Sarcoma
Conditions
Keywords
adult rhabdomyosarcoma, previously untreated childhood rhabdomyosarcoma, adult malignant mesenchymoma, childhood malignant mesenchymoma, metastatic childhood soft tissue sarcoma, stage IV adult soft tissue sarcoma
Brief summary
RATIONALE: Drugs used in chemotherapy, such as vincristine, irinotecan, ifosfamide, etoposide, doxorubicin, cyclophosphamide, and dactinomycin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving high-dose combination chemotherapy together with radiation therapy may kill more tumor cells. PURPOSE: This phase III trial is studying how well giving high-dose combination chemotherapy together with radiation therapy works in treating patients with newly diagnosed metastatic rhabdomyosarcoma or ectomesenchymoma.
Detailed description
OBJECTIVES: Primary * Improve the early disease control interval for patients with newly diagnosed, high-risk, metastatic rhabdomyosarcoma or ectomesenchymoma using intensive, interval-compression therapy (comprising vincristine, irinotecan hydrochloride, ifosfamide, etoposide, doxorubicin hydrochloride, cyclophosphamide, and dactinomycin) that permits maximal early exposure to known effective agents. * Determine the feasibility and assess immediate- and short-term side effects of concurrent irinotecan hydrochloride and radiotherapy in these patients. Secondary * Expand the available data for response to irinotecan hydrochloride and vincristine in previously untreated patients with high-risk rhabdomyosarcoma. * Evaluate, prospectively, and validate gene expression values with the intent to define the best diagnostic predictors and more powerful prognostic classifiers. OUTLINE: This is a prospective, nonrandomized, multicenter study. Patients are stratified according to prognostic factors predictive of outcome (e.g. histology, bone/bone marrow involvement, and number of metastatic sites). Patients receive high-dose chemotherapy comprising vincristine 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 1 hour on days 1-5 of weeks 1, 4, 20, 23, 47, and 50; and ifosfamide IV over 1 hour and etoposide IV over 30-60 minutes on days 1-5 of weeks 9, 13, 17, 26, and 30. Patients also receive doxorubicin hydrochloride IV continuously over 24 hours 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; and dactinomycin IV over 1-5 minutes on day 1 of weeks 35, 38, 41, and 44 in the absence of disease progression or unacceptable toxicity. Patients also receive filgrastim (G-CSF) subcutaneously in weeks 7-9, 11-13, 15-17, 22, 26, 28-30, 32, 33, 35, 38, and 41-44 beginning 24-36 hours after the last chemotherapy dose and continuing until blood counts recover. NOTE: \*Patients undergoing early radiotherapy for intracranial extension do not receive doxorubicin in week 7. Beginning at week 20 (or week 1 for patients with parameningeal tumors with intracranial extension \[or spinal cord compression\] requiring emergency radiotherapy), patients also undergo radiotherapy once a day, 5 days a week, for approximately 5½ weeks. Some patients may also undergo second-look surgery. After completion of study treatment, patients are followed periodically for ≥ 10 years. PROJECTED ACCRUAL: A total of 75 patients will be accrued for this study.
Interventions
BIOLOGICALdactinomycin
Age based dosage: ≥ 1 year 0.045 mg/kg IV x 1(maximum dose 2.5 mg), \< 1 year 0.025 mg/kg. Day 1 of Weeks 35, 38, 41 and 44. Given IV
DRUGcyclophosphamide
Age based dosage: ≥ 3 years 1200 mg/m2, \<3 years 40 mg/kg. Day 1 of weeks 7, 11, 15, 28, 32, 35, 38, 41 and 44. Given IV
DRUGdoxorubicin hydrochloride
Age based dosage: ≥ 1 year: 37.5mg/m²/day, \< 1 year: treat with 50% doses calculated on a m2 basis. Total dose 75 mg/m². Days 1 and 2 of weeks 7, 11, 15, 28 and 32. Given IV
DRUGetoposide
Age based dosage: ≥ 1 year: 100 mg/m²/day, \< 1 year: treat with 50% doses calculated on a m2 basis. Days 1-5 of weeks 9, 13, 17, 26 and 30. Given IV
DRUGifosfamide
Age based dosage: ≥ 1 year: 1800 mg/m²/day, \< 1 year: treat with 50% doses calculated on a m2 basis. Days 1-5 of weeks 9, 13, 17, 26 and 30. Given IV
DRUGirinotecan hydrochloride
Dosage 50 mg/m2-max dose 100 mg/day. Days 1-5 of weeks 1, 4, 20, 23, 47 and 50. Given IV
DRUGvincristine sulfate
Age based dosage: ≥ 3 years 1.5 mg/m2 (max dose 2 mg), ≥ 1 year and \< 3 years 0.05 mg/kg (max dose 2 mg), \< 1 year 0.025 mg/kg. Days 1-5 of weeks 1, 2, 3, 4, 5, 7, 8, 11, 12, 15, 16, 20, 21, 22, 23, 24, 28, 29, 32, 33, 35, 38, 41, 42, 43, 44, 47, 48, 50, and 51. Given IV
PROCEDUREconventional surgery
Resection of the primary tumor with a surrounding envelope of normal tissue
RADIATIONradiation therapy
Radiotherapy beginning at Week 20 to the primary tumor and to the metastatic sites excepting those with parameningeal tumors with intracranial extension (direct extension into the brain) and those requiring emergency radiotherapy
BIOLOGICALfilgrastim
5 micrograms/kg/day (max 300 micrograms) beginning 24-36 hours after the last dose of chemotherapy. Continue at least 7 days, or until the ANC ≥750/μL whichever comes last. Given subcutaneously.
Sponsors
National Cancer Institute (NCI)
Children's Oncology Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 49 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically confirmed high-risk rhabdomyosarcoma or ectomesenchymoma * Prior enrollment on COG-D9902 to confirm local histological diagnosis required * Tissue must be submitted for pathologic review within 2 days of patient registration on COG-D9902 * Newly diagnosed disease * Metastatic disease (stage IV, clinical group IV) * Has undergone initial surgical procedure (including biopsy) that provided the definitive diagnosis within the past 42 days * Parameningeal and paraspinal tumors allowed * Patients with parameningeal (without intracranial extension \[ICE\]) and paraspinal tumors should begin study chemotherapy at week 1 and radiotherapy at week 20 * Patients with evidence of ICE, as defined by contrast MRI showing that primary tumor touches, displaces, invades, distorts, or otherwise causes a signal abnormality of the dura in contiguity to the primary site in brain or spinal cord, are eligible * ICE is presumed to exist if the cerebrospinal fluid cytopathology is positive for tumor at diagnosis * Patients requiring emergency radiotherapy are eligible * Patients requiring emergency radiotherapy (for intracranial extension or spinal cord impingement) should begin study chemotherapy at week 1 (irinotecan hydrochloride and vincristine) concurrently with radiation therapy PATIENT CHARACTERISTICS: * ECOG or Zubrod performance status (PS) 0-2 (Lansky PS 50-100% for patients \< 10 years of age and Karnofsky PS 50-100% for patients ≥ 10 years of age) * Absolute neutrophil count ≥ 750/mm³\* * Platelet count ≥ 75,000/mm³\* * Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min (≥ 40 mL/min for infants \< 1 year 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 * SGPT \< 2.5 times normal * Bilirubin \< 1.5 mg/dL * Shortening fraction ≥ 27% by echocardiogram OR ejection fraction ≥ 50% by MUGA * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception during study and for ≥ 1 month after study completion * No evidence of uncontrolled infection * Able to undergo radiotherapy NOTE: \*Abnormal blood counts allowed if there is bone marrow biopsy or aspirate proven bone marrow involvement by rhabdomyosarcoma PRIOR CONCURRENT THERAPY: * No prior chemotherapy except steroids * No prior radiotherapy * No concurrent aprepitant during ifosfamide or doxorubicin hydrochloride chemotherapy * No concurrent dexrazoxane * No concurrent sargramostim (GM-CSF) or pegfilgrastim
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Complete or Partial Response Assessed by RECIST Criteria | Protocol week 6 evaluation | Volumetric measurements of the primary tumor using an elliptical model (0.5 x the product of the 3 largest perpendicular diameters) to assess response to neoadjuvant therapy. The RECIST (Response Evaluation Criteria in Solid Tumors) from the NCI will be used for assessment of the size of measurable metastases, including nodal metastases. Primary Tumor Measurement: Technical guidelines for cross-sectional imaging computed tomography (CT) slice thickness should be 5mm or less and the diameter of the measurable mass should be at least twice the reconstructed slice thickness. Smaller masses are considered detectable, but will be counted as non-measurable. 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. Progressive Disease (PD): At least 40% increase in tumor volume compared to the smallest volume obtained since the beginning. |
| Percentage of Patients Experiencing Adverse Events Due to Concurrent Therapy | From enrollment to up to 2 years | Adverse events are reported for patients receiving concurrent irinotecan hydrochloride and radiotherapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Event Free at 4 Years Following Study Entry | 4 years | Event-free survival: Time to recurrence, second malignancy, or death as a first event, estimated from a Kaplan Meier curve |
Countries
Australia, Canada, Puerto Rico, Switzerland, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| High_Risk_Rhabdomyosarcoma Parameningeal (without intracranial extension) and paraspinal tumors receive chemotherapy starting Week 1 and begin radiation therapy at Week 20. Weeks 1-6: vincristine sulfate and irinotecan hydrochloride. Weeks 7-34: vincristine sulfate and irinotecan hydrochloride, Cyclophosphamide with MESNA, Doxorubicin hydrochloride, Etoposide, Ifosfamide with MESNA. Weeks 35-54: vincristine sulfate, Dactinomycin, irinotecan hydrochloride and Cyclophosphamide with MESNA and Filgrastim. Radiation therapy beginning at Week 20. Second look conventional surgery: Surgical resection other than biopsy will be applicable for the majority of patients. | 109 |
| Total | 109 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Death | 2 |
| Overall Study | Lack of Efficacy | 11 |
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | Physician Decision | 11 |
| Overall Study | Withdrawal by Subject | 14 |
Baseline characteristics
| Characteristic | High_Risk_Rhabdomyosarcoma |
|---|---|
| Age, Categorical <=18 years | 96 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants |
| Age, Continuous | 11.85 years STANDARD_DEVIATION 6.55 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 18 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 86 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 5 Participants |
| Race (NIH/OMB) Black or African American | 16 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 11 Participants |
| Race (NIH/OMB) White | 76 Participants |
| Region of Enrollment Australia | 6 participants |
| Region of Enrollment Canada | 11 participants |
| Region of Enrollment United States | 92 participants |
| Sex: Female, Male Female | 49 Participants |
| Sex: Female, Male Male | 60 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 95 / 108 |
| serious Total, serious adverse events | 4 / 108 |
Outcome results
Primary
Number of Patients With Complete or Partial Response Assessed by RECIST Criteria
Volumetric measurements of the primary tumor using an elliptical model (0.5 x the product of the 3 largest perpendicular diameters) to assess response to neoadjuvant therapy. The RECIST (Response Evaluation Criteria in Solid Tumors) from the NCI will be used for assessment of the size of measurable metastases, including nodal metastases. Primary Tumor Measurement: Technical guidelines for cross-sectional imaging computed tomography (CT) slice thickness should be 5mm or less and the diameter of the measurable mass should be at least twice the reconstructed slice thickness. Smaller masses are considered detectable, but will be counted as non-measurable. 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. Progressive Disease (PD): At least 40% increase in tumor volume compared to the smallest volume obtained since the beginning.
Time frame: Protocol week 6 evaluation
Population: All eligible patients with protocol week tumor assessment (N=102)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High_Risk_Rhabdomyosarcoma | Number of Patients With Complete or Partial Response Assessed by RECIST Criteria | 63 percentage of participants |
Primary
Percentage of Patients Experiencing Adverse Events Due to Concurrent Therapy
Adverse events are reported for patients receiving concurrent irinotecan hydrochloride and radiotherapy.
Time frame: From enrollment to up to 2 years
Population: Percentage of patients experiencing a grade 3/4/5 toxicity in a course.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| High_Risk_Rhabdomyosarcoma | Percentage of Patients Experiencing Adverse Events Due to Concurrent Therapy | Course 1 | 53.3 percentage of patients |
| High_Risk_Rhabdomyosarcoma | Percentage of Patients Experiencing Adverse Events Due to Concurrent Therapy | Course 2 | 68.4 percentage of patients |
| High_Risk_Rhabdomyosarcoma | Percentage of Patients Experiencing Adverse Events Due to Concurrent Therapy | Course 3 | 79.3 percentage of patients |
| High_Risk_Rhabdomyosarcoma | Percentage of Patients Experiencing Adverse Events Due to Concurrent Therapy | Course 4 | 55.7 percentage of patients |
Secondary
Percentage of Patients Event Free at 4 Years Following Study Entry
Event-free survival: Time to recurrence, second malignancy, or death as a first event, estimated from a Kaplan Meier curve
Time frame: 4 years
Population: All eligible patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High_Risk_Rhabdomyosarcoma | Percentage of Patients Event Free at 4 Years Following Study Entry | 36 Percentage of patients |