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

NCT02446431 | Recruiting Early Phase 1

• 1 other identifier: 001
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 2

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.

Conditions

Solid Tumor

Keywords

Metronomic Drug Therapy

Outcome Measures

Primary Outcomes (2)

• 5 year Event Free Survival

  Imaging studies, laboratory studies, bone marrow exam

  Up to five years off therapy

• Number of Participants with Adverse Events as a Measure of Safety and Tolerability

  Imaging studies, laboratory studies, bone marrow exam

  Up to five years off therapy

Secondary Outcomes (5)

• Site(s) of relapse

  Up to five years off therapy

• Composite Cost of Treatment

  Up to five years off therapy

• Fatigue scores on the PedsQL Fatigue Scale

  420 days per subject

• Pain scores on the Present Functioning Scale

  420 days per subject

• Quality of Life scores on the PedsQL Quality of Life Scale

  420 days per subject

Study Arms (1)

Metronomic Therapy

EXPERIMENTAL

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; Drug: Cyclophosphamide; Drug: Valproic Acid; Drug: Temsirolimus

Interventions

Bevacizumab DRUG

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.

Also known as: Avastin

Metronomic Therapy

Cyclophosphamide DRUG

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.

Also known as: Cytoxan

Metronomic Therapy

Valproic Acid DRUG

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.

Also known as: Depakote

Metronomic Therapy

Temsirolimus DRUG

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.

Also known as: Torisel

Metronomic Therapy

Eligibility Criteria

• Age: 12 Months - 31 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• The following solid tumors will be studied: rhabdomyosarcoma, osteosarcoma, Ewing sarcoma, other soft tissue sarcomas
• Other solid tumors fulfilling the remainder of eligibility criteria and available historical data to determine time to tumor progression
• Expected time to progression of \< 2 years, based on historical data
• All patients will have completed front-line therapy
• All patients will be in remission from their primary diagnosis
• All patients will start metronomic therapy within 6 weeks of completion of front-line treatment
• All patient will have recovered from previous toxicities
• All patients or their parents/legal guardian will have signed an informed consent document
• All institutional eligibility criteria will be meet
• Age: Patients must be ≥ 12 months and \<31 years of age at the time of study entry
• Patients must have had histologic verification of malignancy at original diagnosis
• Patients must have a Lansky or Karnofsky performance status score of ≥ 50, corresponding to ECOG categories 0, 1 or 2.
• Adequate renal function defined as: Normal serum creatinine
• Normal liver tests (ALT/AST/total bilirubin/triglycerides/cholesterol)
• Recovered from all surgical procedures for at least 7 days (minor procedures) or 28 days (major procedures)

You may not qualify if:

• Female patients who are pregnant
• Lactating females are not eligible unless they have agreed to discontinue breastfeeding
• Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained
• 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
• Any primary central nervous system tumor
• Any patient who has experienced relapsed or refractory disease or a second malignancy.
• Any patient not in remission

Sponsors & Collaborators

• Miller Children's & Women's Hospital Long Beach: lead
• Children's Hospital of Orange County: collaborator

Study Sites (2)

Miller Children's and Women's Hospital Long Beach

Long Beach, California, 90806, United States

RECRUITING

Children's Hospital Orange County

Orange, California, 92868, United States

RECRUITING

MeSH Terms

Interventions

Bevacizumab; Cyclophosphamide; Valproic Acid; temsirolimus

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Fatty Acids, Volatile; Fatty Acids; Lipids

Study Officials

• Ted Zwerdling, MD

  Miller Children's and Women's Hospital Long Beach

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ted Zwerdling, MD

CONTACT

562-933-8600; tzwerdling@memorialcare.org

Devin Murphy, MSW

CONTACT

562-933-8601; dmurphy@memorialcare.org

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 28, 2015
• First Posted: May 18, 2015
• Study Start: July 1, 2014
• Primary Completion: July 1, 2024
• Study Completion (Estimated): July 1, 2029
• Last Updated: May 18, 2015

Record last verified: 2015-05

Locations

US (2)