Cixutumumab and Temsirolimus in Treating Younger Patients With Recurrent or Refractory Sarcoma

Study Overview
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Brief Summary
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This phase II trial studies how well cixutumumab and temsirolimus work in treating patients with recurrent or refractory sarcoma. Monoclonal antibodies, such as cixutumumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving cixutumumab and temsirolimus together may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the objective response rate to the combination of cixutumumab and temsirolimus in patients with relapsed or refractory osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, or non-rhabdomyosarcoma soft tissue sarcoma. II. To further describe the toxicities (including dose-limiting toxicities) of cixutumumab and temsirolimus administered on this schedule. SECONDARY OBJECTIVES: I. To assess the progression-free survival for patients treated in each disease stratum with this drug combination. II. To assess the incidence of insulin-like growth factor 1 receptor (IGF-1R), insulin receptor, ERK, RON, and mammalian target of rapamycin (mTOR) pathway activation in archival tumor material, and correlate with response. III. To evaluate minimal residual disease and IGF-1R tumor cell expression in the blood and bone marrow of Ewing sarcoma patients using flow cytometry. OUTLINE: This is a multicenter study. Patients are stratified according to diagnosis (osteosarcoma vs Ewing sarcoma/PNET vs rhabdomyosarcoma vs non-rhabdomyosarcoma soft tissue sarcoma). Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. Archived tumor tissue samples from most recent biopsy are collected and analyzed for IGF-1R, insulin receptor, AKT, ERK, mTOR, and S6 kinase pathway activation by immunohistochemistry (IHC) and banked for future correlative studies. Blood and bone marrow samples, from patients with Ewing sarcoma, may be collected at baseline and periodically during treatment for minimal residual disease analysis by flow cytometry. After completion of study treatment, patients are followed up periodically for 5 years.

Official Title
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A Phase II Study of Cixutumumab (IMC-A12) in Combination With Temsirolimus in Pediatric Patients With Recurrent or Refractory Solid Tumors

Conditions
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Childhood Alveolar Soft Part Sarcoma, Childhood Angiosarcoma, Childhood Epithelioid Sarcoma, Childhood Fibrosarcoma, Childhood Gliosarcoma, Childhood Leiomyosarcoma, Childhood Liposarcoma, Childhood Malignant Peripheral Nerve Sheath Tumor, Childhood Synovial Sarcoma, Previously Treated Childhood Rhabdomyosarcoma, Recurrent Childhood Rhabdomyosarcoma, Recurrent Childhood Soft Tissue Sarcoma, Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Recurrent Osteosarcoma, Rhabdomyosarcoma

Intervention / Treatment
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* Biological: Cixutumumab
* Other: Laboratory Biomarker Analysis
* Drug: Temsirolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with any of the following tumors who have experienced relapse following front-line therapy, or who are refractory to front-line therapy, are eligible: Osteosarcoma Ewing sarcoma/peripheral primitive neuroectodermal tumor (PNET) Rhabdomyosarcoma Non-rhabdomyosarcoma soft tissue sarcoma Patients must have had histologic verification of malignancy at original diagnosis or relapse All patients are required to submit archival tumor samples for immunohistochemical analysis (either paraffin-embedded tumor blocks or unstained slides) Tissue samples collected at original diagnosis or at relapse or at any subsequent resections or biopsies should be available and ready for shipment to the Biopathology Center (BPC) at time of study enrollment; the samples are required even if tissue samples have previously been sent to the BPC for other purposes or studies; blocks or slides should be shipped to the BPC within 7 days of study enrollment Patients must have radiographically measurable disease Measurable disease is defined as the presence of at least one lesion on magnetic resonance imaging (MRI) or computed tomography (CT) scan that can be accurately measured with the longest diameter a minimum of 10 mm in at least one dimension (CT scan slice thickness no greater than 5 mm) The following do not qualify as measurable disease: Malignant fluid collections (e.g., ascites, pleural effusions) Bone marrow infiltration Lesions only detected by nuclear medicine studies (e.g., bone, gallium, or positron emission tomography [PET] scans) Elevated tumor markers in plasma or cerebrospinal fluid(CSF) Previously radiated lesions that have not demonstrated clear progression post radiation Leptomeningeal lesions that do not meet the measurements noted above Patient?s current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life Patients with known central nervous system metastases are excluded unless treated surgically or with radiotherapy and stable with no recurrent lesions for at least 3 months Patients must have a Lansky or Karnofsky performance status score of ? 50%, corresponding to Eastern Cooperative Oncology Group (ECOG) categories 0, 1, or 2; use Karnofsky for patients > 16 years of age and Lansky for patients ? 16 years of age Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score For patients with solid tumors without bone marrow involvement: Peripheral absolute neutrophil count (ANC) ? 1,000/?L Platelet count ? 100,000/?L (transfusion independent, defined as not receiving platelet transfusions within a 7-day period prior to enrollment) Hemoglobin ? 8.0 g/dL (may receive red blood cell [RBC] transfusions) For patients with solid tumors and known bone marrow metastatic disease: ANC ? 750/?L Platelet count ? 50,000/?L (may receive platelet transfusions) Hemoglobin ? 8.0 g/dL (may receive RBC transfusions) For patients with known bone marrow metastatic disease, transfusions are permitted to meet both platelet and hemoglobin criteria; patients must not be known to be refractory to red blood cell or platelet transfusions Creatinine clearance or radioisotope GFR ? 70 mL/min OR a serum creatinine based on age/gender as follows: 0.6 mg/dL (1 to < 2 years of age) 0.8 mg/dL (2 to < 6 years of age) 1.0 mg/dL (6 to < 10 years of age) 1.2 mg/dL (10 to < 13 years of age) 1.5 mg/dL (males) or 1.4 mg/dL (females) (13 to < 16 years of age) 1.7 mg/dL (males) or 1.4 mg/dL (females) ( ? 16 years of age) Total bilirubin ? 1.5 times upper limit of normal (ULN) Serum glutamic pyruvate transaminase(SGPT) (alanine aminotransaminase [ALT]) ? 2.5 times ULN (for the purpose of this study, the ULN for SGPT is 45 U/L) Serum albumin ? 2 g/dL Patients with seizure disorder may be enrolled if receiving non-enzyme-inducing anticonvulsants and well controlled Patients with known type I or type II diabetes mellitus are not eligible Serum glucose values must be within the normal limits for age; if the initial blood glucose is a random sample that is outside normal limits, then a follow-up fasting blood glucose should be obtained and must be within the normal limits for age Serum cholesterol levels must be < grade 2 (< 300 mg/dL), and serum triglyceride levels must be < grade 2 (< 2.5 times ULN) Patients who are pregnant or breast-feeding are not eligible for this study Negative pregnancy tests must be obtained in girls who are post-menarchal Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method for the duration of the study and for 3 months after the last dose of cixutumumab Patients who have an uncontrolled infection are not eligible Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study are not eligible See Disease Characteristics There is no limit to the number of prior treatment regimens; however, patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to study enrollment Patients must not have received myelosuppressive chemotherapy within 3 weeks of enrollment (6 weeks if prior nitrosourea) At least 7 days must have elapsed since the completion of therapy with a growth factor; at least 14 days must have elapsed after receiving pegfilgrastim At least 7 days must have elapsed since the completion of therapy with a biologic agent; for agents that have known adverse events occurring beyond 7 days after administration, this period prior to enrollment must be extended beyond the time during which adverse events are known to occur At least 3 half-lives must have elapsed since prior therapy that included a monoclonal antibody ? 2 weeks must have elapsed since local palliative radiotherapy (XRT) (small port); 3 months must have elapsed if 50% radiation of pelvis; 6 weeks must have elapsed if therapeutic doses of metaiodobenzylguanidine(MIBG) or other substantial bone marrow irradiation was given No evidence of active graft-vs-host disease and 2 months must have elapsed since stem cell transplant or rescue Growth factors that support platelet or white cell number or function must not have been administered within the 7 days prior to enrollment (14 days if Neulasta?) Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for the 7 days prior to enrollment are not eligible Patients who are currently receiving another investigational drug are not eligible Patients who are currently receiving other anti-cancer agents, including chemotherapy, radiotherapy, immunotherapy, or biologic therapy, are not eligible Patients receiving insulin or growth hormone therapy are not eligible Patients who are receiving enzyme-inducing anticonvulsants are not eligible Use of warfarin is not allowed while on study; patients already on warfarin should use alternative anticoagulants while on this study; warfarin must not have been administered within 7 days of starting protocol therapy Patients who have received prior therapy targeting IGF-1R with either monoclonal antibodies or small molecule tyrosine kinase inhibitors are NOT eligible Prior treatment with mTOR inhibitors (e.g., rapamycin, temsirolimus, everolimus, deforolimus) is NOT allowed Patients who have had major surgery within 3 weeks prior to enrollment are not eligible; procedures such as placement of a central vascular catheter or limited tumor biopsy are not considered major surgery

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 30 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: Treatment (cixutumumab, temsirolimus)<br>Patients receive cixutumumab IV over 1 hour and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 25 courses in the absence of disease progression or unacceptable toxicity. | Biological: Cixutumumab<br>* Given IV<br>* Other names: IMC-A12;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Temsirolimus<br>* Given IV<br>* Other names: Torisel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (PR or CR) by Response Evaluation Criteria in Solid Tumors (RECIST). | Per Response evaluation criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions. Overall Response (OR)= CR+PR. The combination of sufficient activity is considered if the true response rate is 35% or greater. | 6 cycles (168 days) | 
| Number of Cycles of Toxicity | The number of patients-cycles where CTC Version 4 grade 3 or higher increased Alanine aminotransferase was observed | Duration of protocol therapy - Up to 25 cycles (700 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Interval | Percentage Probability of remaining progression-free 5 years after enrollment estimated by the method of Kaplan and Meier | 10 months after enrollment | 
| Expression Levels of IGF-1R, Insulin Receptor, ERK, RON, and mTOR | Number of patients expressing insulin-like growth factor 1 receptor (IGF-1R), insulin receptor, ERK, RON, and mammalian target of rapamycin (mTOR) at levels 0, 1+, 2+, 3+ by immunohistochemistry. | Baseline | 
| Number of Patients With Detectable Bone Marrow Micrometastatic Disease Estimated as the Proportion of Eligible Patients Entered Into the Ewing Sarcoma Stratum Who Have Detectable Tumor Cells in the Marrow at Enrollment |  | Baseline |