Multicenter Phase II Study of IMC-A12 in Patients With Thymoma and Thymic Carcinoma Who Have Been Previously Treated With Chemotherapy

Study Overview
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Brief Summary
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Background: Cisplatin-containing chemotherapy is the standard of care for advanced thymoma and thymic carcinoma that cannot be treated with surgery. New options for treatment are necessary in patients with advanced thymoma and thymic carcinoma that have progressed on cisplatin-containing therapy. IMC-A12 is a new (experimental) agent that has not yet been approved by the Food and Drug Administration. IMC-A12 blocks the Insulin-like Growth Factor 1 receptor (IGF-1R). IGF-1R is found on many types of cancer cells, including cancer of the thymus, and is thought to play an important role in helping these cells to grow and divide. Objectives: To determine if IMC-A12 has an effect on tumor growth in patients with cancer of the thymus. To evaluate the safety and tolerability of IMC-A12 in treatment for cancer of the thymus. Eligibility: - Individuals older than 18 years of age who have cancer of the thymus (thymoma, thymic carcinoma, or thymic carcinoid tumors) that has progressed in spite of standard treatment. Design: Treatment will take place in 21-day cycles. Patients will receive one dose of IMC-A12 intravenously once every 3 weeks at the Clinical Center. During the Clinical Center visits, researchers will perform study tests and procedures to see how the study drugs are affecting the body. Patients will undergo a number of tests and procedures during the treatment cycle, including physical examinations, blood and urine samples for standard tests, imaging studies (ultrasound, magnetic resonance imaging (MRI) or computed tomography (CT) scans) to evaluate tumor growth, and blood and urine samples to evaluate the amount of IMC-A12 in the body. Patients may continue to take the drug as long as there are no adverse side effects and as long as the tumor does not grow.

Detailed Description
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Background: Cisplatin-containing chemotherapy is the standard of care for advanced unresectable thymoma and thymic carcinoma. New options for treatment are necessary in patients with advanced thymoma and thymic carcinoma that have progressed on cisplatin-containing therapy. The insulin-like growth factor (IGF) pathway is being studies in various malignancies including thymoma and thymic carcinoma. IMCA12 is an anti-IGF-1R monoclonal antibody that has shown activity in patients with thymic malignancies. Objectives: To determine the objective response rate (partial response (PR)+complete response (CR)) to IMC-A12 monotherapy in patients with advanced or recurrent thymoma or thymic carcinoma. To evaluate time to response, duration of response, progression-free survival (PFS) and overall survival (OS) To assess safety of IMC-A12 To perform immunohistochemistry for IGF1R expression on tumor samples of thymoma and thymic carcinoma (exploratory) To correlate response to therapy with changes in fludeoxyglucose 18F-positron emission tomography (FDG-PET) imaging at baseline and first restaging To perform pharmacokinetic (PK) analysis of IMC-A12 To perform pharmacodynamic (PD) analysis in blood for the detection of IGF1R, AKT and pAKT in peripheral blood mononuclear cells (PBMC's) (exploratory). To assess circulating endothelial cell, circulating endothelial progenitor cells, immune subset analysis and glucose transport in peripheral blood monocytes and lymphocytes (exploratory). To evaluate anti-cytokine antibodies in peripheral blood (exploratory). Eligibility: Patients with histologically confirmed thymic carcinoma or thymoma who have previously been treated on at least one platinum-containing chemotherapy regimen Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria 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 Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 until December 31, 2010, and by CTCAE Version 4.0 beginning January 1, 2011 Tumor response assessments by RECIST 1.0 criteria will be performed every 2 cycles Correlative studies including tissue immunohistochemistry studies will be done on existing tumor blocks Blood samples will be collected for for PK's, PD's, circulating endothelial cells (CEC's), circulating endothelial precursor cells (CEPC's), immune subsets, glucose transport and cytokine antibodies.

Official Title
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Multicenter Phase II Study of IMC-A12 in Patients With Thymoma and Thymic Carcinoma Who Have Been Previously Treated With Chemotherapy

Conditions
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Thymoma, Thymic Carcinoma, Thymic Carcinoid, Thymic Neuroendocrine Tumors

Intervention / Treatment
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* Drug: IMC-12


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Histologically confirmation of invasive recurrent or metastatic thymoma or thymic carcinoma by the pathology department / Center for Cancer Research (CCR) / National Cancer Institute (NCI), or the pathology department of participating institutions. Patients must have had at least one prior platinum-containing chemotherapy regimen. There is no limit to the number of prior chemotherapy regimens received. Progressive disease should have been documented before entry into the study. 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 greater than 20 mm with conventional techniques or as greater than 10 mm with spiral CT scan. See section 11 for the evaluation of measurable disease. Target lesions cannot be selected within previously irradiated areas, if not newly arising or clearly progressing after irradiation as proven by repeat scanning. Patients must have recovered from toxicity related to prior therapy to at least to grade 1 (defined by CTCAE 3.0 until December 31, 2010, and by CTCAE 4.0 beginning January 1, 2011) and 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. Concurrent corticosteroids for myasthenia gravis, or other paraneoplastic syndromes which often accompany thymic malignancies are allowed. Inhaled steroids are also allowed. However since steroids might occasionally induce responses in thymic malignancies patients should be on a stable dose of steroids for greater than or equal to 8 weeks before enrollment in order not to confound the efficacy assessment. Age greater than 18 years. Because no dosing or adverse event data are currently available on the use of IMC-A12 in patients less than 16 years of age, children are excluded from this study but will be eligible for future pediatric phase 1 single-agent trials. 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). Patients must have returned to baseline or grade 1 from any acute toxicity related to prior therapy: 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 the institutional upper limit of normal (ULN) aspartate aminotransferase (AST)(SGOT)/alanine aminotransferase (ALT)(SGPT) less than or equal to 3 times the institutional ULN (5x if LFT elevations due to liver metastases) creatinine less than or equal to 1.5 times the 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 9.0. The patient must have fasting serum glucose less than 120 mg/dL or below the institutional ULN 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 (hormonal or 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. 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 within the normal range (fasting less than 120 mg/dL or below institutional upper limit of normal) and if they are on a stable dietary or therapeutic regimen for this condition. 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 greater than 50 copies HIV/ml), and/or 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 thymic malignancies 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, in situ carcinoma of the cervix, and surgically-removed papillary thyroid cancer 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. 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. IgG antibody may also potentially be secreted in milk and therefore breastfeeding women should be excluded. 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Thymoma<br>Patients will receive IMC-A12 at a dose of 20 mg/kg intravenously once every three weeks. The most common tumors of the thymus are thymomas (well differentiated neoplasms and moderately differentiated neoplasms) and thymic (poorly differentiated neoplasms) carcinomas. | Drug: IMC-12<br>* 20 mg/kg intravenously once every three weeks<br>|
| Experimental: Thymic Carcinoma<br>Patients will receive IMC-A12 at a dose of 20 mg/kg intravenously once every three weeks. The most common tumors of the thymus are thymomas (well differentiated neoplasms and moderately differentiated neoplasms) and thymic (poorly differentiated neoplasms) carcinomas. | Drug: IMC-12<br>* 20 mg/kg intravenously once every three weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (Partial Response (PR)+Complete Response (CR)) to IMC-A12 Monotherapy in Patients With Advanced or Recurrent Thymoma or Thymic Carcinoma. | Objective response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Complete response (CR) is the 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, taking as reference the baseline sum LD. Progressive disease (PD) is at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new 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. | Patients were assessed for response every 2 cycles (every 6 weeks) while receiving the study drug. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module. | 81 months and 17 days | 
| Percentage of Participants Who Respond to Treatment | Percentage of participants who respond to treatment was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). | 39 months | 
| Disease Control Rate (DCR) | Disease control rate is defined as objective response plus stable disease. | 39 months | 
| Time to Progression | Time between the first day of treatment to the day of disease progression. | 39 months | 
| Overall Survival | Time from treatment start date until date of death or date last known alive. | 39 months | 
| Median Number of Cycles of Therapy | A cycle is defined as 21 days or 6 weeks of therapy. | 6 weeks | 
| Correlate Response to Therapy With Changes in FDG-PET Imaging | Participants with scans that showed neither sufficient shrinkage to qualify as an objective response nor sufficient increase to qualify as disease progression, taking as reference the smallest cumulative longest dimension since start of treatment, to have stable disease. | 6 weeks after initiation of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Thymic Malignancies, IMC-A12, Insulin-Like Growth Factor