Clinical trial NCT00061893
Conditions: Sarcoma
Keywords: metastatic Ewing sarcoma/peripheral primitive neuroectodermal tumor
Sponsor: Children's Oncology Group
Start date: 2004-04-01; Completion date: 2013-12-01
Enrollment: 38 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
RATIONALE: Drugs used in chemotherapy, such as vinblastine, work in different ways to stop tumor cells from dividing so they stop growing or die. Celecoxib may stop the growth of Ewing's sarcoma by stopping blood flow to the tumor. Combining more than one chemotherapy drug with celecoxib may kill more tumor cells.

PURPOSE: Phase II trial to study the effectiveness of combining low-dose vinblastine and celecoxib with standard regimens of combination chemotherapy in treating patients who have newly-diagnosed metastatic Ewing's sarcoma family of tumors.

Detailed description:
OBJECTIVES:

* Determine the feasibility and safety of low-dose vinblastine and celecoxib in combination with standard multiagent chemotherapy in patients with newly diagnosed metastatic Ewing's sarcoma family of tumors.
* Determine the event-free survival of patients treated with this regimen.
* Determine the pharmacokinetics of this regimen in these patients.

OUTLINE: This is a pilot, multicenter study.

* Induction therapy: Patients receive the following alternating regimens:

  * VAC (courses 1 and 3): Patients receive vincristine IV and cyclophosphamide IV over 1 hour on day 1 and doxorubicin IV continuously on days 1 and 2 of weeks 1 and 7.
  * IE (courses 2 and 4): Patients receive ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 of weeks 4 and 10.

Patients also receive filgrastim (G-CSF) subcutaneously (SC) beginning 24-48 hours after the last dose of chemotherapy and continuing until blood counts recover.

Treatment repeats every 21 days for a total of 4 courses in the absence of disease progression or unacceptable toxicity.

* Local control and consolidation therapy: Beginning on week 13, patients are assigned to 1 of 4 regimens based on disease status.

  * Regimen A (surgery only): Patients who respond to induction chemotherapy undergo surgery on week 13. Patients then begin consolidation therapy on week 15 with the following alternating regimens:

    * VAC (courses 5, 7, and 9): Patients receive VAC on weeks 15, 21, and 27.
    * IE (courses 6, 8, 10, 12, and 14): Patients receive IE on weeks 18, 24, 30, 36, and 42.
    * VC (courses 11 and 13): Patients receive vincristine IV and cyclophosphamide IV over 1 hour on weeks 33 and 39.
  * Regimen B (radiotherapy only): Patients with unresectable lesions undergo radiotherapy once daily 5 days a week for up to approximately 6 weeks beginning on week 13. Patients also receive consolidation therapy beginning on week 13, with the following alternating regimens:

    * VAC (courses 5, 9, and 11): Patients receive VAC on weeks 13, 25, and 31.
    * IE (courses 6, 8, 10, 12, and 14): Patients receive IE on weeks 16, 22, 28, 34, and 40.
    * VC (courses 7 and 13): Patients receive VC on weeks 19 and 37.
  * Regimen C (surgery and radiotherapy): Patients who respond to induction chemotherapy undergo surgery on week 13. Patients who have inadequate margins after surgery undergo radiotherapy (as in regimen B) beginning on week 15. Patients also receive consolidation therapy, beginning on week 15, with the following alternating regimens:

    * VAC (courses 5, 9, and 11): Patients receive VAC on weeks 15, 27, and 33.
    * IE (courses 6, 8, 10, 12, and 14): Patients receive IE on weeks 18, 24, 30, 36, and 42.
    * VC (courses 7 and 13): Patients receive VC on weeks 21 and 39.
  * Regimen D (preoperative radiotherapy): Patients with bulky lesions who do not have a good clinical and radiographic response to induction therapy begin consolidation therapy on week 13 with VAC (course 5) and undergo concurrent radiotherapy as in regimen B. Patients then receive IE on weeks 16 and 19 for courses 6 and 7. Patients undergo surgery on week 22. Patients continue consolidation therapy with the following alternating regimens:

    * VAC (courses 8 and 9): Patients receive VAC on weeks 24 and 27.
    * IE (courses 10, 12, and 14): Patients receive IE on weeks 30, 36, and 42.
    * VC (courses 11 and 13): Patients receive VC on weeks 33 and 39. Patients receive G-CSF SC (as in induction therapy) during all consolidation courses.

Consolidation therapy continues for 10 courses in the absence of disease progression or unacceptable toxicity.

* Vinblastine and celecoxib therapy: Throughout induction, local control, and consolidation therapies, patients also receive vinblastine IV 3 times a week (twice a week during the weeks that vincristine is given) and oral celecoxib twice daily, beginning on day 1 of course 1 and continuing until the completion of course 14.\* NOTE: \*To assess for safety, the first 6 patients enrolled receive vinblastine only during courses 1 and 2 and celecoxib is then added for all subsequent courses.

Patients are followed every 3 months for 3 years and then every 6 months for 2 years.

PROJECTED ACCRUAL: A total of 6-36 patients will be accrued for this study within 1.17 years.

Arms: arm 1: Metastatic Ewing Sarcoma - 14-cycle study building on conventional tx (cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, ifosfamide, etoposide) and adding two antiangiogenic agents: the vinca alkaloid vinblastine and the cyclooxygenase-2 inhibitor celecoxib. Refer to the Interventions section for dosages, method of delivery and frequency of administration.
Interventions: intervention 1: celecoxib intervention 2: cyclophosphamide intervention 3: doxorubicin hydrochloride intervention 4: etoposide intervention 5: ifosfamide intervention 6: vinblastine sulfate intervention 7: vincristine sulfate intervention 8: conventional surgery intervention 9: radiation therapy intervention 10: MESNA intervention 11: Filgrastim
Intervention descriptions: intervention 1: Given orally, Celecoxib 250 mg/m2 PO BID (500mg/m2/day) from Day 1 of Cycle 1 through Day 21 of Cycle 14. The dose should be rounded off to the nearest 100 mg. If PK studies are being done, Celecoxib should be given 24 hours prior to the other drugs for Cycle 1 only. \[Celecoxib may be interrupted for up to 7 days around the time of surgical procedures.\] . intervention 2: Given IV, 1200 mg/m2 IV infusion over 1 hour with MESNA uroprotection, on Day 1. For children \< 1 year treat with 50% doses calculated on a m2 basis. If tolerated (no delay in administration of the next cycle due to delayed count recovery or delayed resolution of other toxicities and no serious toxicities), consider increasing to 75% and then to 100% of the calculated full dose. intervention 3: Given IV, Doxorubicin 75 mg/ m2 /course continuous IV infusion over 48 hours, beginning Day 1. Note: The total doxorubicin dose per cycle is 75 mg/ m2, which will be given as 37.5 mg/m2/day x 2 days. Doxorubicin may be given as a continuous infusion or brief infusion. intervention 4: Given IV, Vincristine 2 mg/m2 IV push, on Day 1. Maximum dose 2 mg. For children \< 1 year treat with 50% doses calculated on a m2 basis. If tolerated (no delay in administration of the next cycle due to delayed count recovery or delayed resolution of other toxicities and no serious toxicities), consider increasing to 75% and then to 100% of the calculated full dose. intervention 5: Given IV,Ifosfamide 1800 mg/m2 /day IV infusion over 1 hour, Days 1-5 of each cycle. (9,000 mg/m2 max total dose per cycle). Prehydrate for 6 hours, 1,000 ml/m2 total volume (165 ml/m2/hour for 6 hours). For children \< 1 year treat with 50% doses calculated on a m2 basis. If tolerated (no delay in administration of the next cycle due to delayed count recovery or delayed resolution of other toxicities and no serious toxicities), consider increasing to 75% and then to 100% of the calculated full dose. intervention 6: Given IV, Vinblastine 1 mg/m2/d IV push three times per week beginning Day 1 of Cycle 1 and continuing through Day 21 of Cycle 14. In weeks during which vincristine is given, hold one dose of vinblastine and administer only 2 doses of vinblastine during that week. If vinblastine is due the same day as vincristine, hold that dose of vinblastine. \[Vinblastine may be interrupted for up to 7 days around the time of surgical procedures.\] intervention 7: Given IV, Vincristine 2 mg/m2 IV push, on Day 1. Maximum dose 2 mg. For children \< 1 year treat with 50% doses calculated on a m2 basis. If tolerated (no delay in administration of the next cycle due to delayed count recovery or delayed resolution of other toxicities and no serious toxicities), consider increasing to 75% and then to 100% of the calculated full dose. intervention 8: Patients who respond to induction chemotherapy undergo surgery on week 13. Patients who have inadequate margins after surgery undergo radiotherapy beginning on week 15. (see Detailed Description for frequency of administration and groups evaluated) intervention 9: Patients with unresectable lesions undergo radiotherapy 5 days a week for approximately 6 weeks beginning on week 13. (see Detailed Description for frequency of administration and groups evaluated) intervention 10: The total daily MESNA dose is equal to at least 60% of the daily cyclophosphamide or ifosfamide dose, or by continuous infusion of the 60% dose. MESNA continuous infusion should be started at the same time as the cyclophosphamide/ifosfamide and be completed no sooner than 8 hours after the end of the cyclophosphamide or ifosfamide infusion. The oral dose of MESNA is 2x the IV dose. Patients able to tolerate oral MESNA may receive the final dose by mouth at 40% of the oxazaphosphorine (cyclophosphamide or ifosfamide) dose. The dose should be given two hours earlier than the IV dose would be given. Additionally, if the patient vomits within two hours after the oral dose, the dose should be repeated or IV MESNA given. intervention 11: G-CSF (Filgrastim) 5 micrograms/kg/day subcutaneously beginning 24 to 48 hours after the last dose of chemotherapy, and continuing until the absolute neutrophil count is 2,000/µL or greater after nadir.

Protocol documents: