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

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.

Description

Eligibility

Age range

1–31 years

Sex

All

Healthy volunteers

No

Interventions

• 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.

• 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.

• 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.

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