Adult Rhabdomyosarcoma, Childhood Alveolar Rhabdomyosarcoma, Childhood Embryonal Rhabdomyosarcoma, Metastatic Childhood Soft Tissue Sarcoma, Stage IV Adult Soft Tissue Sarcoma, Untreated Childhood Rhabdomyosarcoma
Conditions
Brief summary
This randomized pilot clinical trial is studying the side effects and how well giving temozolomide and cixutumumab together with combination chemotherapy works in treating patients with metastatic rhabdomyosarcoma. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. 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. Giving temozolomide and cixutumumab together with combination chemotherapy may kill more tumor cells.
Detailed description
PRIMARY OBJECTIVES: I. To determine the feasibility of administering IMC-A12 (cixutumumab) in combination with a multi-agent intensive chemotherapy regimen for the treatment of high-risk rhabdomyosarcoma (RMS). II. To determine the feasibility of adding temozolomide to vincristine (vincristine sulfate)/irinotecan (irinotecan hydrochloride) cycles in patients with high-risk RMS. III. To assess immediate and short-term side effects of delivery of concurrent temozolomide-vincristine-irinotecan with irradiation in patients with high-risk RMS. SECONDARY OBJECTIVES: I. To gain a preliminary estimate of the response rate to IMC-A12 or temozolomide plus vincristine/irinotecan in previously untreated high-risk RMS. II. To obtain preliminary efficacy data for IMC-A12 or temozolomide in combination with a multi-agent interval compressed chemotherapy regimen in previously untreated high-risk RMS. III. To determine the effectiveness of detecting metastatic disease with fludeoxyglucose F 18 positron emission tomography (FDG PET) and to compare assessment of response using standard imaging techniques with response assessed by FDG PET. IV. To assess changes in serum levels of insulin-like growth factor (IGF)-I, IGF-II, IGF-BP3 as biomarkers of IGF-IR inhibition. OUTLINE: This is a dose-escalation study of cixutumumab. Patients are assigned to 1 of 2 treatment groups according to the timing of their enrollment onto the study. GROUP 1: Patients receive vincristine sulfate intravenously (IV) over 1 minute on day 1 of weeks 1-5, 7, 8, 11, 12, 15, 16, 20-24, 28, 29, 32, 33, 35, 38, 41-44, 47, 48, 50, and 51; irinotecan hydrochloride IV over 90 minutes on days 1-5 of weeks 1, 4, 20, 23, 47, and 50; ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 of weeks 9, 13, 17, 26, and 30; doxorubicin hydrochloride IV over 1-15 minutes on days 1 and 2 of weeks 7, 11, 15, 28, and 32; cyclophosphamide IV over 30-60 minutes on day 1 of weeks 7, 11, 15, 28, 32, 35, 38, 41, and 44; dactinomycin IV over 1-5 minutes on day 1 of weeks 35, 38, 41, and 44; and cixutumumab IV over 1 hour on day 1 of weeks 1-51. Patients also undergo radiation therapy\* on days 1-5 of weeks 20-24. GROUP 2: Patients receive vincristine sulfate, irinotecan hydrochloride, ifosfamide, etoposide, doxorubicin hydrochloride, cyclophosphamide, and dactinomycin and undergo radiation therapy\* as in group 1. Patients also receive temozolomide orally (PO) on days 1-5 of weeks 1, 4, 20, 23, 47, and 50. GROUP 3: Patients receive vincristine sulfate, irinotecan hydrochloride, ifosfamide, etoposide, doxorubicin hydrochloride, cyclophosphamide, dactinomycin, and cixutumumab and undergo radiation therapy\* as in group 1. Patients also receive temozolomide as in group 2. (Discontinued as of January 2013) NOTE: \*Patients with parameningeal tumors and evidence of intracranial extension or those requiring emergency radiotherapy may receive radiation therapy starting in week 1; cixutumumab should be withheld during radiation therapy. After completion of study therapy, patients are followed up at 3 weeks and then periodically for up to 5 years.
Interventions
BIOLOGICALCixutumumab
Given IV
DRUGCyclophosphamide
Given IV
BIOLOGICALDactinomycin
Given IV
DRUGDoxorubicin Hydrochloride
Given IV
DRUGEtoposide
Given IV
DRUGIfosfamide
Given IV
DRUGIrinotecan Hydrochloride
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGTemozolomide
Given PO
Given IV
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 49 Years
Healthy volunteers
No
Inclusion criteria
* Patients must be eligible for, and enrolled on D9902 prior to enrollment on ARST08P1 * Patients with newly diagnosed, biopsy-proven metastatic rhabdomyosarcoma or ectomesenchymoma (stage IV, clinical group IV) are eligible for this study; patients with stage IV, clinical group IV RMS with parameningeal and paraspinal primary tumors, including those with intracranial extension (ICE) are eligible for ARST08P1; ICE is defined by contrast magnetic resonance imaging (MRI) showing that the primary tumor touches, displaces, invades, distorts, or otherwise causes signal abnormality of the dura in brain or spinal cord in contiguity to the primary site; ICE is also presumed to exist if the cerebrospinal fluid (CSF) cytopathology is positive for tumor at diagnosis * Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2; use Karnofsky for patients \> 16 years of age and Lansky for patients =\< 16 years of age * No prior chemotherapy or radiotherapy except for use of corticosteroids or emergent radiation therapy; patients requiring emergency radiation are eligible * Creatinine clearance or radioisotope glomerular filtration rate (GFR) \>= 70 mL/min/1.73m\^2 OR maximum serum creatinine 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) * 1.0 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) * Patients with urinary tract obstruction by tumor must meet the renal function criteria listed above AND must have unimpeded urinary flow established via decompression of the obstructed portion of the urinary tract * Total bilirubin =\< 1.5 x upper limit of normal (ULN) for age, unless there is evidence of biliary obstruction by the tumor * Shortening fraction \>= 27% by echocardiogram (ECHO) OR ejection fraction \>= 50% by radionuclide angiogram * Absolute neutrophil count (ANC) \>= 750/uL; abnormal blood counts are permissible if there is bone marrow biopsy or aspirate proven bone marrow involvement by rhabdomyosarcoma * Platelet count \>= 75,000/uL; abnormal blood counts are permissible if there is bone marrow biopsy or aspirate proven bone marrow involvement by rhabdomyosarcoma * Sexually active patients of childbearing potential must agree to use effective contraception during therapy (Pilots 1 and 2) and for at least 3 months after the last dose of IMC-A12 (Pilots 1)
Exclusion criteria
* Female patients who are pregnant are not eligible * Female patients who are breastfeeding are not eligible; female patients who are lactating must agree to stop breastfeeding to participate in this study * Patients receiving growth hormone therapy are not eligible * Patients with known type I or type II diabetes mellitus are not eligible for enrollment on Pilot 1 * Patients with evidence of uncontrolled infection are not eligible * All patients and/or their parents or legal guardians must sign a written informed consent * All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Feasibility of the Addition of Cixutumumab to Chemotherapy Determined by Patient Enrollment | From start to week 26 of therapy | Proportion of no Grade 3+ cardiac toxicity. |
| Feasibility of the Addition of Temozolomide to Chemotherapy Determined by Patient Enrollment | From start to week 26 of therapy | Proportion of no Grade 4+ non-hematologic toxicity. |
| Incidence of Adverse Events Assessed by Common Terminology Criteria for Adverse Events Version 4.0 | Up to 54 weeks | Number of patients with grade 3+ adverse events (AE) during therapy. (Grade 3+) = (Grade 3 + Grade 4 + Grade 5) . Grade 3: Severe and undesirable AE; Grade 4: Life threatening or disabling AE; Grade 5: Death related to AE. |
| Event-Free Survival | 3 years | Probability of no relapse, secondary malignancy, or death after 3 years in the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate (CR + PR) | From the start of treatment until a maximum of 2 cycles (21 days per cycle) of treatment in the absence of disease progression or unacceptable toxicities | Proportion of patients with complete or partial response. Complete Response (CR): Complete disappearance of the tumor confirmed at \> 4 weeks. Partial Response (PR): At least 64% decrease in volume compared to the measurement obtained at study enrollment; Overall Response (OR) = CR + PR. |
Countries
Australia, Canada, New Zealand, United States
Participant flow
Pre-assignment details
The number of participants started is 175. Eight patients were declared ineligible by the study chair, and one patient didn't receive treatment.
Participants by arm
| Arm | Count |
|---|---|
| IMC-A12 IMC-A12 + Multi-agent intensive chemotherapy regimen. | 100 |
| Temozolomide Add temozolomide to vincristine/irinotecan cycles. | 75 |
| Total | 175 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 7 | 4 |
| Overall Study | Death | 2 | 1 |
| Overall Study | Ineligible | 3 | 5 |
| Overall Study | Lack of Efficacy | 11 | 19 |
| Overall Study | No treatment | 1 | 0 |
| Overall Study | Physician Decision | 10 | 5 |
| Overall Study | Refusal of further protocol therapy | 10 | 4 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Temozolomide | Total | IMC-A12 |
|---|---|---|---|
| Age, Continuous | 152.04 Months STANDARD_DEVIATION 79.2 | 157.69 Months STANDARD_DEVIATION 72.62 | 161.93 Months STANDARD_DEVIATION 67.36 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 18 Participants | 35 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 55 Participants | 132 Participants | 77 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 8 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 22 Participants | 12 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 11 Participants | 21 Participants | 10 Participants |
| Race (NIH/OMB) White | 53 Participants | 127 Participants | 74 Participants |
| Sex: Female, Male Female | 30 Participants | 83 Participants | 53 Participants |
| Sex: Female, Male Male | 45 Participants | 92 Participants | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 85 / 96 | 63 / 70 |
| serious Total, serious adverse events | 79 / 96 | 40 / 70 |
Outcome results
Primary
Event-Free Survival
Probability of no relapse, secondary malignancy, or death after 3 years in the study.
Time frame: 3 years
Population: 9 participants who were ineligible or did not receive treatment were excluded.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMC-A12 | Event-Free Survival | 0.1627 Probability |
| Temozolomide | Event-Free Survival | 0.1919 Probability |
Primary
Feasibility of the Addition of Cixutumumab to Chemotherapy Determined by Patient Enrollment
Proportion of no Grade 3+ cardiac toxicity.
Time frame: From start to week 26 of therapy
Population: 18 participants were excluded because of ineligibility or insufficient information to assess feasibility.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMC-A12 | Feasibility of the Addition of Cixutumumab to Chemotherapy Determined by Patient Enrollment | 0.9390 Proportion of Participants |
Primary
Feasibility of the Addition of Temozolomide to Chemotherapy Determined by Patient Enrollment
Proportion of no Grade 4+ non-hematologic toxicity.
Time frame: From start to week 26 of therapy
Population: 13 participants were excluded because of ineligibility or insufficient information to assess feasibility.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMC-A12 | Feasibility of the Addition of Temozolomide to Chemotherapy Determined by Patient Enrollment | 0.7097 Proportion of Participants |
Primary
Incidence of Adverse Events Assessed by Common Terminology Criteria for Adverse Events Version 4.0
Number of patients with grade 3+ adverse events (AE) during therapy. (Grade 3+) = (Grade 3 + Grade 4 + Grade 5) . Grade 3: Severe and undesirable AE; Grade 4: Life threatening or disabling AE; Grade 5: Death related to AE.
Time frame: Up to 54 weeks
Population: 9 participants who were ineligible or did not receive treatment were excluded.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMC-A12 | Incidence of Adverse Events Assessed by Common Terminology Criteria for Adverse Events Version 4.0 | 89 Participants |
| Temozolomide | Incidence of Adverse Events Assessed by Common Terminology Criteria for Adverse Events Version 4.0 | 61 Participants |
Secondary
Response Rate (CR + PR)
Proportion of patients with complete or partial response. Complete Response (CR): Complete disappearance of the tumor confirmed at \> 4 weeks. Partial Response (PR): At least 64% decrease in volume compared to the measurement obtained at study enrollment; Overall Response (OR) = CR + PR.
Time frame: From the start of treatment until a maximum of 2 cycles (21 days per cycle) of treatment in the absence of disease progression or unacceptable toxicities
Population: 20 participants were excluded because of ineligibility or absence in overall response evaluation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMC-A12 | Response Rate (CR + PR) | 0.7667 Proportion of Participants |
| Temozolomide | Response Rate (CR + PR) | 0.7846 Proportion of Participants |