Comparison of Chemotherapy Regimens in Treating Children With Relapsed or Progressive Rhabdomyosarcoma

Brief Title

Comparison of Chemotherapy Regimens in Treating Children With Relapsed or Progressive Rhabdomyosarcoma

Official Title

A Groupwide Randomized Phase II Window Study of Two Different Schedules of Irinotecan in Combination With Vincristine And Pilot Assessment of Safety and Efficacy of Tirapazamine Combined With Multiagent Chemotherapy for First Relapse or Progressive Disease in Rhabdomyosarcoma and Related Tumors

Brief Summary

      Randomized phase II trial to compare the effectiveness of different combination chemotherapy
      regimens in treating children who have rhabdomyosarcoma. Drugs used in chemotherapy work in
      different ways to stop tumor cells from dividing so they stop growing or die. Combining more
      than one drug may kill more tumor cells
    

Detailed Description

      OBJECTIVES:

      I. Compare response rate in children with relapsed or progressive rhabdomyosarcoma,
      undifferentiated sarcoma, or ectomesenchymoma treated with 2 different schedules of
      irinotecan and vincristine in an upfront phase II window.

      II. Determine the progression-free and overall survival of patients treated with multiagent
      chemotherapy.

      III. Determine the toxic effects of tirapazamine, doxorubicin, and cyclophosphamide in these
      patients.

      IV. Determine the toxic effects of irinotecan and vincristine in these patients.

      V. Determine whether conversion of irinotecan to its active metabolite SN-38 predicts tumor
      response in these patients.

      OUTLINE: This is a randomized, multicenter study. Patients are stratified according to risk
      status and window therapy eligibility (unfavorable risk and eligible vs unfavorable risk and
      ineligible vs favorable risk).

      UNFAVORABLE-RISK PATIENTS ELIGIBLE FOR WINDOW THERAPY: Patients are stratified according to
      prior topotecan (yes vs no). These patients are randomized to 1 of 2 treatment arms.

      ARM I: Patients receive vincristine IV on days 1 and 8 and irinotecan IV over 1 hour on days
      1-5 and 8-12. Treatment repeats every 21 days for 2 courses in the absence of disease
      progression or unacceptable toxicity.

      ARM II: Patients receive vincristine IV on days 1 and 8 and irinotecan IV over 1 hour on days
      1-5. Treatment repeats every 21 days for 2 courses in the absence of disease progression or
      unacceptable toxicity.

      Patients in both arms with partial response (PR) or complete response (CR) receive 5
      additional courses of irinotecan and vincristine on the previous schedule. In addition,
      patients with PR or CR also receive cyclophosphamide/doxorubicin (CD) and
      ifosfamide/etoposide (IE) chemotherapy.

      CD/IE CHEMOTHERAPY: Patients receive cyclophosphamide IV over 1 hour and doxorubicin IV over
      15-30 minutes on day 1 of weeks 7, 16, 28, 37, and 40. Patients also receive ifosfamide IV
      over 1 hour and etoposide IV over 1 hour on days 1-5 of weeks 10, 19, 22, 31, and 43.
      Treatment continues in the absence of disease progression or unacceptable toxicity.

      Patients with no response or progressive disease on arm I or II proceed to
      tirapazamine/cyclophosphamide/doxorubicin (TCD) and ifosfamide/etoposide (IE) chemotherapy.

      TCD/IE CHEMOTHERAPY: Patients receive tirapazamine IV over 2 hours, cyclophosphamide IV over
      1 hour, and doxorubicin IV over 15-30 minutes on day 1 of weeks 7, 10, 16, 25, and 34.
      Patients also receive ifosfamide IV over 1 hour and etoposide IV over 1 hour on days 1-5 of
      weeks 13, 19, 22, 28, 31, and 37.

      PATIENTS WITH UNFAVORABLE RISK AND INELIGIBLE FOR WINDOW THERAPY: Patients receive
      tirapazamine IV over 2 hours, cyclophosphamide IV over 1 hour, and doxorubicin IV over 15-30
      minutes on day 1 of weeks 1, 4, 10, 19, and 28. Patients also receive ifosfamide IV over 1
      hour and etoposide IV over 1 hour on days 1-5 of weeks 7, 13, 16, 22, 25, and 31. Patients
      also receive filgrastim (G-CSF) or sargramostim (GM-CSF) subcutaneously (SC) beginning 1 day
      after each course of chemotherapy and continuing until blood counts recover. Treatment
      continues in the absence of disease progression or unacceptable toxicity.

      PATIENTS WITH FAVORABLE RISK: Patients receive cyclophosphamide IV over 1 hour and
      doxorubicin IV over 15-30 minutes on day 1 of weeks 1, 4, 10, 19, and 28. Patients also
      receive ifosfamide IV over 1 hour and etoposide IV over 1 hour on days 1-5 of weeks 7, 13,
      16, 22, 25, and 31. Patients also receive G-CSF or GM-CSF SC beginning 1 day after each
      course of chemotherapy and continuing until blood counts recover. Treatment continues in the
      absence of disease progression or unacceptable toxicity.

      Patients are followed every 2 months for 1 year, every 4 months for 2 years, and then
      annually thereafter.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Response at week 6 of investigational window therapy (unfavorable risk patients)

Secondary Outcome

 Incidence of toxicities associated with the two administration schedules of irinotecan in combination with vincristine, graded according to the NCI CTC v 2.0 (unfavorable risk patients)

Condition

Alveolar Childhood Rhabdomyosarcoma

Intervention

vincristine sulfate

Study Arms / Comparison Groups

 Arm I
Description:  Patients receive vincristine IV on days 1 and 8 and irinotecan IV over 1 hour on days 1-5 and 8-12. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

150

Start Date

November 2001


Primary Completion Date

October 2007

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically confirmed rhabdomyosarcoma, undifferentiated sarcoma, or
             ectomesenchymoma

               -  First relapse or first occurrence of disease progression

          -  Unfavorable-risk patients eligible for study window therapy with irinotecan and
             vincristine meeting the following criteria:

               -  Unfavorable risk defined by any of the following:

                    -  Embryonal histology with stage I or group I at initial diagnosis with
                       distant recurrence or with local or regional recurrence after prior
                       cyclophosphamide

                    -  Embryonal histology with initial stage II, III, or IV or group II, III, or
                       IV with any relapse pattern

                    -  Alveolar histology with any stage or group at initial diagnosis

               -  At least unidimensionally measurable disease

               -  No prior irinotecan

               -  Bone marrow must not be only site of relapse

          -  Unfavorable-risk patients ineligible for study window therapy with irinotecan meeting
             the following criteria:

               -  Either no measurable disease OR patient received prior irinotecan

               -  Bone marrow as only site of relapse allowed

          -  Favorable-risk patients meeting the following criteria:

               -  Initial botryoid histology (any stage, any group, or any pattern of relapse)

               -  Embryonal histology if either stage I or group I (with either local or regional
                  recurrence)

               -  No prior cyclophosphamide

          -  No CNS metastases

          -  Performance status - ECOG 0-2

          -  Performance status - Zubrod 0-2

          -  At least 2 months

          -  Absolute neutrophil count at least 750/mm^3

          -  Platelet count at least 75,000/mm^3 (transfusion independent)

          -  Hemoglobin at least 10.0 g/dL (red blood cell transfusion allowed)

          -  Bilirubin no greater than 1.5 times normal

          -  SGPT less than 2.5 times normal

          -  Creatinine no greater than 1.5 times normal

          -  Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min

          -  Shortening fraction at least 27% by echocardiogram

          -  Ejection fraction at least 50% by MUGA

          -  No prior ischemic heart disease

          -  Seizure disorder allowed if well controlled by anticonvulsants

          -  No CNS toxicity greater than grade 2

          -  Not pregnant or nursing

          -  Negative pregnancy test

          -  Fertile patients must use effective contraception

          -  No prior myeloablative therapy with stem cell transplantation

          -  At least 1 week since prior antineoplastic biologic agent

          -  At least 1 week since prior growth factor(s)

          -  Recovered from prior immunotherapy

          -  No concurrent immunomodulating agents

          -  See Disease Characteristics

          -  See Biologic therapy

          -  No more than 1 prior chemotherapy regimen

          -  No prior doxorubicin or daunorubicin

          -  At least 2 weeks since prior myelosuppressive chemotherapy (4 weeks for nitrosoureas)
             and recovered

          -  No other concurrent anticancer chemotherapy

          -  Concurrent corticosteroid therapy allowed

          -  At least 2 weeks since prior small-port radiotherapy.

          -  At least 6 months since prior radiotherapy to 50% or more of pelvis

          -  At least 6 weeks since other prior substantial radiotherapy to bone marrow

          -  Recovered from prior radiotherapy

          -  Concurrent radiotherapy to localized painful lesions allowed provided at least 1
             measurable lesion is not irradiated

          -  No concurrent intensity-modulated radiotherapy
      

Gender

All

Ages

N/A - 20 Years

Accepts Healthy Volunteers

No

Contacts

Philip Breitfeld, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00025363

Organization ID

NCI-2012-01864

Secondary IDs

ARST0121

Responsible Party

Sponsor

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

Philip Breitfeld, Principal Investigator, Children's Oncology Group


Verification Date

January 2013