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Sirolimus and Metronomic Chemotherapy for the Treatment of High-Risk Solid Tumors in Children, AflacST1903 Study

Trial Status: Approved

This phase II trial studies how well sirolimus together with repetitive, low doses of chemotherapy (metronomic chemotherapy) works in treating children with high-risk solid tumors. Sirolimus is used to decrease the body's immune response. Chemotherapy drugs, such as etoposide 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. Celecoxib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving sirolimus together with chemotherapy may help stop tumor growth by preventing blood from getting to the tumor and ultimately prevent the tumor from coming back.

Inclusion Criteria

  • Subjects must have one of the following high-risk malignant pediatric extracranial solid tumors and be in complete remission or have minimal abnormalities* on imaging studies after completion of upfront therapy administered with curative intent (cohort 1) or after completion of initial relapse regimen
  • Prospective Cohort 1: * Metastatic/unresectable osteosarcoma, metastatic Ewing or Ewing-like sarcoma, high-risk rhabdomyosarcoma, metastatic non-rhabdomyosarcoma soft tissue sarcoma, desmoplastic small round cell tumor (DSRCT), malignant rhabdoid tumor * Additional high-risk solid tumors at the request of the treating physician after approval by the study chair * Primary central nervous system (CNS) tumors and lymphomas are not eligible
  • Prospective Cohort 2: * Recurrent extracranial solid tumor (any histology) in second complete remission following completion of initial relapse regimen * It is intended that minimal radiological abnormalities describe imaging studies in which there are residual abnormalities, compatible with fibrosis or necrosis and not considered active disease, and the responsible clinician would be prepared to stop treatment
  • Subjects must have had histologic verification of malignancy at original diagnosis or relapse
  • Subjects must be in complete remission or with minimal radiological abnormalities. Baseline imaging should be the end of therapy imaging obtained at the completion of “standard” upfront therapy (cohort 1) or at the completion of initial relapse regimen (cohort 2)
  • Karnofsky >= 50% for subjects > 16 years of age and Lansky >= 50% for subjects =< 16 years of age * Note: Subjects who are unable to walk because of paralysis but who are up in a wheelchair will be considered ambulatory for the purpose of assessing the performance score
  • Subjects must have fully recovered from the acute non-hematologic toxic effects of all prior anti-cancer therapy and meet hematologic count parameters. Chronic non-hematologic toxic effects of prior anti-cancer therapy (i.e. peripheral neuropathy) must be improved to at least grade 2 and be stable or improving on current management * Myelosuppressive chemotherapy: At least 14 days after the last dose of myelosuppressive chemotherapy * Hematopoietic growth factors: At least 14 days after the last dose of a long-acting growth factor (e.g. pegfilgrastim) or 7 days after the last dose of short-acting growth factor. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair * Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair * Antibodies: At least 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1 * Radiation Therapy: At least 14 days after completion of radiation therapy * Stem Cell Infusion: At least 21 days after infusion of stem cells
  • Absolute neutrophil count (ANC) >= 750/uL
  • Platelet count >= 50,000/uL (transfusion independent, defined as not receiving platelet transfusions within 7 days prior to enrollment)
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) 70 ml/min/1.73 m^2 or serum creatinine based on age/gender as follows: * Age: Maximum serum creatinine (mg/dL) * 0 month to < 6 months: 0.4 (male); 0.4 (female) * 6 months to < 1 year: 0.5 (male); 0.5 (female) * 1 to < 2 years; 0.6 (male): 0.6 (female) * 2 to < 6 years; 0.8 (male): 0.8 (female) * 6 to < 10 years; 1 (male): 1 (female) * 10 to < 13 years; 1.2 (male): 1.2 (female) * 13 to < 16 years; 1.5 (male): 1.4 (female) * >= 16 years: 1.7 (male); 1.4 (female)
  • Total bilirubin =< 2x upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 225 U/L (5 x the ULN). The ULN for AST and ALT will be 45 U/L
  • Serum triglyceride level =< 300 mg/dL and serum cholesterol =< 300 mg/dL. If these labs were drawn non-fasting and do not meet the eligibility criteria then it is suggested that they are repeated fasting, i.e. no food or drink other than water for 8 hours. The use of medication to achieve these parameters is not allowed
  • Random blood glucose =< 1.5 x ULN for age. If the initial blood glucose is a random sample that is > 1.5 x ULN, then a follow-up fasting (no food or drink other than water for 8 hours) blood glucose can be obtained and must be within the upper limits for age
  • Normal pulmonary function tests (PFTs), including diffusion capacity of the lung for carbon monoxide (DLCO), if there is a clinical indication for determination (dyspnea at rest, known requirement for supplemental oxygen)
  • For subjects who do not have respiratory symptoms (no dyspnea at rest, oxygen [O2] saturation [sat] >= 93% on room air), PFTs are NOT required

Exclusion Criteria

  • Pregnant or breast-feeding women will not be entered on this study as there may be fetal risks or teratogenic toxicities. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method during treatment and for 3 months after stopping treatment. This should be documented in the electronic medical records as part of the consent discussion
  • Subjects receiving corticosteroids must be on a stable or decreasing dose of corticosteroid for the prior 7 days
  • Subjects who are currently receiving enzyme inducing anticonvulsants are not eligible
  • Subjects must not be receiving potent CYP3A4 inducers or inhibitors
  • Subjects who are currently receiving another investigational drug are not eligible
  • Subjects who are currently receiving any other anti-cancer agents are not eligible
  • Subjects who have an uncontrolled infection are not eligible
  • Subjects enrolled on a clinical trial for upfront therapy or relapse therapy for those patients in second complete remission
  • Subjects who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible

Georgia

Atlanta
Emory University Hospital / Winship Cancer Institute
Status: APPROVED
Contact: Kathryn S. Sutton
Phone: 404-785-1651

PRIMARY OBJECTIVE:

I. To improve the 2-year progression-free survival in children with high-risk solid tumors who are administered a maintenance regimen with continuous sirolimus administered on a backbone of metronomic chemotherapy following the completion of “standard” therapy, as compared to high-risk solid tumor patients treated with observation alone following completion of “standard” therapy.

SECONDARY OBJECTIVES:

I. To compare the median progression-free survival of children with high-risk solid tumors who are administered a maintenance regimen with sirolimus administered orally once daily in combination with metronomic chemotherapy following the completion of “standard” therapy with that of a historical cohort of matched patients treated with observation alone following completion of “standard’ therapy.

II. To determine the progression-free survival in children with high-risk solid tumors who are administered a maintenance regimen with continuous sirolimus administered orally once daily with celecoxib, and oral etoposide alternating every 21 days with oral cyclophosphamide in a 42-day cycle following the completion of “standard” therapy.

III. To determine the overall survival in children with high-risk solid tumors who are administered a maintenance regimen with sirolimus administered orally once daily for 42 days in combination with metronomic chemotherapy following the completion of “standard” therapy.

IV. To determine the incidence of severe toxicities of sirolimus administered in combination with metronomic chemotherapy administered on this schedule in the maintenance setting.

V. To determine the feasibility of completion of a 12-month course of maintenance chemotherapy following completion of “standard” therapy.

VI. To determine the median progression-free survival of children with recurrent solid tumors in second complete remission following completion of an initial relapse treatment regimen.

EXPLORATORY OBJECTIVES:

I. To determine if a patient-specific assay detecting multiple somatic variants can be developed and subsequently utilized to detect circulating tumor deoxyribinucleic acid (DNA) (ctDNA) in the setting of minimal residual disease in pediatric patients with high-risk solid tumors. If ctDNA is detected while on study, changes in detectability and ctDNA levels will be monitored over time in each patient and descriptively correlated with outcome.

II. To describe the tumor molecular profiles of pediatric high-risk solid tumors and correlate the findings with clinical outcome using Clinical Laboratory Improvement Act (CLIA)-certified molecular profiling platforms already in use at participating institutions.

OUTLINE:

Patients receive sirolimus orally (PO) once daily (QD) and celecoxib PO twice daily (BID) on days 1-42, etoposide PO QD on days 1-21, and cyclophosphamide PO QD on days 22-42. Treatment repeats every 42 days for 8 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up within 30 days and then yearly thereafter.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Children's Healthcare of Atlanta - Egleston

Principal Investigator
Kathryn S. Sutton

  • Primary ID AFLACST1903
  • Secondary IDs NCI-2020-01654, STUDY00000113
  • Clinicaltrials.gov ID NCT04469530