ABT-888, Radiation Therapy, and Temozolomide in Treating Patients With Newly Diagnosed Glioblastoma Multiforme

Sponsor

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Other)

Overall Status

Completed

CT.gov ID

NCT00770471

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Locations

Arm

31.6

Actual Duration (Months)

2.2

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: ABT-888 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving ABT-888 together with radiation therapy and temozolomide may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of ABT-888 when given together with radiation therapy and temozolomide and to see how well it works in treating patients with newly diagnosed glioblastoma multiforme.

Condition or Disease	Intervention/Treatment	Phase
Brain and Central Nervous System Tumors	Drug: temozolomide Drug: veliparib Genetic: DNA methylation analysis Genetic: gene expression analysis Genetic: mutation analysis Genetic: proteomic profiling Other: high performance liquid chromatography Other: immunoenzyme technique Other: laboratory biomarker analysis Other: mass spectrometry Other: pharmacogenomic studies Other: pharmacological study Procedure: adjuvant therapy Radiation: radiation therapy	Phase 1

Detailed Description

OBJECTIVES:

Primary

To determine the maximum tolerated dose (MTD) of ABT-888 when administered in combination with radiotherapy and temozolomide in patients with newly diagnosed glioblastoma multiforme. (Phase I)
To estimate the overall survival of patients treated with ABT-888 when administered at the MTD in combination with radiotherapy and temozolomide. (Phase II)

Secondary

To assess the toxicity associated with this regimen. (Phase I)
To assess and describe the pharmacokinetics of ABT-888. (Phase I)
To estimate the frequency of toxicity associated with this regimen. (Phase II)

OUTLINE: This is a multicenter, phase I dose-escalation study of ABT-888 followed by a phase II study.

Initiation therapy: Patients receive oral ABT-888 twice daily (once on day 1 only) and oral temozolomide once daily (beginning on day 2) in weeks 1-6. Patients enrolled in the phase I dose-escalation/phase II portion of the study also undergo concurrent radiotherapy once daily 5 days a week (beginning on day 2) in weeks 1-6. Treatment continues in the absence of disease progression or unacceptable toxicity.
Maintenance therapy: Beginning 4 weeks after completion of initiation therapy, patients receive oral ABT-888 twice daily on days 1-7 and oral temozolomide once daily on days 1-5. Treatment repeats every 28 days for up to 4 courses (6 courses for patients enrolled in the phase I dose-escalation/phase II portion of the study) in the absence of disease progression or unacceptable toxicity.

Blood samples are collected periodically for pharmacokinetic, pharmacogenetic, and pharmacodynamic analysis. Samples are analyzed for concentration of ABT-888 in plasma by reversed-phase isocratic high performance liquid chromatography with electrospray ionization mass spectrometry; identification of novel markers of treatment response by plasma proteomic evaluation; DNA methylation and/or mutation; and PARP inhibition by ELISA.

After completion of study therapy, patients are followed every 2 months.

Study Design

Study Type:

Interventional

Actual Enrollment :

24 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I/II Trial of Temozolomide and ABT-888 in Subjects With Newly Diagnosed Glioblastoma Multiforme

Actual Study Start Date :

Jul 13, 2009

Actual Primary Completion Date :

Mar 1, 2012

Actual Study Completion Date :

Mar 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dose Escalation	Drug: temozolomide Drug: veliparib Genetic: DNA methylation analysis Genetic: gene expression analysis Genetic: mutation analysis Genetic: proteomic profiling Other: high performance liquid chromatography Other: immunoenzyme technique Other: laboratory biomarker analysis Other: mass spectrometry Other: pharmacogenomic studies Other: pharmacological study Procedure: adjuvant therapy Radiation: radiation therapy

Arm

Intervention/Treatment

Experimental: Dose Escalation

Drug: temozolomide

Drug: veliparib

Genetic: DNA methylation analysis

Genetic: gene expression analysis

Genetic: mutation analysis

Genetic: proteomic profiling

Other: high performance liquid chromatography

Other: immunoenzyme technique

Other: laboratory biomarker analysis

Other: mass spectrometry

Other: pharmacogenomic studies

Other: pharmacological study

Procedure: adjuvant therapy

Radiation: radiation therapy

Outcome Measures

Primary Outcome Measures

Maximum tolerated dose of ABT-888 (Phase I) [continous]
Overall survival (Phase II) [continous]

Secondary Outcome Measures

Toxicity (Phase I) [continous]
Pharmacokinetics of ABT-888 (Phase I) [continous]
Frequency of toxicity (Phase II) [continous]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 120 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Histologically confirmed supratentorial grade IV astrocytoma (glioblastoma multiforme)
Newly diagnosed disease
Patients enrolled in the phase I initial safety portion of the study must meet the following additional criteria:
Received 90% of planned radiotherapy and ≥ 80% of planned concurrent temozolomide within the past 28-49 days
No grade 3-4 toxicity attributed to temozolomide
Has undergone gadolinium MRI or contrast CT scan within the past 28 days
Patients enrolled in the phase I dose-escalation/phase II portion of the study must meet the following additional criteria:
Recovered from immediate post-operative period and maintained on a stable corticosteroid regimen (no increase in 5 days) prior to starting study treatment
Has undergone gadolinium MRI or contrast CT scan within the past 14 days

PATIENT CHARACTERISTICS:

Karnofsky performance status 60-100%
Life expectancy ≥ 3 months
ANC ≥ 1,500/mm^3
Platelet count ≥ 100,000/mm^3
Hemoglobin ≥ 9.0 g/dL
Creatinine ≤ 2.0 mg/dL OR creatinine clearance ≥ 60 mL/min
Total bilirubin ≤ 1.5 mg/dL
Transaminases ≤ 2.5 times upper limit of normal
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception prior to, during, and for 3 months after completion of study therapy
Mini Mental State Exam score ≥ 15
Able to swallow and retain oral medications
No concurrent serious infection or medical illness that would jeopardize the ability of the patient to receive study treatment with reasonable safety
No other malignancy within the past 5 years except for curatively treated carcinoma in situ or basal cell carcinoma of the skin
No known uncontrolled seizure disorder (i.e., status epilepticus) or seizures occurring ≥ 3 times per week over the past month

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
More than 10 days since prior cytochrome P450-inducing anticonvulsants (e.g., phenytoin, carbamazepine, phenobarbital, primidone, or oxcarbazepine)
At least 1 week since prior biopsy or resection of tumor (for patients enrolled in the phase I dose-escalation/phase II portion of the study)
No prior radiotherapy, chemotherapy, immunotherapy, hormonal therapy, or biological therapy (including immunotoxins, immunoconjugates, antisense therapy, peptide receptor antagonists, interferons, interleukins, tumor-infiltrating lymphocytes, lymphokine-activated killer cells, or gene therapy) for treatment of brain tumor (for patients enrolled in the phase I dose-escalation/phase II portion of the study)
Prior glucocorticoid therapy allowed
No other prior chemotherapy or investigational agents (for patients enrolled in the phase I initial safety portion of the study)
Prior Gliadel wafers allowed (for patients enrolled in the phase I portion of the study)
No prior Gliadel wafers (for patients enrolled in the phase II portion of the study)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UAB Comprehensive Cancer Center	Birmingham	Alabama	United States	35294-3410
2	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California	United States	94115
3	Winship Cancer Institute of Emory University	Atlanta	Georgia	United States	30322
4	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland	United States	21231
5	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
6	Josephine Ford Cancer Center at Henry Ford Hospital	Detroit	Michigan	United States	48202
7	Wake Forest University Comprehensive Cancer Center	Winston-Salem	North Carolina	United States	27157-1096
8	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio	United States	44195
9	Abramson Cancer Center of the University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104-4283
10	UPMC Cancer Centers	Pittsburgh	Pennsylvania	United States	15232
11	University of Wisconsin Comprehensive Cancer Center	Madison	Wisconsin	United States	53792-6164