Clinical trial NCT01871766: Risk-Adapted Focal Proton Beam Radiation and/or Surgery in Patients With Low, Intermediate and High Risk Rhabdomyosarcoma Receiving Standard or Intensified Chemotherapy
Official title: Risk-Adapted Focal Proton Beam Radiation and/or Surgery in Patients With Low, Intermediate and High Risk Rhabdomyosarcoma Receiving Standard or Intensified Chemotherapy
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Rhabdomyosarcoma
Keywords: Rhabdomyosarcoma
Radiation therapy
Proton beam
Lead sponsor: St. Jude Children's Research Hospital
Sponsor class: OTHER
First posted: 2013-06-07
Enrollment: 115
Sex: ALL
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will treat participants with newly diagnosed, low, intermediate and high risk rhabdomyosarcoma (RMS) using multi-modality risk-adapted therapy with standard or intensified dose chemotherapy, radiation and surgical resection. Intermediate and high risk participants will receive an additional 12 weeks (4 cycles) of maintenance therapy with anti-angiogenic chemotherapy.

PRIMARY OBJECTIVE:

* Estimate event-free survival for intermediate risk participants treated with vincristine, dactinomycin and cyclophosphamide with the addition of maintenance anti-angiogenic therapy.

SECONDARY OBJECTIVES:

* Estimate the false negative rate and incidence of additional positive lymph nodes in participants undergoing sentinel lymph node biopsy followed by limited nodal dissection.
* Maintain a high local control rate in participants treated with surgery and/or limited volume proton and photon radiation without dose escalation.
* Define the incidence and type of failure in participants who receive risk-adapted local therapy relative to the primary tumor volume.
* Establish the feasibility of delivering 4 cycles of maintenance anti-angiogenic chemotherapy in intermediate and high risk patients following standard chemotherapy.
* Estimate the event free survival for high risk patients receiving interval dose compressed therapy and maintenance anti-angiogenic therapy.
* Define the incidence of CTC grade 3 and higher toxicities (and specific grade 1-2 toxicities) related to proton beam therapy.

Detailed description: Participants will be stratified based on both a pretreatment staging system and a post-surgery surgico/pathologic clinical grouping system. Treatment for low-risk (subset 1) participants will consist of chemotherapy and radiation. Low-risk (subset 2) and intermediate-risk participants will receive chemotherapy and radiation and/or undergo surgery to destroy/remove the tumor. Intermediate-risk participants will also receive 16 weeks of maintenance chemotherapy. High-risk participants will receive chemotherapy and radiation therapy. High-risk participants will also receive additional maintenance therapy with anti-angiogenic chemotherapy.

Eligibility criteria: Inclusion Criteria:

* Newly diagnosed participants with localized rhabdomyosarcoma (RMS).
* Must have either low-, intermediate-, or high-risk disease, defined as:

  * Low-risk: Embryonal, botryoid, spindle cell tumors only (Subset 1: Stage 1, Group I; Stage 1 Group I; Stage 1 Group III orbital only; Stage 2 Group I; Stage 2 Group II) (Subset 2: Stage 1 Group III non orbit; Stage 3 Group I, II)
  * Intermediate-risk: Embryonal, botryoid, or spindle cell RMS Stage 2 or 3 and Group III; Alveolar, undifferentiated, or anaplastic RMS: Stage 1-3, group I-I; I)
  * High-risk: Embryonal, botryoid, spindle cell, alveolar, undifferentiated, or anaplastic RMS with metastatic disease at diagnosis (stage 4).
  * Participants treated on this protocol in the low or intermediate risk arm who experience disease progression prior to week 13 will transfer to the high risk arm and proceed with high risk chemotherapy starting at week 1 of the protocol.
* Age \< 22 years (eligible until 22nd birthday)
* Performance level corresponding to ECOG score of 0, 1, or 2. The Lansky performance score should be used for participants \< 16 years
* Participant has received no prior radiotherapy or chemotherapy for rhabdomyosarcoma (excluding steroids) unless an emergency situation requires local tumor treatment. Prior biopsy, surgical resection and lymph node sampling is allowed.
* Initiation of chemotherapy is planned within 6 weeks (42 days) of the definitive biopsy or surgical resection.
* Adequate bone marrow function defined as:

  * Peripheral absolute neutrophil count (ANC) ≥ 750/μL
  * Platelet count ≥ 75,000/μL (transfusion independent)
* Adequate liver function defined as total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age. Participants with biliary or hepatic primaries with bilirubin values greater than 1.5 x ULN may be enrolled on study if all other eligibility criteria are met.
* Adequate renal function defined as:

  * Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.732 or
  * Serum creatinine based on age and gender
  * Participants 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.
* Patients requiring emergency radiation therapy are eligible for enrollment on this study.
* Females of child-bearing potential cannot be pregnant or breast-feeding. Female participants ≥ 10 years of age or post-menarchal must have a negative serum or urine pregnancy test within 24 hours prior to beginning treatment. Female participants who are breast feeding must agree to stop breast feeding.
* Sexually active patients of childbearing potential must be willing to use effective contraception during therapy and for at least 1 month after treatment is completed.
* No evidence of active, uncontrolled infection.
* All participants and/or their parents or legal guardians must sign a written informed consent.

Exclusion Criteria:

* Participants who fail to meet one or more of the inclusion criteria will be excluded.

Inclusion Criteria for Contrast-Enhanced Ultrasound (CEUS) Sub-Study:

* Newly diagnosis or suspected diagnosis of previously untreated participants with rhabdomyosarcoma (RMS). NOTE: Patients with suspected diagnosis of RMS may enroll on screening part of study but must have histologic diagnosis to enroll on treatment part of study.
* Must have either intermediate-risk or high risk disease.
* 0-21 years of age.

Exclusion Criterial for CEUS Sub-Study:

* Undergoing upfront surgical resection of the primary tumor.
* History of allergy to Optison(TM) contrast agent or blood products.

Primary outcomes:
measure: Event-free survival (intermediate risk arm)
timeFrame: 2 years after last intermediate risk arm enrollment
Secondary outcomes:
measure: Event-free survival (high risk arm)
timeFrame: 5 years after last high-risk arm enrollment
measure: Rate of false negative and false positive the sentinel lymph node procedure (low and intermediate risk arms)
timeFrame: 2 years after last low or intermediate arm enrollment
measure: Rate of false negative and false positive the sentinel lymph node procedure (high risk arm)
timeFrame: 5 years after last high risk arm enrollment
measure: Local failure rate (low and intermediate risk arms)
timeFrame: 2 years after last low or intermediate risk arm enrollment
measure: Local failure rate (high risk arm)
timeFrame: 5 years after last high risk arm enrollment
measure: Patterns of failure (low and intermediate risk arms)
timeFrame: 2 years after last low or intermediate risk arm enrollment
measure: Patterns of failure (high risk arm)
timeFrame: 5 years after last high risk arm enrollment
measure: Number of patients that complete all cycles of maintenance chemotherapy (intermediate risk arm)
timeFrame: 2 years after last low or intermediate risk arm enrollment
measure: Number of patients that complete all cycles of maintenance chemotherapy (high risk arm)
timeFrame: 5 years after last high risk arm enrollment
measure: Incidence of CTC grade 3 and higher toxicities related to proton bream therapy (low and intermediate and high risk arms)
timeFrame: 2 years after last enrollment
Other outcomes:
Locations:
city: Jacksonville
country: United States
facility: University of Florida Proton Therapy Institute
state: Florida
city: Jacksonville
country: United States
facility: Nemours Children's Clinic
state: Florida
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Fort Worth
country: United States
facility: Cook Children's Medical Center
state: Texas
Study officials:
affiliation: St. Jude Children's Research Hospital
name: Matthew J. Krasin, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Patel AG, Chen X, Huang X, Clay MR, Komorova N, Krasin MJ, Pappo A, Tillman H, Orr BA, McEvoy J, Gordon B, Blankenship K, Reilly C, Zhou X, Norrie JL, Karlstrom A, Yu J, Wodarz D, Stewart E, Dyer MA. The myogenesis program drives clonal selection and drug resistance in rhabdomyosarcoma. Dev Cell. 2022 May 23;57(10):1226-1240.e8. doi: 10.1016/j.devcel.2022.04.003. Epub 2022 Apr 27.