Sirolimus in Combination With Metronomic Chemotherapy in Children With High-Risk Solid Tumors

• Status: Recruiting
• Trial end date: 2023-09-01
• Target enrollment: 0
• Participant gender: All

Summary

Primary objective of the study is 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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Emory University
• Collaborator: PeachBowl LegACy Fund
• Treatments: Celecoxib; Cyclophosphamide; Etoposide; Sirolimus

Criteria

Inclusion Criteria:

1. Age: Subjects must be ≥ 12 months and ≤ 30 years of age at the time of study enrollment.

2. Diagnosis:

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:

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.

2. Additional high-risk solid tumors at the request of the treating physician after approval by the study chair.

3. Primary CNS tumors and lymphomas are not eligible.

Prospective Cohort 2:

4. 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 3 Disease Status: Subjects must be in complete remission or with minimal radiological abnormalities as described in 2.1. 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)

4. Performance Level: Karnofsky ≥ 50% for subjects > 16 years of age and Lansky ≥ 50% for subjects ≤ 16 years of age (see Appendix I).

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.

5. Prior Therapy

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 (ie peripheral neuropathy) must be improved to at least grade 2 and be stable or improving on current management.

1. Myelosuppressive chemotherapy: At least 14 days after the last dose of myelosuppressive chemotherapy.

2. 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.

3. 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.

4. 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.

5. Radiation Therapy: At least 14 days after completion of radiation therapy.

6. Stem Cell Infusion: At least 21 days after infusion of stem cells.

6. Organ Function Requirements

6.1 Adequate bone marrow function defined as:

1. Absolute neutrophil count (ANC) ≥ 750/μL

2. Platelet count ≥ 50,000/μL (transfusion independent, defined as not receiving platelet transfusions within 7 days prior to enrollment).

6.2 Adequate renal function defined as creatinine clearance or radioisotope GFR 70ml/min/1.73 m2 or serum creatinine based on age/gender values derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the CDC.

6.3 Adequate liver function defined as:

1. Total bilirubin ≤ 2x upper limit of normal (ULN) and

2. AST (SGOT) and ALT (SGPT) ≤ 225 U/L (5x the ULN). The ULN for AST and ALT will be 45 U/L.

6.4 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.

6.5 Random blood glucose ≤ 1.5x ULN for age. If the initial blood glucose is a random sample that is > 1.5x 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.

6.6 Adequate pulmonary function defined as:

1. Normal pulmonary function tests (PFTs), including DLCO, if there is a clinical indication for determination (dyspnea at rest, known requirement for supplemental oxygen).

2. For subjects who do not have respiratory symptoms (no dyspnea at rest, O2 sat ≥ 93% on room air), PFTs are NOT required.

Exclusion Criteria:

1. Pregnancy or Breast-Feeding: 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.

2. Concomitant Medication

2.1 Corticosteroids: Subjects receiving corticosteroids must be on a stable or decreasing dose of corticosteroid for the prior 7 days.

2.2 Enzyme-inducing anticonvulsants: Subjects who are currently receiving enzyme inducing anticonvulsants are not eligible (see Appendix IV).

2.3 CYP3A4 active agents: Subjects must not be receiving potent CYP3A4 inducers or inhibitors as outlined in Appendix IV.

2.4 Investigational Drugs: Subjects who are currently receiving another investigational drug are not eligible.

2.5 Anti-cancer Agents: Subjects who are currently receiving any other anti-cancer agents are not eligible.

3. Infection: Subjects who have an uncontrolled infection are not eligible.

4. Subjects enrolled on a clinical trial for upfront therapy or relapse therapy for those patients in second complete remission.

5. 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.