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Temozolomide With or Without Veliparib in Treating Patients With Newly Diagnosed Glioblastoma Multiforme

A Phase II/III Randomized Trial of Veliparib or Placebo in Combination With Adjuvant Temozolomide in Newly Diagnosed Glioblastoma With MGMT Promoter Hypermethylation

Status
Active, not recruiting
Phases
Phase 2Phase 3
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT02152982
Enrollment
447
Registered
2014-06-02
Start date
2014-12-15
Completion date
2026-12-26
Last updated
2026-07-31

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Glioblastoma, Gliosarcoma

Brief summary

This randomized phase II/III trial studies how well temozolomide and veliparib work compared to temozolomide alone in treating patients with newly diagnosed glioblastoma multiforme. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether temozolomide is more effective with or without veliparib in treating glioblastoma multiforme.

Detailed description

PRIMARY OBJECTIVE: I. Test whether the experimental combination of ABT-888 (veliparib) combined with TMZ (temozolomide), compared to the control of placebo combined with TMZ, significantly extends overall survival in newly diagnosed glioblastoma multiforme (GBM) patients with tumor MGMT promoter hypermethylation. SECONDARY OBJECTIVES: I. Test whether the experimental treatment significantly extends progression-free survival. II. Test whether the experimental treatment improves objective tumor response. III. Test whether the experimental treatment is associated with significantly greater rates of grade 3 or higher adverse events. CORRELATIVE SCIENCE OBJECTIVES: I. Evaluate the utility of dynamic susceptibility contrast (DSC) and diffusion weighted imaging (DWI) magnetic resonance imaging (MRI) techniques in defining time to progression in the setting of a large multi-institutional clinical trial. II. Test the concordance between site-determined MGMT methylation status and central laboratory determination of MGMT status in cases with local testing. III. Evaluate whether genetic or epigenetic alterations in deoxyribonucleic acid (DNA) repair or replication genes are associated with overall survival, progression-free survival, and objective tumor response. IV. Test whether polymorphisms in MGMT, PARP1, or other DNA repair proteins, are associated with overall survival, progression-free survival, objective tumor response, or rates of grade 3 or higher adverse events. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive temozolomide orally (PO) once daily (QD) on days 1-5 and placebo PO twice daily (BID) on days 1-7. Treatment repeats every 28 days for 6 cycles in the absence of disease progression (confirmed progression) or unacceptable toxicity. ARM II: Patients receive temozolomide as in Arm I and veliparib PO BID on days 1-7. Treatment repeats every 28 days for 6 cycles in the absence of disease progression (confirmed progression) or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 3 years, every 6 months for 2 years.

Interventions

OTHERLaboratory Biomarker Analysis

Correlative studies

OTHERPlacebo Administration

Given PO

OTHERQuality-of-Life Assessment

Ancillary studies

DRUGTemozolomide

Given PO

DRUGVeliparib

Given PO

Sponsors

National Cancer Institute (NCI)
Lead SponsorNIH

Study design

Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No

Inclusion criteria

* Histologic documentation: newly diagnosed World Health Organization (WHO) grade IV intracranial glioblastoma or gliosarcoma; GBM with oligodendroglial features are NOT PERMITTED in this study if they are 1p19q codeleted; sites submitting GBM with oligodendroglial features will be asked to provide results of 1p/19q codeletion status * Sufficient tissue available for central pathology review and MGMT methylation status evaluation * Patients who have had a local MGMT testing that is unmethylated are not allowed to participate * Tumor MGMT promoter hypermethylation determined by central testing at MD Anderson * Confirmation by central pathology review of WHO grade IV glioblastoma or gliosarcoma * Absolute neutrophil count (ANC) \>= 1500 cells/mm\^3 (within 14 days prior to study registration) * Platelets \>= 100,000 cells/mm\^3 (within 14 days prior to study registration) * Creatinine =\< 1.5 x upper limit of normal (ULN) (within 14 days prior to study registration) * Bilirubin =\< 1.5 x ULN (within 14 days prior to study registration; unless patient has Gilbert's disease) * Alanine aminotransferase (ALT) =\< 3 x ULN (within 14 days prior to study registration) * Aspartate aminotransferase (AST) =\< 3 x ULN (within 14 days prior to study registration) * Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 * Measurable disease or non-measurable disease; extent of resection: patients with complete resection, partial resection, or biopsy are eligible * Progression: patients deemed to have progressive disease based on clinical deterioration after chemoradiation or radiographic progression outside of the radiation field are not eligible; patients deemed to have pseudoprogression are eligible * Prior treatment: * Must have completed standard radiotherapy and concomitant TMZ therapy as defined and determined by the study oncologist * Besides concomitant TMZ with radiation, no other therapy (neo-adjuvant or adjuvant) can be given prior to study registration, including chemotherapy (also including Gliadel/carmustine \[BCNU\] wafers), biologics, immunotherapy, radiation therapy; the only exception is the Optune device (NovoTTF-100A), which may be started any time after end of radiation therapy up through the initiation of Cycle 1; intent to use Optune must be declared at registration for stratification * No prior allogeneic bone marrow transplant or double umbilical cord blood transplantation * Not pregnant and not nursing; females of childbearing potential must have negative urine or serum pregnancy test within 7 days of registration but before start of treatment; a female of childbearing potential is a sexually mature female who: * Has not undergone a hysterectomy or bilateral oophorectomy; or * Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months) * Concomitant medications: patients receiving anticoagulation should be on stable dose 2 weeks prior to registration * Comorbid conditions: patients are unable to participate due to the following: * Generalized or partial seizure disorder that is uncontrolled at the time of registration; the definition of controlled generalized seizures is patients must be on a stable dose of anti-seizure medication and without generalized seizures for at least 10 days prior to registration; the definition of controlled partial seizures is patients must be on a stable dose of anti-seizure medication for at least 10 days prior to registration; patients with occasional breakthrough partial seizures are allowed at treating physician's discretion * Grade 3 or 4 thromboembolic disease within 6 months (mo) of registration * Known history of prolonged QT syndrome * No history of major surgery =\< 14 days prior to registration * Patients must have adequate organ and marrow function measured within 28 days prior to administration of ABT-888 as defined below: * \>= 10.0 g/dL hemoglobin (Hb) with no blood transfusion in the past 28 days * No Patients with treatment-related acute myeloid leukemia (AML) (t-AML)/myelodysplastic syndrome (MDS) or with features suggestive of AML/MDS

Design outcomes

Primary

MeasureTime frameDescription
Overall Survival (OS)83 monthsThe distribution of OS for each arm will be estimated using the Kaplan-Meier method and compared with a stratified logrank test.

Secondary

MeasureTime frameDescription
Interaction With Optune Device10 yearsCox proportional hazards model will be used to evaluate whether there is a potential interaction between the treatment arm and the Optune device. If an interaction is detected, separate analyses of treatment effect (using Cox models) will be done for patients treated with the Optune device and patients who were not treated with the Optune device.
Progression-free Survival (PFS)120 monthsThe distribution of PFS for each arm will be estimated using the Kaplan-Meier method, and be compared using Cox proportional hazard models with all stratification factors adjusted. Progression (PD): Defined by any of the following: 1. \> 25% increase in sum of products of perpendicular diameters of enhancing lesions, compared with the smallest tumor measurement obtained either at baseline or best response 2. Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing doses of corticosteroids compared with baseline scan or best response after therapy initiation (stable doses of steroids include patient not on steroids) not caused by comorbid events 3. Any new lesion 4. Clear clinical deterioration not attributable to other causes apart from tumor or change in corticosteroid dose 5. Failure to return for evaluation as a result of death or deteriorating condition 6. Clear progression of non-measurable disease
Objective Tumor Response5 yearsDefined as complete response (CR) or partial response (PR) as specified in the Revised Assessment in Neuro-Oncology (RANO) criteria. An objective tumor response will be evaluated for each patient and the tumor response count will be summarized for each arm and compared using the Chi-square test. For CR, all of the following must be true: disappearance of all enhancing measurable and non-measurable disease; no new enhancing lesions; stable or improved non-enhancing lesions; patients must be off corticosteroids; stable or improved clinically A PR requires all of the following: \> 50% decrease in sum of products of perpendicular diameters of all measurable enhancing lesions compared with baseline; no progression of non-measurable disease; no new lesions; stable or improved non-enhancing lesions on same or lower dose of corticosteroids compared with baseline scan; steroid dose should be same or lower compared with baseline scan; stable or improved clinically
Overall Adverse Event Rates for Grade 3 or Higher Adverse Events5 yearsAssessed using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (version 5 beginning April 1, 2018). The overall adverse event rates for grade 3 or higher adverse events will be summarized and be compared using Chi-Square or Fisher's Exact tests between treatment arms. The maximum grade for each type of treatment-related adverse event will be recorded for each patient, and frequency tables for each arm will be reviewed to determine patterns. Treatment-related adverse events will be tabulated for each arm.

Countries

Puerto Rico, United States

Contacts

PRINCIPAL_INVESTIGATORJann N Sarkaria

Alliance for Clinical Trials in Oncology

Participant flow

Participants by arm

ArmCount
Arm I (Temozolomide, Placebo)
Patients receive temozolomide as in Arm II and placebo PO BID on days 1-7. Treatment repeats every 28 days for 6 cycles in the absence of disease progression (confirmed progression) or unacceptable toxicity. \> \> Laboratory Biomarker Analysis: Correlative studies \>\> Placebo Administration: Given PO \>\> Quality-of-Life Assessment: Ancillary studies \>\> Temozolomide: Given PO
224
Arm II (Temozolomide, Veliparib)
Patients receive temozolomide PO QD on days 1-5 and veliparib PO BID on days 1-7. Treatment repeats every 28 days for 6 cycles in the absence of disease progression (confirmed progression) or unacceptable toxicity. \> \> Laboratory Biomarker Analysis: Correlative studies \>\> Quality-of-Life Assessment: Ancillary studies \>\> Temozolomide: Given PO \>\> Veliparib: Given PO
223
Total447

Baseline characteristics

CharacteristicArm II (Temozolomide, Veliparib)TotalArm I (Temozolomide, Placebo)
Age, Continuous58.8 years
STANDARD_DEVIATION 11.55
58.5 years
STANDARD_DEVIATION 11.97
58.3 years
STANDARD_DEVIATION 12.4
ECOG Performance Status
0-1
205 Participants410 Participants205 Participants
ECOG Performance Status
2
18 Participants37 Participants19 Participants
Ethnicity (NIH/OMB)
Hispanic or Latino
7 Participants16 Participants9 Participants
Ethnicity (NIH/OMB)
Not Hispanic or Latino
212 Participants420 Participants208 Participants
Ethnicity (NIH/OMB)
Unknown or Not Reported
4 Participants11 Participants7 Participants
Extent of Resection
Gross total resection
140 Participants280 Participants140 Participants
Extent of Resection
Subtotal resection or biopsy
83 Participants167 Participants84 Participants
Planned concomitant use of Optune device
No
194 Participants385 Participants191 Participants
Planned concomitant use of Optune device
Yes
29 Participants62 Participants33 Participants
Race (NIH/OMB)
American Indian or Alaska Native
0 Participants1 Participants1 Participants
Race (NIH/OMB)
Asian
4 Participants8 Participants4 Participants
Race (NIH/OMB)
Black or African American
6 Participants17 Participants11 Participants
Race (NIH/OMB)
More than one race
0 Participants0 Participants0 Participants
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
0 Participants0 Participants0 Participants
Race (NIH/OMB)
Unknown or Not Reported
14 Participants25 Participants11 Participants
Race (NIH/OMB)
White
199 Participants396 Participants197 Participants
Sex: Female, Male
Female
96 Participants190 Participants94 Participants
Sex: Female, Male
Male
127 Participants257 Participants130 Participants
Side of Lesion
Bilateral
8 Participants11 Participants3 Participants
Side of Lesion
Left
106 Participants213 Participants107 Participants
Side of Lesion
Midline
2 Participants3 Participants1 Participants
Side of Lesion
Right
107 Participants220 Participants113 Participants
Tumor Location
Frontal
65 Participants132 Participants67 Participants
Tumor Location
Multiple locations
74 Participants156 Participants82 Participants
Tumor Location
Occipital
9 Participants12 Participants3 Participants
Tumor Location
Other
3 Participants4 Participants1 Participants
Tumor Location
Parietal
24 Participants50 Participants26 Participants
Tumor Location
Temporal
45 Participants87 Participants42 Participants
Tumor Location
Thalamus
3 Participants6 Participants3 Participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
deaths
Total, all-cause mortality
175 / 213183 / 218
other
Total, other adverse events
207 / 213217 / 218
serious
Total, serious adverse events
47 / 21343 / 218

Outcome results

Primary

Overall Survival (OS)

The distribution of OS for each arm will be estimated using the Kaplan-Meier method and compared with a stratified logrank test.

Time frame: 83 months

ArmMeasureValue (MEDIAN)
Arm I (Temozolomide, Placebo)Overall Survival (OS)24.8 months
Arm II (Temozolomide, Veliparib)Overall Survival (OS)28.1 months
p-value: 0.1673Log Rank
Secondary

Interaction With Optune Device

Cox proportional hazards model will be used to evaluate whether there is a potential interaction between the treatment arm and the Optune device. If an interaction is detected, separate analyses of treatment effect (using Cox models) will be done for patients treated with the Optune device and patients who were not treated with the Optune device.

Time frame: 10 years

Population: Analysis population is patients that reported actual optune use

ArmMeasureGroupValue (NUMBER)
Arm I (Temozolomide, Placebo)Interaction With Optune DeviceReporting actual Optune use42 participants
Arm I (Temozolomide, Placebo)Interaction With Optune DeviceNo actual Optune use182 participants
Arm II (Temozolomide, Veliparib)Interaction With Optune DeviceReporting actual Optune use42 participants
Arm II (Temozolomide, Veliparib)Interaction With Optune DeviceNo actual Optune use181 participants
p-value: 0.665995% CI: [0.53, 1.5]Type 3 likelihood-ratio p-value
Secondary

Objective Tumor Response

Defined as complete response (CR) or partial response (PR) as specified in the Revised Assessment in Neuro-Oncology (RANO) criteria. An objective tumor response will be evaluated for each patient and the tumor response count will be summarized for each arm and compared using the Chi-square test. For CR, all of the following must be true: disappearance of all enhancing measurable and non-measurable disease; no new enhancing lesions; stable or improved non-enhancing lesions; patients must be off corticosteroids; stable or improved clinically A PR requires all of the following: \> 50% decrease in sum of products of perpendicular diameters of all measurable enhancing lesions compared with baseline; no progression of non-measurable disease; no new lesions; stable or improved non-enhancing lesions on same or lower dose of corticosteroids compared with baseline scan; steroid dose should be same or lower compared with baseline scan; stable or improved clinically

Time frame: 5 years

Population: All patients randomized to the trial with measurable disease per RANO criteria at registration and at one or more assessment(s) post-baseline.

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
Arm I (Temozolomide, Placebo)Objective Tumor Response34 Participants
Arm II (Temozolomide, Veliparib)Objective Tumor Response37 Participants
p-value: 0.7018Chi-squared
Secondary

Overall Adverse Event Rates for Grade 3 or Higher Adverse Events

Assessed using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (version 5 beginning April 1, 2018). The overall adverse event rates for grade 3 or higher adverse events will be summarized and be compared using Chi-Square or Fisher's Exact tests between treatment arms. The maximum grade for each type of treatment-related adverse event will be recorded for each patient, and frequency tables for each arm will be reviewed to determine patterns. Treatment-related adverse events will be tabulated for each arm.

Time frame: 5 years

Population: Only includes patients that began treatment

ArmMeasureValue (NUMBER)
Arm I (Temozolomide, Placebo)Overall Adverse Event Rates for Grade 3 or Higher Adverse Events93 participants with at least 1 grade 3+ AE
Arm II (Temozolomide, Veliparib)Overall Adverse Event Rates for Grade 3 or Higher Adverse Events133 participants with at least 1 grade 3+ AE
p-value: 0.0003Chi-squared
Secondary

Progression-free Survival (PFS)

The distribution of PFS for each arm will be estimated using the Kaplan-Meier method, and be compared using Cox proportional hazard models with all stratification factors adjusted. Progression (PD): Defined by any of the following: 1. \> 25% increase in sum of products of perpendicular diameters of enhancing lesions, compared with the smallest tumor measurement obtained either at baseline or best response 2. Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing doses of corticosteroids compared with baseline scan or best response after therapy initiation (stable doses of steroids include patient not on steroids) not caused by comorbid events 3. Any new lesion 4. Clear clinical deterioration not attributable to other causes apart from tumor or change in corticosteroid dose 5. Failure to return for evaluation as a result of death or deteriorating condition 6. Clear progression of non-measurable disease

Time frame: 120 months

ArmMeasureValue (MEDIAN)
Arm I (Temozolomide, Placebo)Progression-free Survival (PFS)12.1 months
Arm II (Temozolomide, Veliparib)Progression-free Survival (PFS)13.2 months
p-value: 0.316495% CI: [0.86, 1.29]Stratified Log Rank
Other Pre-specified

Change in Quality of Life (QOL)

Measured by the fatigue/uniscale tool. The fatigue/uniscale tool will be used as a measure of QOL. Potential differences in fatigue levels of patients treated on the two different arms will be evaluated. Changes in this measure will be evaluated over the course of treatment for both arms and will be compared using a two-sample t-test at each timepoint. Will also compute a normalized area under the curve (AUC) for the values of each patient over time and compare the mean AUCs for patients on the two arms.

Time frame: Baseline to up to 5 years

Other Pre-specified

MGMT Status

The concordance between site-determined MGMT methylation status and central laboratory determination of MGMT status will be analyzed using the Chi-Square test of proportions and 95% confidence intervals for the proportion of tests in disagreement with the local site.

Time frame: Baseline

Source: ClinicalTrials.gov · Data processed: Aug 1, 2026