Trial Information

A Protocol For Nonmetastatic Rhabdomyosarcoma [RMS-2005]

OBJECTIVES:

- Improve the outcome in pediatric patients with low-risk rhabdomyosarcoma (RMS) treated
with vincristine and dactinomycin alone.

- Evaluate whether the outcome for older patients with standard-risk RMS with favorable
features may be improved/maintained by administering a treatment with limited
intensity.

- Evaluate whether chemotherapy intensity for patients with standard-risk RMS can be
reduced, by lowering the cumulative dose of ifosfamide.

- Evaluate whether treatment can be reduced in a subgroup of patients with standard-risk
RMS arising in an unfavorable site (e.g., parameningeal or other site) but with
favorable site and age.

- Compare the value of standard chemotherapy comprising ifosfamide, vincristine, and
dactinomycin with vs without doxorubicin (as early intensification in the initial part
of treatment) in patients with high-risk RMS.

- Determine the role of low-dose maintenance chemotherapy comprising 6 months of
cyclophosphamide and vinorelbine in patients with high-risk RMS.

- Improve the results in patients with poor prognosis (very high-risk) RMS treated with
more intensive ifosfamide, vincristine, dactinomycin, and doxorubicin followed by
maintenance chemotherapy.

OUTLINE: This is a non-blinded, randomized, prospective, multicenter study. Patients are
stratified according to risk group (low risk vs standard risk vs high risk vs very high
risk) and participating country.

- Stratum 1 (low-risk group): Patients receive vincristine IV on day 1 in weeks 1-4,
7-10, 13-16, and 19-22 and dactinomycin IV on day 1 in weeks 1, 4, 7, 10, 13, 16, 19,
and 22.

- Stratum 2 (standard-risk group): Patients are assigned to 1 of 3 treatment groups
according to their standard-risk subgroup.

- Subgroup B: Patients receive ifosfamide IV over 3 hours on days 1 and 2 in weeks
1, 4, 7, and 10; vincristine IV on day 1 in weeks 1-7, 10, 13, 16, 19, 22, and 25;
and dactinomycin IV on day 1 in weeks 1, 4, 7, 10, 13, 16, 19, 22, and 25.

- Subgroup C: Patients receive ifosfamide IV over 3 hours on days 1 and 2 in weeks
1, 4, and 7; vincristine IV on day 1 in weeks 1-7; and dactinomycin IV on day 1 in
weeks 1, 4, and 7. Patients are evaluated for tumor response in week 9. Patients
in complete remission (CR) with favorable age and tumor size continue to receive
ifosfamide, vincristine, and dactinomycin as above in weeks 10, 13, 16*, 19, 22,
and 25. Patients may also undergo radiotherapy beginning in week 13 and continuing
for 5-6 weeks. Patients in CR with unfavorable age or tumor size OR in partial
remission (PR) (i.e., > 1/3 tumor volume reduction) continue to receive ifosfamide
as above in weeks 10 and 16 and vincristine and dactinomycin as above in weeks 10,
13, 16*, 19, 22, and 25. These patients also undergo radiotherapy beginning in
week 13 and continuing for 5-6 weeks. Patients with stable or progressive disease
in week 9 proceed to second-line therapy and radiotherapy. Patients with residual
disease after completion of chemotherapy in week 10 undergo surgical resection
followed by ifosfamide, vincristine, and dactinomycin (with or without
radiotherapy) as above in weeks 13, 16*, 19, 22, and 25.

- Subgroup D: Patients receive ifosfamide IV over 3 hours on days 1 and 2 in weeks
1, 4, and 7; vincristine IV on day 1 in weeks 1-7; and dactinomycin IV on day 1 in
weeks 1, 4, and 7. Patients are evaluated for tumor response in week 9. Patients
in CR or PR continue to receive ifosfamide, vincristine, and dactinomycin as above
in weeks 10, 13, 16*, 19, 22, and 25. Patients may also undergo radiotherapy
beginning in week 13 and continuing for 5-6 weeks. Patients with stable or
progressive disease in week 9 proceed to second-line therapy and radiotherapy.
Patients with residual disease after completion of chemotherapy in week 10 undergo
surgical resection followed by ifosfamide, vincristine, and dactinomycin (with or
without radiotherapy) as above in weeks 13, 16*, 19, 22, and 25.

NOTE: *Dactinomycin may be omitted during radiotherapy in week 16.

- Stratum 3 (high-risk group): Patients are randomized to 1 of 2 treatment arms.

- Arm I: Patients receive ifosfamide, vincristine, and dactinomycin as in subgroups
C and D of stratum 2. Patients are evaluated for tumor response in week 9.
Patients in CR or PR continue to receive ifosfamide, vincristine, and dactinomycin
as in subgroups C and D of stratum 2. Patients may also undergo radiotherapy
beginning in week 13 and continuing for 5-6 weeks. Patients with stable or
progressive disease in week 9 proceed to second-line therapy and radiotherapy.
Patients with residual disease after completion of chemotherapy in week 10 undergo
surgical resection followed by ifosfamide, vincristine, and dactinomycin (with or
without radiotherapy) as above in weeks 13, 16*, 19, 22, and 25.

- Arm II: Patients receive ifosfamide, vincristine, and dactinomycin as in subgroups
C and D of stratum 2. Patients also receive doxorubicin IV over 4 hours on days 1
and 2 in weeks 1, 4, and 7. Patients are evaluated for tumor response in week 9.
Patients in CR or PR continue to receive ifosfamide, vincristine, dactinomycin,
and doxorubicin as above in week 10 and then ifosfamide, vincristine, and
dactinomycin as above in weeks 13, 16*, 19, 22, and 25. Patients may also undergo
radiotherapy beginning in week 13 and continuing for 5-6 weeks. Patients with
stable or progressive disease in week 9 proceed to second-line therapy and
radiotherapy. Patients with residual disease after completion of chemotherapy in
week 10 undergo surgical resection followed by ifosfamide, vincristine, and
dactinomycin (with or without radiotherapy) as above in weeks 13, 16*, 19, 22, and
25.

NOTE: *Dactinomycin may be omitted during radiotherapy in week 16.

- Maintenance chemotherapy: Patients who remain in CR or with minimal abnormalities on
imaging studies after completion of therapy according to their randomized arm (as
above) undergo a second randomization. Randomization occurs within 6 weeks after
administration of the last course of chemotherapy on arm I or II.

- Arm I: Patients receive no maintenance chemotherapy.

- Arm II: Patients receive vinorelbine IV over 5-10 minutes on days 1, 8, and 15 and
oral cyclophosphamide once daily on days 1-28. Treatment repeats every 28 days for
up to 6 courses.

- Stratum 4 (very high-risk group): Patients receive ifosfamide, vincristine,
and dactinomycin as in subgroups C and D of stratum 2. Patients also receive
doxorubicin as in arm II of stratum 3. Patients are evaluated for tumor
response in week 9. Patients in CR or PR continue to receive ifosfamide,
vincristine, dactinomycin, and doxorubicin as in arm II of stratum 3.
Patients may also undergo radiotherapy beginning in week 13 and continuing
for 5-6 weeks. Patients with stable or progressive disease in week 9 proceed
to second-line therapy and radiotherapy. Patients with residual disease after
completion of chemotherapy in week 10 undergo surgical resection followed by
ifosfamide, vincristine, and dactinomycin (with or without radiotherapy) as
above in weeks 13, 16, 19, 22, and 25. After completion of chemotherapy,
patients with a limited quantity of viable tumor proceed to maintenance
chemotherapy.

- Maintenance chemotherapy: Patients receive vinorelbine IV over 5-10 minutes on days 1,
8, and 15 and oral cyclophosphamide once daily on days 1-28. Treatment repeats every 28
days for up to 6 courses.

- Second-line therapy: Patients in any stratum with stable or progressive disease in
week 9 receive 1 of 2 second-line therapy regimens.

- Regimen 1: Patients receive topotecan IV on days 1-3 and carboplatin IV on days 4 and 5
in weeks 1 and 4. Patients are then evaluated for tumor response. Patients with good
response receive topotecan IV on days 1-3 and cyclophosphamide IV on days 1 and 2 in
weeks 7 and 13 and etoposide IV on days 1-3 and carboplatin IV on days 4 and 5 in weeks
10 and 16. Patients with no response receive local therapy or a new chemotherapy
regimen.

- Regimen 2: Patients receive doxorubicin IV on day 1 and carboplatin IV on days 1 and 2
in weeks 1 and 4. Patients are then evaluated for tumor response. Patients with good
response receive doxorubicin IV on day 1 in weeks 7, 10, 13, and 16; cyclophosphamide
IV on days 1 and 2 in weeks 7 and 13; and carboplatin IV on days 1 and 2 of weeks 10
and 16. Patients with no response receive local therapy or a new chemotherapy regimen.

After completion of therapy, patients are followed periodically for at least 5 years.

PROJECTED ACCRUAL: A total of 600 patients will be accrued for this study.