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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02446431
Recruitment Status : Recruiting
First Posted : May 18, 2015
Last Update Posted : May 18, 2015
Children's Hospital of Orange County
Information provided by (Responsible Party):
Miller Children's & Women's Hospital Long Beach

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Solid Tumor Drug: Bevacizumab Drug: Cyclophosphamide Drug: Valproic Acid Drug: Temsirolimus Early Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Metronomic Therapy for Pediatric Patients With Solid Tumors at High Risk of Recurrence: A Multi-Institutional Study
Study Start Date : July 2014
Estimated Primary Completion Date : July 2024
Estimated Study Completion Date : July 2029

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Metronomic Therapy

There 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).

  1. Bevacizumab: IV, 10 mg/kg, Days 1, 8
  2. Cyclophosphamide: PO, 25 mg/m2 Days 1-14 (max dose = 50mg/dose)
  3. Valproic Acid: PO, 5 mg/kg, three times per day (TID), Days 22-35
  4. Temsirolimus: IV, 25 mg/m2, Days 22, 29
Drug: Bevacizumab
Avastin is an anti-angiogenic therapy that disrupts a tumor's ability to grow by blocking the vascular endothelial growth factor protein, or VEGF. In tumors, cells produce excess VEGF therefore avastin's ability to block VEGF may prevent the growth of new blood vessels, including normal blood vessels and blood vessels that feed tumors. Avastin is not a chemotherapy; the purpose of Avastin is to block the blood supply that feeds the tumor. In this study Avastin is given IV at 10 mg/kg twice monthly for 10 cycles. This totals 20 administrations over a 1.12 year period.
Other Name: Avastin

Drug: Cyclophosphamide
Cyclophosphamide is an alkylating agent related to nitrogen mustard and is inactive until it is metabolized by P450 isoenzymes (CYP2B6, CYP2C9, and CYP3A4) in the liver to active compounds. The initial product is 4-hydroxycyclophosphamide (4-HC) which is in equilibrium with aldophosphamide which spontaneously releases acrolein to produce phosphoramide mustard. Phosphoramide mustard has been shown to produce interstrand DNA cross-link analogous to those produced by mechlorethamine. The plasma half-life ranges from 4.1 to 16 hours after IV administration. Cytoxan is taken orally as a 25 mg/m2 tablet daily for 14 days for 10 cycles (max dose =50mg). This totals 140 days over a 1.12 year period.
Other Name: Cytoxan

Drug: Valproic Acid
Valproic acid is a short chain fatty acid (VPA, 2-propylpetanoic acid) and approved for the treatment of epilepsy, bipolar disorders, migraines, and clinically used for schizophrenia. Currently, VPA is examined in numerous clinical trials for different leukemias and solid tumor entities. In addition to clinical assessment, the experimental examination of VPA as anti-cancer drug is ongoing. Although other mechanisms may also contribute to VPA-induced anti-cancer effects, inhibition of histone deacetylases appears to play a central role. Valproic acid is either given in suspension or tablet form 5 mg/kg, TID for 13 days for 10 cycles. This totals 130 days in a 1.12 year period.
Other Name: Depakote

Drug: Temsirolimus
Temsirolimus [an ester of the immunosuppressive compound sirolimus, (rapamycin, Rapamune®)] blocks cell cycle progression from the G1 to the S phase by binding to the intracellular cytoplasmic protein, FK506 binding protein (FKBP)12. This complex inhibits activity of the enzyme mTOR (mammalian target of rapamycin), inhibiting translation of several key proteins that regulate progression through the G1 phase in response to growth factors. Sirolimus, the major metabolite of temsirolimus, also binds to FKBP12. Given twice monthly at 25 mg/m2 via IV administration for 10 cycles totalling 20 administrations for 1.12 years.
Other Name: Torisel

Primary Outcome Measures :
  1. 5 year Event Free Survival [ Time Frame: Up to five years off therapy ]
    Imaging studies, laboratory studies, bone marrow exam

  2. Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: Up to five years off therapy ]
    Imaging studies, laboratory studies, bone marrow exam

Secondary Outcome Measures :
  1. Site(s) of relapse [ Time Frame: Up to five years off therapy ]
    Imaging studies, laboratory studies, bone marrow exam

  2. Composite Cost of Treatment [ Time Frame: Up to five years off therapy ]
    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

  3. Fatigue scores on the PedsQL Fatigue Scale [ Time Frame: 420 days per subject ]
    PedsQL Fatigue Scale

  4. Pain scores on the Present Functioning Scale [ Time Frame: 420 days per subject ]
    Present Functioning Scale

  5. Quality of Life scores on the PedsQL Quality of Life Scale [ Time Frame: 420 days per subject ]
    PedsQL Quality of Life Scale

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   12 Months to 31 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

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 identifier (NCT number): NCT02446431

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Contact: Ted Zwerdling, MD 562-933-8600
Contact: Devin Murphy, MSW 562-933-8601

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United States, California
Miller Children's and Women's Hospital Long Beach Recruiting
Long Beach, California, United States, 90806
Contact: Ted Zwerdling, MD    562-933-8600   
Contact: Devin Murphy, MSW    562-933-8601   
Children's Hospital Orange County Recruiting
Orange, California, United States, 92868
Contact: Elyssa Rubin, MD    714-509-4348   
Contact: Dorian Chan, RN,BSN,CCRC    714-509-7868    dchan@CHOC.ORG   
Principal Investigator: Elyssa Rubin, MD         
Sponsors and Collaborators
Miller Children's & Women's Hospital Long Beach
Children's Hospital of Orange County
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Principal Investigator: Ted Zwerdling, MD Miller Children's and Women's Hospital Long Beach
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Responsible Party: Miller Children's & Women's Hospital Long Beach Identifier: NCT02446431    
Other Study ID Numbers: 001
First Posted: May 18, 2015    Key Record Dates
Last Update Posted: May 18, 2015
Last Verified: May 2015
Keywords provided by Miller Children's & Women's Hospital Long Beach:
Metronomic Drug Therapy
Additional relevant MeSH terms:
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Disease Attributes
Pathologic Processes
Valproic Acid
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, Immunological
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Enzyme Inhibitors
GABA Agents
Neurotransmitter Agents
Antimanic Agents