A Phase I Study of ABT-888, an Oral Inhibitor of Poly(ADP-ribose) Polymerase and Temozolomide in Children With Recurrent/Refractory CNS Tumors

NCT00994071 | Completed Phase 1

• 2 other identifiers: 09024309-C-0243
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

Brief Summary

Background: \- 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. Objectives:

• 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. Eligibility: \- 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. Design:
• 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.

Conditions

Medulloblastoma; Pontine Glioma; Ependymoma; Astrocytoma; PNET

Keywords

Brain Tumor; CNC Tumor; Pediatric; PARP Inhibitor; Oral Chemotherapy

Outcome Measures

Primary Outcomes (2)

• 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 ...

Secondary Outcomes (1)

• To measure non-homologous end-joining (NHEJ) activity in peripheral blood mononuclear cells (PBMC) prior to and following ABT-888 administration.

Interventions

Temozolomide DRUG

ABT-888 DRUG

Eligibility Criteria

• Age: Up to 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Age:
• Patients must be less than or equal to 21 years of age at the time of study enrollment. At the time the MTD or the dose to be recommended for future trials is identified, up to 12 additional patients will be enrolled at that dose level to further define the toxicity profile. Six of these patients will be less than 12 years of age and the other half will be greater than or equal to 12 years.
• Tumor:
• 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. All patients must have had histological verification of malignancy at initial diagnosis or relapse, excluding patients with diffuse intrinsic brain stem tumors, optic pathway tumors or CNS germ cell tumors with elevations of reliable serum or CSF tumor markers (alpha-fetoprotein or beta-HCG). Patients with intrinsic pontine gliomas or optic pathway tumors do not require histological confirmation of disease but should have clinical and/or radiographic evidence of progression.
• Performance Status:
• Patients must have Karnofsky Performance Score (for patients greater than 16 years of age) or Lansky Performance Score (for patients less than or equal to 16 years of age) greater than or equal to 50% assessed within two weeks of study enrollment.
• Neurological Status:
• Patients must be able to take oral medications (either capsules or liquid). Patients with neurologic deficits must have been stable for a minimum of 1 week prior to study entry. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• Prior/Concurrent Therapy:
• Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study. Recovery is defined as all AE s, attributable to prior therapy, having improved to grade 2 or better or as outlined below.
• Myelosuppressive chemotherapy:
• Patients must have received their last dose of known myelosuppressive anticancer chemotherapy at least three (3) weeks prior to study registration.
• Patients must have received their last dose of nitrosourea (including Gliadel) at least six (6) weeks prior to study registration.
• Biologic agent (anti-neoplastic): Patient must have received their last dose of other biologic agent greater than or equal to 7 days prior to study registration.
• For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair.

You may not qualify if:

• Organ Function: Documented within 14 days of registration and within 7 days of starting treatment.
• Bone Marrow:
• Hgb greater than 8 gm/dL (transfusion independent)
• Platelet count greater than 100,000/mm(3) (transfusion independent)
• Absolute neutrophil count (ANC) greater than 1,500/mm(3)
• Hepatic:
• Total Bilirubin (sum of conjugated + unconjugated) less than or equal to 1.5 times institutional upper limit of normal (ULN) for age
• SGPT (ALT) less than or equal to 2.5 times institutional ULN for age
• Serum albumin greater than or equal to 2 g/dL
• Renal:
• Creatinine clearance or radioisotope GFR greater than or equal to 70 ml/min/1.73m(2) or a serum creatinine based on age as follows:
• Age less than 5 (years): a Maximum Serum Creatinine (mg/dL) of 0.8
• Age greater than 5 (years) but less than 10: a Maximum Serum Creatinine (mg/dL) of 1
• Age greater than 10 (years) but less than 15: a Maximum Serum Creatinine (mg/dL) of 1.2
• Age greater than 15 (years): a Maximum Serum Creatinine (mg/dL) of 1.5

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Newlands ES, Stevens MF, Wedge SR, Wheelhouse RT, Brock C. Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials. Cancer Treat Rev. 1997 Jan;23(1):35-61. doi: 10.1016/s0305-7372(97)90019-0. No abstract available.

  PMID: 9189180 BACKGROUND

• Sankar A, Thomas DG, Darling JL. Sensitivity of short-term cultures derived from human malignant glioma to the anti-cancer drug temozolomide. Anticancer Drugs. 1999 Feb;10(2):179-85. doi: 10.1097/00001813-199902000-00006.

  PMID: 10211548 BACKGROUND

• Patel M, McCully C, Godwin K, Balis FM. Plasma and cerebrospinal fluid pharmacokinetics of intravenous temozolomide in non-human primates. J Neurooncol. 2003 Feb;61(3):203-7. doi: 10.1023/a:1022592913323.

  PMID: 12675312 BACKGROUND

MeSH Terms

Conditions

Medulloblastoma; Ependymoma; Astrocytoma; Neuroectodermal Tumors, Primitive; Brain Neoplasms

Interventions

Temozolomide; veliparib

Condition Hierarchy (Ancestors)

Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Katherine E Warren, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH

Study Record Dates

• First Submitted: October 10, 2009
• First Posted: October 14, 2009
• Study Start: September 22, 2009
• Study Completion: March 19, 2013
• Last Updated: December 9, 2019

Record last verified: 2014-07-16

Locations

US (1)