Phase II Study of IMC-A12 in Patients With Mesothelioma Who Have Been Previously Treated With Chemotherapy

Study Overview
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Brief Summary
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Background: Background: - IMC-A12, a new cancer treatment that has not yet been approved by the U.S. Food and Drug Administration, is an antibody that is designed to block the effects of a protein called Type I Insulin-Like Growth Factor (IGF-1R). IMC-A12 blocks the receptors in cells that respond to IGF-1R, which are thought to play an important role in helping cancer cells to grow and divide. Researchers are interested in determining whether IMC-A12 is an effective treatment for individuals who have mesothelioma that has not responded to standard chemotherapy. Objectives: - To evaluate the safety and effectiveness of IMC-A12 treatment in individuals with mesothelioma who have previously had chemotherapy. Eligibility: - Individuals at least 18 years of age who have been diagnosed with mesothelioma that has not responded to chemotherapy. Design: Eligible participants will be screened with a full physical examination and medical history, blood and urine samples, and imaging studies. Participants will receive IMC-A12 once every 3 weeks (21-day cycle), and will be evaluated before the start of each new cycle with blood tests and imaging studies if needed. Treatment cycles will continue for as long as needed, unless severe side effects develop or the disease progresses.

Detailed Description
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Background: Platinum-based chemotherapy is the standard of care for advanced unresectable malignant mesothelioma. New options for treatment are necessary in patients with advanced disease that have progressed on platinum-based therapy. The insulin-like growth factor (IGF) pathway is being studies in various malignancies including mesothelioma. IMC-A12 is an anti-IGF-1R monoclonal antibody that has shown activity in patients with various malignancies. Objectives: Primary Objective: - To determine the clinical response rate (partial response (PR)+complete response (CR)) to IMC-A12 monotherapy in patients with advanced mesothelioma. Secondary Objectives: To determine response duration, progression free survival (PFS) and overall survival (OS). To assess safety of IMC-A12 in patients with mesothelioma Exploratory Objectives: To evaluate tumor IGF-1R expression and correlation with response To correlate response to therapy with changes in fludeoxyglucose 18F-positron emission tomography (FDG-PET) imaging. To monitor serum mesothelin and cancer antigen 125 or carbohydrate antigen 125 (CA-125) levels prior to and during therapy. Eligibility: Patients with histologically confirmed malignant pleural or peritoneal mesothelioma who have previously been treated on at least one platinum-containing chemotherapy regimen with progressive disease documented prior to study entry, or have refused cytotoxic chemotherapy. Measurable disease by modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria for pleural mesothelioma or by RECIST criteria for peritoneal mesothelioma. Adequate renal, hepatic and hematopoietic function. No major surgery, radiotherapy, chemotherapy or biologic therapy within 28 days of IMC-A12 therapy Design: Patients will receive IMC-A12 at a dose of 20 mg/kg intravenously once every three weeks. Treatment with IMC-A12 alone will continue until disease progression. Toxicity will be assessed every cycle by the Cancer Therapy Evaluation Program (CTEP) Version 4.0 of Common Terminology Criteria for Adverse Events (CTCAE). Tumor response assessments will be performed every 2 cycles.

Official Title
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Phase II Study of IMC-A12 in Patients With Mesothelioma Who Have Been Previously Treated With Chemotherapy

Conditions
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Pleural Mesothelioma, Peritoneal Mesothelioma

Intervention / Treatment
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* Drug: IMC-A12


Participation Criteria
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Eligibility Criteria
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-INCLUSION CRITERIA: Subjects must have histologically confirmed pleural or peritoneal mesothelioma not amenable to potentially curative surgical resection. The diagnosis will be confirmed by the pathology department / Center for Cancer Research (CCR) / National Cancer Institute (NCI). Patients must have had at least one prior platinum-containing chemotherapy regimen. There is no limit to the number of prior chemotherapy regimens received. 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 computed tomography (CT) scan. 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 mesothelioma is extremely rare in children they are excluded from this study. Life expectancy of greater than 3 months. Performance status Eastern Cooperative Oncology Group (ECOG) less than or equal to 2. Patients must have adequate organ and marrow function (as defined below). leukocytes greater than or equal to 3,000/mm^3 absolute neutrophil count greater than or equal to 1,500/mm^3 hemoglobin greater than or equal to 9 g/dL platelets greater than or equal to 100,000/ mm^3 total bilirubin less than or equal to 1.5 times institutional upper limit of normal (ULN) Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) serum glutamic pyruvic transaminase(SGPT) less than or equal to 3 times institutional ULN (5 times if liver function test (LFT) elevations due to liver metastases) creatinine less than or equal to 1.5 times institutional ULN OR - creatinine clearance greater than or equal to 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal Patients may be transfused to obtain a hemoglobin of greater than or equal to 9 g/Dl. The patient must have fasting serum glucose < 160 mg/dL The effects of IMC-A12 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 IMC-A12. 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. Inclusion of 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. EXCLUSION CRITERIA: 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 3 months without steroids may be enrolled at the discretion of the principal investigator. Patients with poorly controlled diabetes mellitus. Patients with a history of diabetes mellitus are allowed to participate, provided their blood glucose is below 160 mg/dL when fasting and if they are on a stable dietary or therapeutic regimen for this condition with their HbA1C of less than 7%. 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 with poorly controlled viral loads (viral load > 50 copies HIV/ml), and/or acquired immune deficiency syndrome (AIDS)-defining illnesses will be excluded due to the possibility that IMC-A12 may worsen their condition and the likelihood that the underlying condition may obscure the attribution of adverse events with respect to IMC-A12. HIV positive patients with mesothelioma not meeting the above criteria can be considered for inclusion in the study. Patients may not be receiving any other investigational agents. History of another invasive malignancy in the last five years. Adequately treated non-invasive, non-melanoma skin cancers as well as in situ carcinoma of the cervix will be allowed. Prior treatment with drugs of the IGF-1R inhibitor class. Patients with tumor amenable to potentially curative therapy as assessed by the investigator. In patients with peritoneal mesothelioma who have had no prior surgery, a surgical consultation will be obtained to see if the patient is a candidate for debulking surgery. Pregnant women are excluded from this study because IMC-A12 is a monoclonal antibody to IGF-1R with the potential for teratogenic or abortifacient effects. Immunoglobulin G (IgG) antibody 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. Patients must not be on hormonal forms of birth control or hormone replacement therapy, as this may affect the study drug. Patients must be off hormonal forms of birth control or hormone replacement therapy for at least 4 weeks prior to initiating the study. History of allergic reactions attributed to compounds of similar chemical or biologic composition to IMC-A12.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IMC-A12 Monotherapy in Patients<br>20 mg/kg intravenous over 60 minutes or not to exceed 25 mg/minute once every 3 weeks (+ or -1 day cycle 3 and beyond) | Drug: IMC-A12<br>* 20 mg/kg intravenous over 60 minutes or not to exceed 25 mg/minute once every 3 weeks (+ or -1 day cycle 3 and beyond)<br>* Other names: A12 Cixutumumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Response Rate (PR+CR) | Clinical response is assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response is complete disappearance of all target lesions. 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. | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of IMC-A12 in Patients With Mesothelioma | Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module. | Date treatment consent signed to date off study, approximately 36 months | 
| Duration of Overall Response | Duration of Overall Response is assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) and is measured from the time measurement criteria are met for complete response (CR) or partial response (PR) (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 complete disappearance of all target lesions. 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 longest diameter of target lesions. 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). | 36 months | 
| Progression Free Survival (PFS) | Progression Free Survival is defined as the time interval from the start of treatment to documented evidence of disease progression. Progressive disease is at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study longest diameter (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). | To study completion, an average of 3 years | 
| Overall Survival (OS) | Overall survival is the time interval from the start of treatment to the date of death. | To study completion, an average of 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Monoclonal Antibody, Pleural Mesothelioma, Peritoneal Mesothelioma