Risk Adapted Focal Proton Beam Radiation and/or Surgery in Patients with Low, Intermediate, and High Risk Rhabdomyosarcoma Receiving Standard or Intensified Chemotherapy
This phase II trial studies how well chemotherapy, surgery, and radiation therapy work in treating patients with newly diagnosed rhabdomyosarcoma that has spread to other parts of the body. Drugs used in chemotherapy, such as vincristine sulfate, dactinomycin, and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving combination chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving combination chemotherapy and radiation therapy after surgery may kill any tumor cells that remain after surgery.
Inclusion Criteria
- Newly diagnosed participants with rhabdomyosarcoma (RMS)
- Must have low, intermediate-risk or high-risk disease, defined as: * Low-risk: Embryonal, botryoid, spindle cell tumors only ** Subset 1 *** Stage 1, Group I, Group II *** Stage 1 Group III orbital only *** Stage 2, Group I, 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-III * High-risk: Embryonal, botryoid, spindle cell, alveolar, undifferentiated, or anaplastic RMS with metastatic disease at diagnosis (stage 4) * Patients treated on RMS13 in the low or intermediate risk arm that 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
- Performance level corresponding to Eastern Cooperative Oncology Group (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 (discuss with principal investigator [PI]); at least 6 weeks must have passed since last dose of myelosuppressive chemotherapy or radiation therapy for conditions other than RMS; patients must have recovered from acute toxicity of any prior myelosuppressive chemotherapy or radiation therapy; 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
- Peripheral absolute neutrophil count (ANC) >= 750/uL
- Platelet count >= 75,000/uL (transfusion independent)
- 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
- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73^2 or serum creatinine based on age/gender as follows: * Age: Maximum serum creatinine (mg/dL) for gender * Age 1 month to < 6 months: 0.4 for males and 0.4 for females * Age 6 months to < 1 year: 0.5 for males and 0.5 for females * Age 1 to < 2 years: 0.6 for males and 0.6 for females * Age 2 to < 6 years: 0.8 for males and 0.8 for females * Age 6 to < 10 years: 1 for males and 1 for females * Age 10 to < 13 years: 1.2 for males and 1.2 for females * Age 13 to < 16 years: 1.5 for males and 1.4 for females * Age >= 16 years: 1.7 for males and 1.4 for females ** 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 trial
- 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
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT01871766.
PRIMARY OBJECTIVE:
I. Estimate event-free survival for intermediate risk participants treated by vincristine sulfate, dactinomycin, cyclophosphamide (VAC) with the addition of maintenance anti-angiogenic therapy.
SECONDARY OBJECTIVES:
I. Estimate the false negative rate and incidence of additional positive lymph nodes in participants undergoing sentinel lymph node biopsy followed by limited nodal dissection.
II. Maintain a high local control rate in participants treated with surgery and/or limited volume proton and photon radiation without dose escalation.
III. Define the incidence and type of failure in participants who receive risk-adapted local therapy relative to the primary tumor volume.
IV. Establish the feasibility of delivering 4 cycles of maintenance antiangiogenic chemotherapy (bevacizumab/sorafenib [sorafenib tosylate]/low dose cyclophosphamide) in intermediate and high risk patients following standard chemotherapy.
V. Estimate the event-free survival for high risk patients receiving interval dose compressed therapy and maintenance anti-angiogenic therapy.
VI. Define the incidence of Common Toxicity Criteria (CTC) grade 3 and higher toxicities (and specific grade 1-2 toxicities) related to proton beam therapy.
EXPLORATORY OBJECTIVES:
I. Study the association between radiation dosimetry in participants receiving proton beam radiation therapy (PBRT) and musculoskeletal toxicity.
II. Compare dosimetrically, the ability of PBRT to spare adjacent normal tissues compared to photon-based radiation therapy.
III. Define the relation of distribution, intensity and change in carbon (C)11-methionine computed tomography positron emission tomography (CTPET) imaging of the primary site to local control and disease specific survival.
IV. Compare quantitative functional imaging parameters obtained in tumor and adjacent normal tissue at base line and following therapy with diffusion weighted imaging (DWI) and to local control and disease specific survival.
V. Evaluate if patterns of metabolic and functional imaging at baseline and response are consistent and reproducible to allow for the development of a biologically guided target volumes (BTV) for radiation therapy planning in subsequent trial.
VI. Evaluate the feasibility of contrast-enhanced ultrasound of primary tumors at baseline, day 7, and subsequent protocol driven imaging time-points during neoadjuvant therapy in intermediate and high-risk patients.
VII. Obtain tissue to better identify genetic subgroups of rhabdomyosarcoma.
VIII. Assess serial changes in genetic lesions during therapy and at recurrence.
IX. Assess potential of serum microribonucleic acid (RNA)-206 levels as biomarker of disease status.
X. Collect additional pharmacokinetic (PK) and pharmacogenomic (PG) datasets in a newly diagnosed patient population to further refine sorafenib PK models.
XI. Relate toxicities seen during the maintenance phase of therapy to sorafenib exposure levels.
OUTLINE: Patients are assigned to 1 of 4 treatment groups.
GROUP I (LOW-RISK SUBSET 1): Patients receive vincristine sulfate intravenously (IV) over 1 minute on day 1 of weeks 1-10 (omit week 9), 13-20, and 22; dactinomycin IV over 1-5 minutes on day 1 of weeks 1, 4, 7, 10, 13, 16, 19, and 22 (omit weeks 16 and 19 doses during radiation therapy); and cyclophosphamide IV over 30-60 minutes on day 1 of weeks 1, 4, 7, and 10. Patients undergo surgical resection at 11 weeks. Patients also undergo proton beam radiation therapy daily, external beam radiation therapy daily, or brachytherapy twice daily (BID) during weeks 13-18.
GROUP II (LOW-RISK SUBSET 2): Patients receive vincristine sulfate IV over 1 minute on day 1 of weeks 1-10, 13-19, 22-25, 28, 31-37, and 40; dactinomycin IV over 1-5 minutes on day 1 of weeks 1, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, and 40 (omit weeks 16, 19, 37, and 40 during radiation therapy); and cyclophosphamide IV over 30-60 minutes on day 1 of weeks 1, 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, and 40. Patients undergo surgical resection at 11 weeks. Patients also radiation therapy as in Group I during weeks 13-18 or 37-40 for very young patients.
GROUP III (INTERMEDIATE RISK): Patients receive chemotherapy as in Group II and radiation therapy at week 4 or week 13. Patients with sites that qualify for upfront radiation therapy at week 4 also receive vincristine sulfate IV over 1 minute, dactinomycin IV over 1-5 minutes, and cyclophosphamide IV over 30-60 minutes on week 4 before beginning radiation therapy. Patients then receive maintenance therapy comprising bevacizumab IV over 30-90 minutes on day 1 of weeks 43, 46, 49, and 52, sorafenib tosylate orally (PO) or nasogastrically (NG) BID from day 1 of week 43 through day 7 of week 54, and cyclophosphamide PO or NG once daily (QD) from day 1 of week 43 through day 7 of week 54.
Patients with low- or intermediate-risk disease experiencing disease progression prior to week 13 may cross over to the High-Risk Arm.
GROUP IV (HIGH RISK): Patients receive vincristine sulfate 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 60 minutes on days 1-5 of weeks 1, 4, 20, 23, 47, and 50; ifosfamide IV over 1 hour on days 1-5 of week 9, 13, 17, 26, and 30; and etoposide IV over 60-120 minutes on days 1-5 or according to body weight for patients < 1 year in weeks 9, 13, 17, 26, and 30; doxorubicin hydrochloride IV over 1 hour or according to body weight on days 1 and 2 of weeks 7, 11, 15, and 28-32; dactinomycin IV over 1-5 minutes on day 1 of weeks 35, 38, 41, and 44; cyclophosphamide IV over 30-60 minutes on day 1 of weeks, 7, 11, 15, 28, 32, 35, 38, 41, and 44; and undergo radiation therapy at week 4 or week 20. Patients then receive maintenance therapy comprising bevacizumab IV over 30-90 minutes on day 1 of weeks 55, 58, 61 and 64, sorafenib tosylate PO or NG BID from day 1 of week 55 through day 7 of week 66, and cyclophosphamide PO or NG QD from day 1 of week 55 through day 7 of week 66.
After completion of study treatment, patients are followed up every 3 months for 1 year, every 4 months for 2 years, every 6 months for 1 year, and then annually for 1 year.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationSaint Jude Children's Research Hospital
Principal InvestigatorMatthew James Krasin
- Primary IDRMS13
- Secondary IDsNCI-2013-00913
- ClinicalTrials.gov IDNCT01871766