A Phase I Study of ABT-888, an Oral Inhibitor of Poly(ADP-ribose) Polymerase and Temozolomide in Children With Recurrent/Refractory CNS Tumors
- An experimental drug called ABT-888 has been studied in combination with temozolomide (a type of chemotherapy) in adults who have certain kinds of cancer. ABT-88 has been shown to increase tumor sensitivity to temozolomide and improve treatment outcomes in people who have cancer. More research is needed to determine if this combination of drugs will work well as an effective treatment for children who have brain tumors. This will be the first time this combination has been studied in pediatric patients.
- To determine the maximum doses of ABT-888 and temozolomide when given in combination in children with brain tumors.
- To learn how children metabolize and clear ABT-888 from their bodies so that appropriate doses of this medication can be recommended for future clinical trials of this drug.
- To learn what side effects may occur when ABT-888 and temozolomide are given together.
- To learn how certain tumors respond to this combination of drugs by studying the characteristics of these tumors in a laboratory.
- Individuals less than 21 years of age who have been diagnosed with a cancer of the nervous system (including brain and brain stem tumors) that has not responded to standard therapy.
- Before beginning the study, participants will have a full medical history and physical examination, and may also be required to have scans of the brain and spine or provide samples of cerebrospinal fluid.
- Treatment will consist of up to 13 28-day cycles of therapy, for a total of 52 weeks (1 year). Participants will receive a dose of ABT-888 twice daily for 5 days, and will receive a dose of temozolomide once daily for 5 days, every 28 days. The morning dose of ABT-888 will be given 60-90 minutes before the dose of temozolomide.
- Participants will have routine blood tests at least once a week throughout the treatment cycles, and will have scans of the brain and spine performed as required by the researchers.
|Study Design:||Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Primary Purpose: Treatment
|Official Title:||A Phase I Study of ABT-888, an Oral Inhibitor of Poly(ADP-Ribose) Polymerase and Temozolomide in Children With Recurrent/Refractory CNS Tumors|
- To estimate the maximum tolerated dose (MTD) of ABT-888 in combination with Temozolomide in children with recurrent or refractory CNS tumors
- -To study the plasma pharmacokinetics (PK) of ABT-888 and PARPinhibition in peripheral blood mononuclear cells (PBMC) in order torecommend a Phase 2 dose of ABT-888 in combination with temozolomide in children with recurrent or refractory ...
- To measure non-homologous end-joining (NHEJ) activity in peripheral blood mononuclear cells (PBMC) prior to and following ABT-888 administration.
|Study Start Date:||September 22, 2009|
|Study Completion Date:||March 19, 2013|
- A subset of patients with pediatric CNS tumors continue to have a poor prognosis despite advances in surgery and radiation. Novel strategies are required for improving outcome for these patients.
- Temozolomide, an oral alkylating agent, has shown modest activity in recurrent pediatric CNS tumors, including high-grade gliomas, medulloblastoma/PNET, and low-grade gliomas.
- Temozolomide induces single-stranded DNA breaks, the majority of which are repaired by the base excision repair (BER) pathway. Poly(ADP-ribose) polymerase, or PARP, is a critical nuclear enzyme that binds to DNA breaks, recruits and activates key proteins in the BER and other DNA repair pathways, halts DNA replication, and facilitates repair of damaged DNA.
- ABT-888 is a potent and orally bioavailable PARP inhibitor that has been shown to enhance cytotoxicity of temozolomide and other chemotherapy agents in several pre-clinical models of human tumors.
- To estimate the maximum tolerated dose (MTD) of ABT-888 in combination with temozolomide in children with recurrent or refractory CNS tumors.
- To study the plasma pharmacokinetics (PK) of ABT-888 and PARP inhibition in peripheral blood mononuclear cells (PBMC) in order to recommend a Phase 2 dose of ABT-888 in combination with temozolomide in children with recurrent or refractory CNS tumors.
- To describe the toxicities of the combination of ABT-888 and temozolomide in children with recurrent or refractory CNS tumors.
- Patient must be less than or equal to 21 years of age at registration.
- Patients with a diagnosis of a primary CNS malignancy (including low-grade glioma) that is recurrent or refractory to standard therapy and for which there is no known curative therapy Progression and recurrence will be documented by review of MRI scans. If time permits we will have the diagnosis confirmed by the NCI Laboratory of Pathology. Patients with intrinsic brain stem tumors must have radiographic evidence of progression.
- Karnofsky Performance Scale (KPS for greater than 16 yrs of age) or Lansky Performance Score (LPS for less than or equal to 16 years of age) greater than or equal to 50 assessed within two weeks of study enrollment.
- Patients must have recovered from the toxic effects of all prior therapy.
- Patients who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to registration.
-ABT-888 will be given twice daily on day 1-5, and temozolomide will be given once daily on day 1-5, every 28 days. The morning dose of ABT-888 will be given 60-90 minutes prior to temozolomide.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00994071
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Katherine E Warren, M.D.||National Cancer Institute (NCI)|