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Sirolimus in Combination With Metronomic Chemotherapy in Children With High-Risk Solid Tumors (AflacST1903)

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ClinicalTrials.gov Identifier: NCT04469530
Recruitment Status : Recruiting
First Posted : July 14, 2020
Last Update Posted : December 22, 2020
Sponsor:
Collaborator:
PeachBowl LegACy Fund
Information provided by (Responsible Party):
Kathryn S. Sutton, Emory University

Brief 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.

Condition or disease Intervention/treatment Phase
Solid Tumor Drug: SIROLIMUS Drug: Cyclophosphamide Drug: VP-16 Drug: Celecoxib Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Masking Description: Three cohorts of patients will be treated: 1) common solid tumors in complete remission, 2) common solid tumors in second complete remission, and 3) historical control cohort of patients derived from the electronic medical record matched with same diagnosis, metastatic site, and date of diagnosis utilizing a 2:1 ratio
Primary Purpose: Treatment
Official Title: A Maintenance Protocol of Sirolimus in Combination With Metronomic Chemotherapy in Children With High-Risk Solid Tumors
Actual Study Start Date : September 16, 2020
Estimated Primary Completion Date : September 2023
Estimated Study Completion Date : September 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Sirolimus

Arm Intervention/treatment
Experimental: Maintenance regimen
Maintenance 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
Drug: SIROLIMUS
Sirolimus is a macrocyclic lactone produced by Streptomyces hygroscopicus. Dose of 2 mg/m2 once daily. The amber oral dose syringe should be used to withdraw the prescribed amount of sirolimus oral solution from the bottle. The solution can be drunk or administered at once to assure delivery of all of the medication. It is safe for administration through a nasogastric or G-tube. For tablets, the tablet should not be crushed, split, or otherwise altered. As with the liquid dosing form, the tablets should be given within two hours each day and should be at consistent intervals with regard to meals.
Other Name: AY-22989, rapamycin, Rapamune

Drug: Cyclophosphamide

A synthetic antineoplastic drug chemically related to the nitrogen mustards. The drug is administered orally daily, in the formulation appropriate for age.

The solution should be diluted in 20-30 ml of appropriate liquid before administration through NG tube or G tube, with adequate flushing after administration to prevent obstruction of the feeding tube.


Drug: VP-16
A semisynthetic derivative of podophyllotoxin which functions as mitotic inhibitor but does not interfere with microtubular assembly. The drug is administered orally daily, in the formulation appropriate for age.
Other Name: Etoposide VePesid, NSC # 141540

Drug: Celecoxib
The empirical formula for celecoxib is C 17 H 14 F 3 N 3 O 2 S. The drug is administered orally daily, in the formulation appropriate for age.The solution is safe for administration through a nasogastric or G-tube.

No Intervention: Observation
Observation alone following the completion of "standard" therapy



Primary Outcome Measures :
  1. Number of 2-year progression-free survivors [ Time Frame: up to 2 years ]
    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 :
  1. 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 ]
    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

  2. 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 ]
    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

  3. 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 ]
    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

  4. 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 ]
    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

  5. Number of patients who come off protocol therapy due to toxicity or non-compliance [ Time Frame: up to 2 years ]
    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.

  6. 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 ]
    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



Information from the National Library of Medicine

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Ages Eligible for Study:   1 Year to 30 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04469530


Contacts
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Contact: Kathryn Sutton, MD 404-785-1651 Kathryn.Sutton@choa.org

Locations
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United States, Georgia
Aflac Cancer & Blood Disorders Centers Recruiting
Atlanta, Georgia, United States, 30322
Contact: Kathryn Sutton, MD    404-785-1651    Kathryn.Sutton@choa.org   
Children's Healthcare of Atlanta Recruiting
Atlanta, Georgia, United States, 30322
Contact: Kathryn Sutton, MD    404-785-1651    Kathryn.Sutton@choa.org   
Sponsors and Collaborators
Emory University
PeachBowl LegACy Fund
Investigators
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Principal Investigator: Kathryn Sutton, MD Emory University
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Responsible Party: Kathryn S. Sutton, Principal Investigator, Emory University
ClinicalTrials.gov Identifier: NCT04469530    
Other Study ID Numbers: STUDY00000113
First Posted: July 14, 2020    Key Record Dates
Last Update Posted: December 22, 2020
Last Verified: December 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Data will be shared in the future after data analysis is completed if asked/requested or felt it would be of value to a particular research community.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: TBD after data analysis is completed by the study team
Access Criteria: TBD after data analysis is completed by the study team

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Kathryn S. Sutton, Emory University:
Pediatrics
Chemotherapy
Remission
Survival
Additional relevant MeSH terms:
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Neoplasms
Sirolimus
Celecoxib
Cyclophosphamide
Etoposide
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Anti-Inflammatory Agents
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors