Adult Rhabdomyosarcoma, Adult Synovial Sarcoma, Childhood Hepatoblastoma, Childhood Synovial Sarcoma, Neuroectodermal Tumor, 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, Recurrent Neuroblastoma, Recurrent Osteosarcoma, Recurrent Retinoblastoma, Recurrent Wilms Tumor and Other Childhood Kidney Tumors
Conditions
Brief summary
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
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.
Interventions
BIOLOGICALcixutumumab
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.
OTHERlaboratory biomarker analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
7 Months to 30 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease Response | First six treatment cycles - 24 weeks | Response rates will be calculated as the percent of patients whose best response is a Complete Response (CR) or Partial Response (PR). |
Countries
Australia, Canada, United States
Participant flow
Recruitment details
No patients were enrolled in Group 10, recurrent or refractory retinoblastoma.
Participants by arm
| Arm | Count |
|---|---|
| Group 1 - Recurrent or Refractory Hepatoblastoma 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.
cixutumumab: Given IV
laboratory biomarker analysis: Correlative studies | 10 |
| Group 2 - Recurrent or Refractory Synovial Sarcoma 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.
cixutumumab: Given IV
laboratory biomarker analysis: Correlative studies | 12 |
| Group 3 - Recurrent or Refractory Rhabdomyosarcoma 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.
cixutumumab: Given IV
laboratory biomarker analysis: Correlative studies | 21 |
| Grp 4-Recurrent or Refractory Adrenocortical Carcinoma 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.
cixutumumab: Given IV
laboratory biomarker analysis: Correlative studies | 10 |
| Grp 5-Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor 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.
cixutumumab: Given IV
laboratory biomarker analysis: Correlative studies | 14 |
| Grp 6 - Neuroblastoma-MIBG Positive Without Measurable Disease Group 6 - Recurrent or Refractory Neuroblastoma -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.
cixutumumab: Given IV
laboratory biomarker analysis: Correlative studies | 20 |
| Grp 7-Neuroblastoma With Measurable Disease 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.
cixutumumab: Given IV
laboratory biomarker analysis: Correlative studies | 10 |
| Group 8 - Recurrent Osteosarcoma 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.
cixutumumab: Given IV
laboratory biomarker analysis: Correlative studies | 10 |
| Group 9 - Recurrent or Refractory Wilms Tumor 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.
cixutumumab: Given IV
laboratory biomarker analysis: Correlative studies | 9 |
| Group 10 - Recurrent or Refractory Retinoblastoma 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.
cixutumumab: Given IV
laboratory biomarker analysis: Correlative studies | 0 |
| Total | 116 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 | 0 | 0 | 1 | 1 | 2 | 0 | 0 | 0 |
| Overall Study | Death | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Ineligible | 0 | 1 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Lack of Efficacy | 8 | 10 | 15 | 8 | 11 | 17 | 8 | 9 | 7 | 0 |
| Overall Study | Physician Decision | 0 | 1 | 3 | 1 | 1 | 1 | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Group 3 - Recurrent or Refractory Rhabdomyosarcoma | Grp 4-Recurrent or Refractory Adrenocortical Carcinoma | Group 2 - Recurrent or Refractory Synovial Sarcoma | Grp 5-Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor | Grp 6 - Neuroblastoma-MIBG Positive Without Measurable Disease | Group 1 - Recurrent or Refractory Hepatoblastoma | Grp 7-Neuroblastoma With Measurable Disease | Group 8 - Recurrent Osteosarcoma | Group 9 - Recurrent or Refractory Wilms Tumor |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 93 participants | 16 participants | 8 participants | 8 participants | 9 participants | 18 participants | 10 participants | 7 participants | 8 participants | 9 participants |
| Age, Categorical >=65 years | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Age, Categorical Between 18 and 65 years | 23 participants | 5 participants | 2 participants | 4 participants | 5 participants | 2 participants | 0 participants | 3 participants | 2 participants | 0 participants |
| Age, Continuous | 13 years | 14 years | 14 years | 17.5 years | 17 years | 10.5 years | 3 years | 14.5 years | 14.5 years | 7 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 15 participants | 3 participants | 2 participants | 4 participants | 0 participants | 2 participants | 1 participants | 1 participants | 1 participants | 1 participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 96 participants | 17 participants | 8 participants | 8 participants | 14 participants | 18 participants | 7 participants | 8 participants | 9 participants | 7 participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 participants | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 2 participants | 1 participants | 0 participants | 1 participants |
| Gender Female | 55 participants | 6 participants | 6 participants | 6 participants | 6 participants | 8 participants | 3 participants | 9 participants | 3 participants | 8 participants |
| Gender Male | 61 participants | 15 participants | 4 participants | 6 participants | 8 participants | 12 participants | 7 participants | 1 participants | 7 participants | 1 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race (NIH/OMB) Asian | 5 participants | 1 participants | 0 participants | 1 participants | 1 participants | 0 participants | 1 participants | 1 participants | 0 participants | 0 participants |
| Race (NIH/OMB) Black or African American | 15 participants | 4 participants | 1 participants | 0 participants | 0 participants | 3 participants | 2 participants | 0 participants | 3 participants | 2 participants |
| Race (NIH/OMB) More than one race | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race (NIH/OMB) Unknown or Not Reported | 16 participants | 3 participants | 1 participants | 2 participants | 1 participants | 1 participants | 3 participants | 3 participants | 1 participants | 1 participants |
| Race (NIH/OMB) White | 80 participants | 13 participants | 8 participants | 9 participants | 12 participants | 16 participants | 4 participants | 6 participants | 6 participants | 6 participants |
| Region of Enrollment Australia | 6 participants | 3 participants | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Canada | 2 participants | 0 participants | 1 participants | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Region of Enrollment United States | 108 participants | 18 participants | 9 participants | 11 participants | 14 participants | 19 participants | 10 participants | 9 participants | 10 participants | 8 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 10 | 7 / 10 | 14 / 20 | 5 / 10 | 8 / 13 | 9 / 20 | 9 / 10 | 5 / 9 | 9 / 9 | 0 / 0 |
| serious Total, serious adverse events | 7 / 10 | 3 / 10 | 4 / 20 | 5 / 10 | 5 / 13 | 5 / 20 | 4 / 10 | 4 / 9 | 5 / 9 | 0 / 0 |
Outcome results
Primary
Disease Response
Response rates will be calculated as the percent of patients whose best response is a Complete Response (CR) or Partial Response (PR).
Time frame: First six treatment cycles - 24 weeks
Population: Grp 2, 12 enrolled 1 ineligible, 1 progressive disease prior to first dose of therapy. Grp 3, 21 enrolled, 1 ineligible. Grp 5, 14 enrolled, 1 ineligible. Grp 8, 10 enrolled, 1 not evaluable (patient didn't receive any drug).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1 - Recurrent or Refractory Hepatoblastoma | Disease Response | Non-Responder | 10 patient |
| Group 1 - Recurrent or Refractory Hepatoblastoma | Disease Response | Responder | 0 patient |
| Group 2 - Recurrent or Refractory Synovial Sarcoma | Disease Response | Non-Responder | 10 patient |
| Group 2 - Recurrent or Refractory Synovial Sarcoma | Disease Response | Responder | 0 patient |
| Group 3 - Recurrent or Refractory Rhabdomyosarcoma | Disease Response | Non-Responder | 19 patient |
| Group 3 - Recurrent or Refractory Rhabdomyosarcoma | Disease Response | Responder | 1 patient |
| Grp 4-Recurrent or Refractory Adrenocortical Carcinoma | Disease Response | Non-Responder | 10 patient |
| Grp 4-Recurrent or Refractory Adrenocortical Carcinoma | Disease Response | Responder | 0 patient |
| Grp 5-Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor | Disease Response | Non-Responder | 11 patient |
| Grp 5-Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor | Disease Response | Responder | 2 patient |
| Grp 6 - Neuroblastoma-MIBG Positive Without Measurable Disease | Disease Response | Responder | 4 patient |
| Grp 6 - Neuroblastoma-MIBG Positive Without Measurable Disease | Disease Response | Non-Responder | 16 patient |
| Grp 7-Neuroblastoma With Measurable Disease | Disease Response | Responder | 0 patient |
| Grp 7-Neuroblastoma With Measurable Disease | Disease Response | Non-Responder | 10 patient |
| Group 8 - Recurrent Osteosarcoma | Disease Response | Non-Responder | 9 patient |
| Group 8 - Recurrent Osteosarcoma | Disease Response | Responder | 0 patient |
| Group 9 - Recurrent or Refractory Wilms Tumor | Disease Response | Non-Responder | 9 patient |
| Group 9 - Recurrent or Refractory Wilms Tumor | Disease Response | Responder | 0 patient |