Cixutumumab in Treating Patients With Relapsed or Refractory Solid Tumors

Study Overview
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Brief Summary
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This phase II trial is studying the side effects and how well cixutumumab works in treating patients with relapsed or refractory solid tumors. 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.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the response rate to IMC-A12 (cixutumumab) administered in various strata of recurrent/refractory malignant solid tumors in childhood and young adulthood. II. To further define and describe the toxicities of IMC-A12. III. To further characterize the pharmacokinetics of IMC-A12. SECONDARY OBJECTIVES: I. To examine the relationship between tumor expression of insulin-like growth factor (IGF)-I, IGF-II, and IGF-I receptor (IR) and response to IMC-A12. II. To determine the human anti-human antibody (HAHA) response after treatment with IMC-A12. III. To further evaluate the effect of IMC-A12 on circulating levels of proteins involved in linear growth and glucose homeostasis, including IGF-I, IGF-II, IGF-BP3, growth hormone, insulin, and C-peptide. OUTLINE: This is a multicenter study. Patients are stratified according to disease type. Patients receive cixutumumab intravenously (IV) over 1 hour on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection periodically for correlative laboratory studies. Samples are analyzed for IGF-I, IGF-II, IGF-BP3, growth hormone, insulin, and C-peptide levels and for immunogenicity.

Official Title
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A Phase II Study of IMC-A12 (Anti-IGF-I Receptor Monoclonal Antibody, NSC #742460) in Children With Relapsed/Refractory Solid Tumors

Conditions
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Adult Rhabdomyosarcoma, Adult Synovial Sarcoma, Childhood Hepatoblastoma, Childhood Synovial Sarcoma, Previously Treated Childhood Rhabdomyosarcoma, Recurrent Adrenocortical Carcinoma, Recurrent Adult Soft Tissue Sarcoma, Recurrent Childhood Liver Cancer, Recurrent Childhood Rhabdomyosarcoma, Recurrent Childhood Soft Tissue Sarcoma, Recurrent Ewing Sarcoma/Peripheral Primitive, Neuroectodermal Tumor, Recurrent Neuroblastoma, Recurrent Osteosarcoma, Recurrent Retinoblastoma, Recurrent Wilms Tumor and Other Childhood Kidney Tumors

Intervention / Treatment
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* Biological: cixutumumab
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed malignant solid tumor, including the following: Osteosarcoma Ewing sarcoma/peripheral primitive neuroectodermal tumor Rhabdomyosarcoma Neuroblastoma Wilms tumor Synovial sarcoma Hepatoblastoma Adrenocortical carcinoma Retinoblastoma No known curative therapy or therapy proven to prolong survival with an acceptable quality of life exists Radiographically measurable disease*, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by MRI or CT scan or ≥ 10 mm by spiral CT scan The following are not considered measurable disease: Ascites, pleural effusions, or other malignant fluid collections Bone marrow infiltration by tumor Lesions detected only by non-MIBG nuclear medicine studies (e.g., bone scan) Previously irradiated lesions that have not demonstrated clear progression post-radiotherapy No known Central Nervous System (CNS) metastases unless they were treated by surgery or radiotherapy AND are stable with no recurrent lesions for ≥ 3 months Lansky or Karnofsky performance status (PS) 50-100% OR Eastern Cooperative Oncology Group (ECOG) PS 0-2 Absolute neutrophil count (ANC) ≥ 1,000/mm³ (> 250/mm³ for patients with neuroblastoma) Platelet count ≥ 75,000/mm³ (> 25,000/mm³ for patients with neuroblastoma) (transfusion independent) Hemoglobin ≥ 8.0 g/dL (≥ 7.5 g/dL for patients with neuroblastoma) (RBC transfusion allowed) Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR serum creatinine normal based on age/gender as follows: ≤ 0.4 mg/dL (for patients 1 to 5 months of age) ≤ 0.5 mg/dL (for patients 6 to 11 months of age) ≤ 0.6 mg/dL (for patients 1 year of age) ≤ 0.8 mg/dL (for patients 2 to 5 years of age) ≤ 1 mg/dL (for patients 6 to 9 years of age) ≤ 1.2 mg/dL (for patients 10 to 12 years of age) ≤ 1.5 mg/dL (males) or 1.4 mg/dL (females) (for patients 13 to 15 years of age) ≤ 1.7 mg/dL (males) or 1.4 mg/dL (females) (for patients ≥ 16 years of age) Total bilirubin ≤ 1.5 times upper limit of normal for age Alanine transaminase (ALT) ≤ 110 U/L Serum albumin ≥ 2 g/dL Blood glucose normal Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 3 months after completion of study treatment Able to comply with safety monitoring requirements of study No history of allergic reactions attributed to compounds of similar chemical or biologic composition to study drug No uncontrolled infection No known type I or II diabetes mellitus Recovered from prior chemotherapy, immunotherapy, or radiotherapy More than 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosoureas) At least 7 days since prior hematopoietic growth factors (14 days for pegfilgrastim) At least 6 weeks since prior monoclonal antibody therapy At least 7 days since other prior antineoplastic biologic agents No prior monoclonal antibody targeting the IGF-IR No prior small molecule kinase inhibitors of IGF-IR At least 2 weeks since prior local palliative (small port) radiotherapy At least 3 months since prior total-body irradiation, craniospinal radiotherapy, or radiotherapy to ≥ 50% of the pelvis At least 6 weeks since other prior substantial bone marrow radiotherapy At least 2 months since prior stem cell transplantation No evidence of graft-versus-host disease Concurrent corticosteroids allowed provided dose is stable or decreasing over the past 7 days Intermittent use of corticosteroids to manage infusional reactions allowed No other concurrent anticancer therapy, including chemotherapy, radiotherapy, immunotherapy, or biologic therapy No other concurrent investigational agents No concurrent insulin or growth hormone therapy

Ages Eligible for Study
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Minimum Age: 7 Months
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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 - Recurrent or Refractory Hepatoblastoma<br>Group 1 - Recurrent or Refractory Hepatoblastoma. Patients receive cixutumumab IV over 1 hour on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. | Biological: cixutumumab<br>* Given IV: Week 1 day 1, 9 mg/kg/dose over 1 hour. Week 2 Day 8, 9 mg/kg/dose over 1 hour. Week 3 Day 15, 9 mg/kg/dose over 1 hour. Week 4 Day 22, 9 mg/kg/dose over 1 hour.<br>* Other names: IMC-A12;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Group 2 - Recurrent or Refractory Synovial Sarcoma<br>Group 2 - Recurrent or Refractory Synovial Sarcoma. Patients receive cixutumumab IV over 1 hour on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. | Biological: cixutumumab<br>* Given IV: Week 1 day 1, 9 mg/kg/dose over 1 hour. Week 2 Day 8, 9 mg/kg/dose over 1 hour. Week 3 Day 15, 9 mg/kg/dose over 1 hour. Week 4 Day 22, 9 mg/kg/dose over 1 hour.<br>* Other names: IMC-A12;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Group 3 - Recurrent or Refractory Rhabdomyosarcoma<br>Group 3 - Recurrent or Refractory Rhabdomyosarcoma. Patients receive cixutumumab IV over 1 hour on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. | Biological: cixutumumab<br>* Given IV: Week 1 day 1, 9 mg/kg/dose over 1 hour. Week 2 Day 8, 9 mg/kg/dose over 1 hour. Week 3 Day 15, 9 mg/kg/dose over 1 hour. Week 4 Day 22, 9 mg/kg/dose over 1 hour.<br>* Other names: IMC-A12;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Grp 4-Recurrent or Refractory Adrenocortical Carcinoma<br>Group 4 - Recurrent or Refractory Adrenocortical Carcinoma. Patients receive cixutumumab IV over 1 hour on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. | Biological: cixutumumab<br>* Given IV: Week 1 day 1, 9 mg/kg/dose over 1 hour. Week 2 Day 8, 9 mg/kg/dose over 1 hour. Week 3 Day 15, 9 mg/kg/dose over 1 hour. Week 4 Day 22, 9 mg/kg/dose over 1 hour.<br>* Other names: IMC-A12;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Grp 5-Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor<br>Group 5 - Recurrent or Refractory Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor. Patients receive cixutumumab IV over 1 hour on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. | Biological: cixutumumab<br>* Given IV: Week 1 day 1, 9 mg/kg/dose over 1 hour. Week 2 Day 8, 9 mg/kg/dose over 1 hour. Week 3 Day 15, 9 mg/kg/dose over 1 hour. Week 4 Day 22, 9 mg/kg/dose over 1 hour.<br>* Other names: IMC-A12;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Grp 6 - Neuroblastoma-MIBG Positive Without Measurable Disease<br>Group 6 - Recurrent or Refractory Neuroblastoma -meta-iodobenzylguanidine (MIBG) Positive Without Measurable Disease. Patients receive cixutumumab IV over 1 hour on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. | Biological: cixutumumab<br>* Given IV: Week 1 day 1, 9 mg/kg/dose over 1 hour. Week 2 Day 8, 9 mg/kg/dose over 1 hour. Week 3 Day 15, 9 mg/kg/dose over 1 hour. Week 4 Day 22, 9 mg/kg/dose over 1 hour.<br>* Other names: IMC-A12;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Grp 7-Neuroblastoma with measurable disease<br>Group 7 - Recurrent or Refractory Neuroblastoma -With Measurable Disease. Patients receive cixutumumab IV over 1 hour on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. | Biological: cixutumumab<br>* Given IV: Week 1 day 1, 9 mg/kg/dose over 1 hour. Week 2 Day 8, 9 mg/kg/dose over 1 hour. Week 3 Day 15, 9 mg/kg/dose over 1 hour. Week 4 Day 22, 9 mg/kg/dose over 1 hour.<br>* Other names: IMC-A12;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Group 8 - Recurrent Osteosarcoma<br>Group 8 - Recurrent Osteosarcoma. Patients receive cixutumumab IV over 1 hour on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. | Biological: cixutumumab<br>* Given IV: Week 1 day 1, 9 mg/kg/dose over 1 hour. Week 2 Day 8, 9 mg/kg/dose over 1 hour. Week 3 Day 15, 9 mg/kg/dose over 1 hour. Week 4 Day 22, 9 mg/kg/dose over 1 hour.<br>* Other names: IMC-A12;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Group 9 - Recurrent or Refractory Wilms Tumor<br>Group 9 - Recurrent or Refractory Wilms Tumor. Patients receive cixutumumab IV over 1 hour on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. | Biological: cixutumumab<br>* Given IV: Week 1 day 1, 9 mg/kg/dose over 1 hour. Week 2 Day 8, 9 mg/kg/dose over 1 hour. Week 3 Day 15, 9 mg/kg/dose over 1 hour. Week 4 Day 22, 9 mg/kg/dose over 1 hour.<br>* Other names: IMC-A12;Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Experimental: Group 10 - Recurrent or Refractory Retinoblastoma<br>Group 10 - Recurrent or Refractory Retinoblastoma. Patients receive cixutumumab IV over 1 hour on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. | Biological: cixutumumab<br>* Given IV: Week 1 day 1, 9 mg/kg/dose over 1 hour. Week 2 Day 8, 9 mg/kg/dose over 1 hour. Week 3 Day 15, 9 mg/kg/dose over 1 hour. Week 4 Day 22, 9 mg/kg/dose over 1 hour.<br>* Other names: IMC-A12;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Response | Response rates will be calculated as the percent of patients whose best response is a Complete Response (CR) or Partial Response (PR). | First six treatment cycles - 24 weeks |