• Active bacterial or fungal infection
• Baseline coagulopathy ≥ grade 3 (unless due to anticoagulant therapy)
• HIV-positive serology
• Hepatitis B surface antigen positivity
• Uncontrolled, symptomatic, intercurrent illness including, but not limited to, any of the following:
• Infections requiring systemic antibiotics
• Unstable angina pectoris
• Cardiac arrhythmia
• Psychiatric illness or social situation that would limit compliance with study requirements

PRIOR CONCURRENT THERAPY:

• More than 4 weeks since prior radiotherapy (except palliative extra-thoracic localized radiotherapy) or biologic therapy for malignant pleural mesothelioma
• More than 2 weeks since prior surgery or pleurodesis
• No prior systemic chemotherapy for malignant pleural mesothelioma

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National Cancer Institute (NCI)

Overall Clinical Trial Officials and Contacts

Raffit Hassan, MD Principal Investigator National Cancer Institute (NCI)  

Information obtained from ClinicalTrials.gov on September 05, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00575770

Study ID Number: CDR0000579640

ClinicalTrials.gov Identifier: NCT00575770

Health Authority: Unspecified

Clinical trial summary from the National Cancer Institute's PDQ® database