Clinical Trials /

Metronomic Therapy for Pediatric Patients With Solid Tumors at High Risk of Recurrence

NCT02446431

Description:

Most pediatric patients with solid tumors respond to initial high-dose, intensive therapy and complete treatment in remission. High-risk patients however, frequently have recurrent disease which is then treated with ad hoc regimens or early phase therapies with little benefit to the patient. Metronomic therapy (MC), defined as lower dose continuous drug exposure, has been successfully tested in pediatric leukemias with excellent results in terms of improved outcome, toxicity profiles, and cost. MC has been applied to solid tumors with little success, but has been implemented usually in the relapsed setting at a time of high tumor burden and disease resistance.

Related Conditions:
  • Ewing Sarcoma
  • Malignant Solid Tumor
  • Osteosarcoma
  • Rhabdomyosarcoma
  • Soft Tissue Sarcoma
Recruiting Status:

Recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Metronomic Therapy for Pediatric Patients With Solid Tumors at High Risk of Recurrence
  • Official Title: Metronomic Therapy for Pediatric Patients With Solid Tumors at High Risk of Recurrence: A Multi-Institutional Study

Clinical Trial IDs

  • ORG STUDY ID: 001
  • NCT ID: NCT02446431

Conditions

  • Solid Tumor

Interventions

DrugSynonymsArms
BevacizumabAvastinMetronomic Therapy
CyclophosphamideCytoxanMetronomic Therapy
Valproic AcidDepakoteMetronomic Therapy
TemsirolimusToriselMetronomic Therapy

Purpose

Most pediatric patients with solid tumors respond to initial high-dose, intensive therapy and complete treatment in remission. High-risk patients however, frequently have recurrent disease which is then treated with ad hoc regimens or early phase therapies with little benefit to the patient. Metronomic therapy (MC), defined as lower dose continuous drug exposure, has been successfully tested in pediatric leukemias with excellent results in terms of improved outcome, toxicity profiles, and cost. MC has been applied to solid tumors with little success, but has been implemented usually in the relapsed setting at a time of high tumor burden and disease resistance.

Detailed Description

      Most pediatric patients with solid tumors respond to initial high-dose, intensive therapy and
      complete treatment in remission. High-risk patients however, frequently have recurrent
      disease which is then treated with ad hoc regimens or early phase therapies with little
      benefit to the patient. Metronomic therapy (MC), defined as lower dose continuous drug
      exposure, has been successfully tested in pediatric leukemias with excellent results in terms
      of improved outcome, toxicity profiles, and cost. MC has been applied to solid tumors with
      little success, but has been implemented usually in the relapsed setting at a time of high
      tumor burden and disease resistance. This protocol's overall objective is to improve on
      historical outcome for high risk pediatric patients who are in remission by initiating MC
      treatment after completion of front-line therapy.

      This protocol 1) will treat patients when they have minimal disease burden, 2) will treat
      patients with agents either not previously incorporated into front-line therapy or given in a
      different manner and, 3) is designed to be given in the outpatient setting. The 4 agents will
      take advantage of targeting frequently disrupted signaling pathways, epigenetic
      abnormalities, and classical cell killing mechanisms. An analysis of cost will be undertaken
      to help define part of the financial impact to families and on the health care system to
      deliver this therapy. The hypothesis of this protocol is: Introduction of metronomic
      treatment after completion of standard therapy for patients with high-risk, solid tumors in
      remission will improve time to tumor progression compared with historical controls. The
      primary and secondary goals (specific aims) of this protocol are: To determine the time to
      tumor progression for patients at high-risk of relapse with solid tumors; To define and
      describe the toxicity profile of the chemotherapy regimen; To determine the site(s) of
      relapse for patients receiving treatment;To determine part of the cost of delivering
      treatment; and finally to understand how this added therapy impacts quality of life.

      Chemotherapy will be started within 6 weeks of completion of front-line treatment,
      documentation of remission status and fulfillment of all eligibility criteria. Documentation
      of remission will be by appropriate evaluations including history, physical examination,
      laboratory testing and radiographic imaging and follow criteria for initial staging, when
      appropriate.

      There will be two study blocks. Each block will be of 21 days duration consisting of 14
      treatment days followed by 7 rest days. The following block will start on day 22 of the
      cycle. There will be 10 cycles of therapy (approximately 60 weeks) and each cycle is defined
      by 42 days. Each block will be separated by a 1 week rest period (no chemotherapy) and
      patients will be evaluated for disease status every two cycles of therapy. Therapy will
      continue for 10 cycles or until patients relapse or are intolerant of therapy.

      Block A consists of bevacizumab weekly X 2 weeks at 10 mg/kg, IV, on days 1 and 8, and oral
      cyclophosphamide X 14 days at 25 mg/m2, on days 1-14. The maximum dose of cyclophosphamide
      will be 50 mg. Block B will consist of temsirolimus weekly X 2 weeks, 25 mg/m2, IV, on days
      22 and 29, and valproic acid, 5 mg/kg, by mouth, on days 22-35. Valproic acid trough levels
      will be maintained at 75-100 ucg/mL by adjusting doses as appropriate. The rest periods are
      on days 15-21 and 36-42.

      Blocks of chemotherapy interrupted because of toxicity will not be repeated or time extended
      to complete. The next block will be started when toxicity has improved to grade II or less
      and if two blocks of treatment are interrupted for toxicity, dose reductions instituted as
      defined in this protocol.

      Additionally, subjects enrolled on MC and a control group will complete three quality of life
      (PedsQL) instruments at three study time points: PedsQL Cancer Module, PedsQL Fatigue Module,
      and the Present Functioning scale. These indicators will assess how added therapy has
      impacted quality of life.

      There are no investigational procedures, and no placebo involved in this protocol.

      The potential benefits of this protocol are prolongation of remission status for the patient
      with minimal toxicity, few anticipated hospitalizations and minimal additional cost of care.
      Some patients may be cured as a result of this treatment. Should this study improve outcome
      for this group of patients, the benefits to society would be great. Outcome for high risk
      patients has stagnated for at least the last 10 years and additional high-dose chemotherapy
      is unlikely to improve outcome because of poor tolerability (side effects). Studying some of
      the cost associated with this treatment is important because of the lack of information on
      out-patient care cost in general and to understand the economic impact on families and
      society.
    

Trial Arms

NameTypeDescriptionInterventions
Metronomic TherapyExperimentalThere is only one arm in this study. All subjects receive the same therapy for a period of 420 days (42 day cycles x 10 cycles). Bevacizumab: IV, 10 mg/kg, Days 1, 8 Cyclophosphamide: PO, 25 mg/m2 Days 1-14 (max dose = 50mg/dose) Valproic Acid: PO, 5 mg/kg, three times per day (TID), Days 22-35 Temsirolimus: IV, 25 mg/m2, Days 22, 29
  • Bevacizumab
  • Cyclophosphamide
  • Valproic Acid
  • Temsirolimus

Eligibility Criteria

        Inclusion Criteria:

          1. The following solid tumors will be studied: rhabdomyosarcoma, osteosarcoma, Ewing
             sarcoma, other soft tissue sarcomas

          2. Other solid tumors fulfilling the remainder of eligibility criteria and available
             historical data to determine time to tumor progression

          3. Expected time to progression of < 2 years, based on historical data

          4. All patients will have completed front-line therapy

          5. All patients will be in remission from their primary diagnosis

          6. All patients will start metronomic therapy within 6 weeks of completion of front-line
             treatment

          7. All patient will have recovered from previous toxicities

          8. All patients or their parents/legal guardian will have signed an informed consent
             document

          9. All institutional eligibility criteria will be meet

         10. Age: Patients must be ≥ 12 months and <31 years of age at the time of study entry

         11. Patients must have had histologic verification of malignancy at original diagnosis

         12. Patients must have a Lansky or Karnofsky performance status score of ≥ 50,
             corresponding to ECOG categories 0, 1 or 2.

         13. Adequate renal function defined as: Normal serum creatinine

         14. Normal liver tests (ALT/AST/total bilirubin/triglycerides/cholesterol)

         15. Recovered from all surgical procedures for at least 7 days (minor procedures) or 28
             days (major procedures)

         16. Adequate cardiac function defined as: Shortening fraction of ≥ 27% by echocardiogram,
             or ejection fraction of ≥ 50% by radionuclide angiogram

         17. Platelet count 100,000K/uL (transfusion independent), hemoglobin 8.0 g/dL

         18. Adequate bone marrow function: Peripheral absolute neutrophil count (ANC) 1,000K/uL

         19. Signed Informed Consent document and/or Assent document

        Exclusion Criteria:

          1. Female patients who are pregnant

          2. Lactating females are not eligible unless they have agreed to discontinue
             breastfeeding

          3. Female patients of childbearing potential are not eligible unless a negative pregnancy
             test result has been obtained

          4. Sexually active patients of reproductive potential are not eligible unless they have
             agreed to use an effective contraceptive method for the duration of study
             participation

          5. Any primary central nervous system tumor

          6. Any patient who has experienced relapsed or refractory disease or a second malignancy.

          7. Any patient not in remission
      
Maximum Eligible Age:31 Years
Minimum Eligible Age:12 Months
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:5 year Event Free Survival
Time Frame:Up to five years off therapy
Safety Issue:
Description:Imaging studies, laboratory studies, bone marrow exam

Secondary Outcome Measures

Measure:Site(s) of relapse
Time Frame:Up to five years off therapy
Safety Issue:
Description:Imaging studies, laboratory studies, bone marrow exam
Measure:Composite Cost of Treatment
Time Frame:Up to five years off therapy
Safety Issue:
Description:1) Day Hospital charges/costs, 2) physician fees, 3) laboratory/radiology cost/charges, 4) transfusions cost/charges, 5) drug costs/charges, 6) other supportive care charges/costs and 7) all charges/costs which directly result from consequences of this treatment protocol (i.e. need for hospitalization or Emergency Department visits) for 10 patients
Measure:Fatigue scores on the PedsQL Fatigue Scale
Time Frame:420 days per subject
Safety Issue:
Description:PedsQL Fatigue Scale
Measure:Pain scores on the Present Functioning Scale
Time Frame:420 days per subject
Safety Issue:
Description:Present Functioning Scale
Measure:Quality of Life scores on the PedsQL Quality of Life Scale
Time Frame:420 days per subject
Safety Issue:
Description:PedsQL Quality of Life Scale

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Miller Children's & Women's Hospital Long Beach

Trial Keywords

  • Metronomic Drug Therapy

Last Updated

May 13, 2015