Clinical Trials /

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

NCT04469530

Description:

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.

Related Conditions:
  • Desmoplastic Small Round Cell Tumor
  • Ewing Sarcoma
  • Ewing-like Sarcoma
  • Osteosarcoma
  • Rhabdoid Tumor
  • Rhabdomyosarcoma
  • Soft Tissue Sarcoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Sirolimus in Combination With Metronomic Chemotherapy in Children With High-Risk Solid Tumors
  • Official Title: A Maintenance Protocol of Sirolimus in Combination With Metronomic Chemotherapy in Children With High-Risk Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: STUDY00000113
  • NCT ID: NCT04469530

Conditions

  • Solid Tumor

Interventions

DrugSynonymsArms
SIROLIMUSAY-22989, rapamycin, RapamuneMaintenance regimen
CyclophosphamideMaintenance regimen
VP-16Etoposide VePesid, NSC # 141540Maintenance regimen
CelecoxibMaintenance regimen

Purpose

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.

Detailed Description

      This study has three cohorts: a prospective cohort of patients with high-risk extracranial
      solid tumor, a prospective cohort of patients with recurrent solid tumors (any histology) in
      second complete remission, and a historical control cohort of patients matched on diagnosis,
      age, metastatic site, and date of diagnosis. The matched historical controls will be obtained
      from the same treating institution as the corresponding case to account for institutional
      differences in treatment and supportive care.

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Maintenance regimenExperimentalMaintenance chemotherapy regimen administered as a 12-month course of continuous sirolimus with celecoxib and low-dose oral etoposide alternating every 21 days with low-dose oral cyclophosphamide following the completion of "standard" therapy
  • SIROLIMUS
  • Cyclophosphamide
  • VP-16
  • Celecoxib
ObservationNo InterventionObservation alone following the completion of "standard" therapy

    Eligibility 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.
          
    Maximum Eligible Age:30 Years
    Minimum Eligible Age:1 Year
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Number of 2-year progression-free survivors
    Time Frame:up to 2 years
    Safety Issue:
    Description:Number of 2-year progression-free survivors among children who are administered a maintenance regimen with continuous sirolimus administered on a backbone of metronomic chemotherapy following the completion of "standard" therapy compared to children treated with observation alone following completion of "standard" therapy

    Secondary Outcome Measures

    Measure:Median progression-free survival of children on a maintenance regimen with sirolimus orally once daily in combination with metronomic chemotherapy compared to children treated with observation alone
    Time Frame:up to 2 years
    Safety Issue:
    Description:Median progression-free survival of children on a maintenance regimen with sirolimus orally once daily in combination with metronomic chemotherapy following the completion of "standard" therapy compared to children treated with observation alone following completion of "standard" therapy
    Measure:Median progression-free survival in children on a maintenance regimen with sirolimus orally once daily with celecoxib, and oral etoposide alternating every 21 days with oral cyclophosphamide in a 42-day cycle compared to observation alone
    Time Frame:up to 2 years
    Safety Issue:
    Description:Median progression-free survival in children on a maintenance regimen with continuous sirolimus 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 compared to children treated with observation alone following completion of "standard" therapy
    Measure:Median overall survival in children on a maintenance regimen with sirolimus orally once daily for 42 days in combination with metronomic chemotherapy compared to children treated with observation alone
    Time Frame:up to 2 years
    Safety Issue:
    Description:Median overall survival in children on a maintenance regimen with sirolimus orally once daily for 42 days in combination with metronomic chemotherapy following the completion of "standard" therapy compared to patients treated with observation alone following completion of "standard" therapy will be assessed
    Measure:Number of cases of severe toxicities of sirolimus administered in combination with metronomic chemotherapy administered on this schedule in the maintenance setting
    Time Frame:up to 2 years
    Safety Issue:
    Description:Number of cases of severe toxicities of sirolimus administered in combination with metronomic chemotherapy administered on this schedule in the maintenance setting will be documented
    Measure:Number of patients who come off protocol therapy due to toxicity or non-compliance
    Time Frame:up to 2 years
    Safety Issue:
    Description:Feasibility of completion of a 12-month course of maintenance chemotherapy following completion of "standard" therapy will be evaluated by number of patients who come off protocol therapy due to toxicity or non-compliance.
    Measure:Median progression-free survival of children with recurrent solid tumors in second complete remission following completion of an initial relapse treatment regimen
    Time Frame:up to 2 years
    Safety Issue:
    Description:Median progression-free survival of children with recurrent solid tumors in second complete remission following completion of an initial relapse treatment regimen will be evaluated

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:Emory University

    Trial Keywords

    • Pediatrics
    • Chemotherapy
    • Remission
    • Survival

    Last Updated

    July 9, 2020