Recruiting
Early Phase 1

Metronomic Therapy

Sponsor:

Miller Children's & Women's Hospital Long Beach

Code:

NCT02446431

Conditions

Solid Tumor

Eligibility Criteria

Sex: All

Age: 1 - 31

Healthy Volunteers: Not accepted

Interventions

Bevacizumab

Cyclophosphamide

Valproic Acid

Temsirolimus

Study Details

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

Study ID

NCT02446431

Start date

Jul, 2014

Status verified date

May, 2015

Completion date

Jul, 2029

Anticipated

Primary completion date

Jul, 2024

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 1 - 31

Healthy Volunteers: Not accepted

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

Study Design

Enrollment

20 participants

Anticipated

Intervention Model

Single group

Primary purpose

Prevention

Interventions and Outcome Measures

Arms

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

Interventions

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.

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.

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.

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.

Primary outcome measure

  • 5 year Event Free Survival [ Time Frame: Up to five years off therapy ]
  • Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: Up to five years off therapy ]

Central Contacts and Locations

Central contacts

Ted Zwerdling, MD

562-933-8600tzwerdling@memorialcare.org

Devin Murphy, MSW

562-933-8601dmurphy@memorialcare.org

Locations

Miller Children's and Women's Hospital Long Beach

Recruiting

Long Beach, California, United States, 90806

Contacts

Ted Zwerdling, MD

562-933-8600tzwerdling@memorialcare.org

Devin Murphy, MSW

562-933-8601dmurphy@memorialcare.org

Children's Hospital Orange County

Recruiting

Orange, California, United States, 92868

Contacts

Elyssa Rubin, MD

714-509-4348erubin@choc.org

Dorian Chan, RN,BSN,CCRC

714-509-7868dchan@CHOC.ORG

Principal Investigator:

Elyssa Rubin, MD

More Information

Sponsor

Miller Children's & Women's Hospital Long Beach

Last update posted

May 18, 2015

Last verified

May, 2015

Keywords

  • Metronomic Drug Therapy

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-09. This information was provided to ClinicalTrials.gov by Miller Children's & Women's Hospital Long Beach on 2015-05-18.