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

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

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.

Study Overview

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

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 Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294-3410
      • UAB Comprehensive Cancer Center
  • California
    • San Francisco, California, United States, 94115
      • UCSF Helen Diller Family Comprehensive Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute of Emory University
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Josephine Ford Cancer Center at Henry Ford Hospital
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157-1096
      • Wake Forest University Comprehensive Cancer Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Taussig Cancer Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104-4283
      • Abramson Cancer Center of the University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • UPMC Cancer Centers
  • Wisconsin
    • Madison, Wisconsin, United States, 53792-6164
      • University of Wisconsin Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Dose Escalation

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum tolerated dose of ABT-888 (Phase I)	continous
Overall survival (Phase II)	continous

Secondary Outcome Measures

Outcome Measure	Time Frame
Toxicity (Phase I)	continous
Pharmacokinetics of ABT-888 (Phase I)	continous
Frequency of toxicity (Phase II)	continous

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Larry Kleinberg, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study record dates

Study Major Dates

• Study Start (Actual): July 13, 2009
• Primary Completion (Actual): March 1, 2012
• Study Completion (Actual): March 1, 2012

Study Registration Dates

• First Submitted: October 9, 2008
• First Submitted That Met QC Criteria: October 9, 2008
• First Posted (Estimate): October 10, 2008

Study Record Updates

• Last Update Posted (Actual): June 27, 2018
• Last Update Submitted That Met QC Criteria: June 25, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: adult glioblastoma; adult giant cell glioblastoma; adult gliosarcoma
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Nervous System Neoplasms; Central Nervous System Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Poly(ADP-ribose) Polymerase Inhibitors; Temozolomide; Veliparib
• Other Study ID Numbers: NABTT-0801 CDR0000616542; U01CA062475 (U.S. NIH Grant/Contract); ABTC-0801; NABTT-0801; ABBOTT-M10-190

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No