Veliparib and Temozolomide in Treating Patients With Recurrent Glioblastoma

NCT01026493 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: RTOG-0929CDR0000660545
• Study Type: interventional
• Target: 257
• Locations: 1 country
• Sites: 17

Brief Summary

RATIONALE: Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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 veliparib together with temozolomide may kill more tumor cells. PURPOSE: This randomized phase I/II trial is studying the side effects and best dose of giving veliparib together with temozolomide and to see how well it works in treating patients with recurrent glioblastoma.

Conditions

Brain and Central Nervous System Tumors

Keywords

adult giant cell glioblastoma; adult glioblastoma; adult gliosarcoma; recurrent adult brain tumor; adult anaplastic astrocytoma; adult anaplastic ependymoma; adult anaplastic oligodendroglioma; adult brain stem glioma; adult mixed glioma; adult pineal gland astrocytoma

Outcome Measures

Primary Outcomes (2)

• Phase 1: Maximum Tolerated Dose (MTD)

  Dose limiting toxicity (DLT) = any of the following events within 1st 8 weeks of treatment attributable to study drugs: Any grade (gr) 3/4 thrombocytopenia, gr 4 anemia, gr 3 neutropenia with fever (\>100.4). gr 4 neutropenia lasting \> 7 days; Any non-hematologic (NH) gr 3+ toxicity (TOX), excluding alopecia, despite maximal medical therapy (MLT); NH TOX such as rash, nausea, vomiting, diarrhea, mucositis, hypophosphatemia, and hypertension will only be considered DLTs if they remain gr 3+ despite MLT; 2nd occurrence of thromboembolism; Failure to recover from TOX (\<= gr 1) to be eligible for re-treatment with study drugs \<= 14 days of last dose of either drug; Any episode of non-infectious radiologically observed pneumonitis gr 2-4 any duration. Dose level will be considered acceptable if \<= 1 of the 1st 6 eligible patients experiences a DLT. If current level is considered acceptable, dose escalation occurs. Otherwise preceding acceptable dose level will be declared the MTD.

  Start of treatment to 8 weeks.

• Phase II: 6-month Progression-free Survival (PFS) Rate for Patients With Measurable Disease After Surgery

  For patients with measureable disease after surgery: Progression defined as ≥ 25% increase in size of enhancing tumor or any new tumor; or neurologically worse, and steroids stable/increased. Bevacizumab (BEV)-naïve group: p0= 15% as estimate of 6-mo. PFS \[null hypothesis (NH)\], p1= 30%, with a 15% absolute increase \[alternative hypothesis (AH)\]. Error rates of 10% alpha and 10% beta. If \<= 11 patients experience 6-month PFS of the first 53 analyzable patients, then do not reject the null hypothesis that the 6-month PFS rate of experimental arm is less than 15%; BEV-failure group: p0 = 2% as a conservative estimate of 6-month PFS \[NH\], p1 = 15%, with a 13% absolute increase \[AH\]. Using first 26 analyzable subjects for each experimental arm, there is \>= 90% power to detect \>= 15% increase at a significance level of 0.10, using a 1-sided binomial test. If \>= 2 patients (8%) are progression free at 6 mo., then claim this regimen to be promising in the patient group.

  Randomization to 6 months.

Secondary Outcomes (2)

• Phase II: Objective Response (Partial and Complete Response) Rate for Patients With Measurable Disease After Surgery

  Analysis occurs after all patients have been on study for at 6 months. (Patients are followed from randomization to death or study termination whichever occurs first.)

• Phase II: Overall Survival (OS)

  Analysis occurs after all patients have been on study for at 6 months. (Patients are followed from randomization to death or study termination whichever occurs first.)

Study Arms (8)

Phase I: Dose Level 1

EXPERIMENTAL

ABT-888 20 mg x 21 days plus temozolomide 60 mg x 21 days

Drug: temozolomide 60 mg x 21 days; Drug: ABT-888 20 mg x 21 days

Phase I: Dose Level 2a

EXPERIMENTAL

ABT-888 40 mg x 21 days plus temozolomide 60 mg x 21 days

Drug: temozolomide 60 mg x 21 days; Drug: ABT-888 40 mg x 21 days

Phase I: Dose Level 2b

EXPERIMENTAL

ABT-888 20 mg x 21 days plus temozolomide 75 mg x 21 days

Drug: temozolomide 75 mg x 21 days; Drug: ABT-888 20 mg x 21 days

Phase I: Dose Level 3

EXPERIMENTAL

ABT-888 40 mg x 21 days plus temozolomide 75 mg x 21 days

Drug: temozolomide 75 mg x 21 days; Drug: ABT-888 40 mg x 21 days

Phase II: Arm 1/BEV-NAIVE

EXPERIMENTAL

ABT-888 40 mg x 21 days plus temozolomide 75 mg x 21 days

Drug: temozolomide 75 mg x 21 days; Drug: ABT-888 40 mg x 21 days

Phase II: Arm 2/BEV-NAIVE

EXPERIMENTAL

ABT-888 40 mg x 5 days plus temozolomide 150 mg x 5 days

Drug: Temozolomide 150 mg x 5 days; Drug: ABT-888 40 mg x 5 days

Phase II: Arm 1/BEV-FAILURE

EXPERIMENTAL

ABT-888 40 mg x 21 days plus temozolomide 75 mg x 21 days

Drug: temozolomide 75 mg x 21 days; Drug: ABT-888 40 mg x 21 days

Phase II: Arm 2/BEV-FAILURE

EXPERIMENTAL

ABT-888 40 mg x 5 days plus temozolomide 150 mg x 5 days

Drug: Temozolomide 150 mg x 5 days; Drug: ABT-888 40 mg x 5 days

Interventions

temozolomide 60 mg x 21 days DRUG

Temozolomide 60 mg/m2 x 21 days, with a 28-day cycle. Treatment will continue until progressive disease unless toxicity or the discretion of the treating physician precludes further therapy.

Also known as: Temodar, Temodal, Temcad

Phase I: Dose Level 1; Phase I: Dose Level 2a

temozolomide 75 mg x 21 days DRUG

Temozolomide 75 mg/m2 x 21 days, with a 28-day cycle. Treatment will continue until progressive disease unless toxicity or the discretion of the treating physician precludes further therapy.

Also known as: Temodar, Temodal, Temcad

Phase I: Dose Level 2b; Phase I: Dose Level 3; Phase II: Arm 1/BEV-FAILURE; Phase II: Arm 1/BEV-NAIVE

ABT-888 20 mg x 21 days DRUG

20 mg bid x 21 days, with a 28-day cycle. Treatment will continue until progressive disease unless toxicity or the discretion of the treating physician precludes further therapy.

Also known as: Veliparib

Phase I: Dose Level 1; Phase I: Dose Level 2b

ABT-888 40 mg x 21 days DRUG

40 mg bid x 21 days/28-day cycle. Treatment continues until progressive disease unless toxicity or the discretion of the treating physician preclude further therapy

Also known as: Veliparib

Phase I: Dose Level 2a; Phase I: Dose Level 3; Phase II: Arm 1/BEV-FAILURE; Phase II: Arm 1/BEV-NAIVE

Temozolomide 150 mg x 5 days DRUG

150 mg/m2 x 5 days (up to 200 mg/m2 after 2nd cycle)\*, with a 28-day cycle; dose reduction to 125 mg/m2 if necessary. Treatment continues until progressive disease unless toxicity or the discretion of the treating physician preclude

Also known as: Temodar, Temcad, Temodal

Phase II: Arm 2/BEV-FAILURE; Phase II: Arm 2/BEV-NAIVE

ABT-888 40 mg x 5 days DRUG

40 mg bid x 5 days/28-day cycle. Treatment continues until progressive disease unless toxicity or the discretion of the treating physician preclude

Also known as: Veliparib

Phase II: Arm 2/BEV-FAILURE; Phase II: Arm 2/BEV-NAIVE

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

DISEASE CHARACTERISTICS: * Histologically confirmed diagnosis of 1 of the following: * Any intracranial high-grade glioma (phase I\*) * Glioblastoma or gliosarcoma (phase II\*) * Patients whose original histology was low-grade glioma are eligible provided they were subsequently diagnosed with glioblastoma or gliosarcoma * Unequivocal radiographic evidence for tumor progression by MRI within 14 days prior to registration and with a stable or decreasing dose of steroids at least 5 days prior to scanning OR recent resection (registration within 30 days of resection) as long as all of the following conditions are met: * Patients must have recovered from the effects of surgery * Residual disease following resection of recurrent glioblastoma is not mandated for eligibility into the study; to best assess the extent of residual disease post-operatively, a post-operative MRI scan should be performed within 28 days prior to registration and within 96 hours post surgery (although 24 hours would be optimum) * Prior radiation is required for the phase I\* arm * Patients must have completed a course of radiation therapy and at least 2 consecutive adjuvant cycles of temozolomide (phase II\*) * A stable or decreasing dose of steroids at least 5 days prior to scanning is not mandated for patients who had a recent resection * No evidence of acute (i.e., new and active) intratumoral hemorrhage on MRI * Patients with MRI demonstrating old hemorrhage or subacute blood after a neurosurgical procedure (biopsy or resection) are eligible Note: \*Phase I was closed and phase II was opened on 3/6/12. PATIENT CHARACTERISTICS: * Karnofsky performance status 70-100% * White blood cell (WBC) count ≥ 3,000/mm\^3 * Absolute neutrophil count (ANC) ≥ 1,500/mm\^3 * Platelet count ≥ 100,000/mm\^3 * Hemoglobin ≥ 10.0 g/dL (transfusion or other intervention allowed) * Serum glutamic oxaloacetic transaminase (SGOT) ≤ 3.0 times upper limit of normal (ULN) * Serum glutamic pyruvic transaminase (SGPT) ≤ 3.0 times ULN * Bilirubin ≤ 1.25 times ULN * Creatinine \< 1.7 mg/dL OR estimated glomerular filtration rate (GFR) ≥ 30 mL/min * Urine protein:creatinine ratio ≤ 0.5 OR urine protein \< 1,000 mg by 24-hour urine collection\*\* * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception during and for ≥ 6 months after completion of study therapy * Able to undergo brain MRI scans with IV gadolinium * Able to swallow oral medications * Patients with a history of seizure, or new onset of seizures, should be clinically controlled with no seizures for at least 14 days prior to registration * No other prior invasive malignancy (except for nonmelanomatous skin cancer or carcinoma in situ of the cervix) unless the patient has been disease-free and off therapy for that disease for ≥ 3 years * No severe, active comorbidity, including any of the following: * Transmural myocardial infarction or unstable angina within the past 6 months * Evidence of recent myocardial infarction or ischemia as indicated by S-T elevations of ≥ 2 mm on EKG performed within the past 14 days * New York Heart Association (NYHA) class II-IV congestive heart failure requiring hospitalization within the past 12 months * Stroke or transient ischemic attack within the past 6 months * Cerebral vascular accident within the past 6 months * Serious and inadequately controlled cardiac arrhythmia * Clinically significant peripheral vascular disease * Evidence of bleeding diathesis or coagulopathy * Serious non-healing would, ulcer, or bone fracture * Abdominal fistula, gastrointestinal (GI) perforation, or intra-abdominal abscess within the past 28 days * Significant traumatic injury within the past 28 days * Acute bacterial or fungal infection requiring IV antibiotics at the time of study registration * Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within the past 14 days * AIDS based upon current Centers for Disease Control and Prevention (CDC) definition (HIV testing is not required) * No condition that would impair the ability to swallow pills (e.g., GI tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease) * No disease that would obscure toxicity or dangerously alter drug metabolism * Not on dialysis * No history of chronic hepatitis B or C Note: \*\*Required for patients who received prior bevacizumab and developed known clinically significant nephrotic syndrome during treatment and whose baseline values have not returned to normal. PRIOR CONCURRENT THERAPY: * See Disease Characteristics * Recovered from the toxic effects of prior therapy * Prior interstitial brachytherapy, Gliadel wafer, or stereotactic radiosurgery allowed provided there is confirmation of progressive disease by positron emission tomography (PET) scan, thallium scan, MRI spectroscopy, perfusion MRI, or surgical documentation * No more than 3 prior treatment regimens (phase I\*) * No more than 2 prior treatment regimens for recurrent glioblastoma/gliosarcoma (phase II\*) * More than 28 days since prior major surgical procedure or open biopsy (with the exception of craniotomy) * At least 28 days since prior investigational agents or cytotoxic agents (42 days for nitrosoureas, 21 days for procarbazine, and 14 days for vincristine) * At least 14 days since prior non-cytotoxic agents (e.g., bevacizumab, interferon, tamoxifen, thalidomide, isotretinoin, or tyrosine kinase inhibitors) * No concurrent highly-active antiretroviral therapy * No concurrent herbal products of unknown constitution * No concurrent major surgical procedures Note: \*Phase I was closed and phase II was opened on 3/6/12.

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• Radiation Therapy Oncology Group: lead
• National Cancer Institute (NCI): collaborator
• NRG Oncology: collaborator

Study Sites (17)

Rebecca and John Moores UCSD Cancer Center

La Jolla, California, 92093-0658, United States

Location

Cedars-Sinai Medical Center

Los Angeles, California, 90048, United States

Location

Cancer Research Center of Hawaii

Honolulu, Hawaii, 96813, United States

Location

Queen's Cancer Institute at Queen's Medical Center

Honolulu, Hawaii, 96813, United States

Location

Hawaii Medical Center - East

Honolulu, Hawaii, 96817, United States

Location

Leeward Radiation Oncology

‘Ewa Beach, Hawaii, 96706, United States

Location

University of Chicago Cancer Research Center

Chicago, Illinois, 60637-1470, United States

Location

CCOP - Kansas City

Prairie Village, Kansas, 66208, United States

Location

Central Baptist Hospital

Lexington, Kentucky, 40503-9985, United States

Location

Louisville Oncology at Norton Cancer Institute - Louisville

Louisville, Kentucky, 40202, United States

Location

Regional Cancer Center at Singing River Hospital

Pascagoula, Mississippi, 39581, United States

Location

Renown Institute for Cancer at Renown Regional Medical Center

Reno, Nevada, 89502, United States

Location

Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center

Lebanon, New Hampshire, 03756-0002, United States

Location

Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School

New Brunswick, New Jersey, 08903, United States

Location

Highland Hospital of Rochester

Rochester, New York, 14620, United States

Location

James P. Wilmot Cancer Center at University of Rochester Medical Center

Rochester, New York, 14642, United States

Location

Legacy Good Samaritan Hospital & Comprehensive Cancer Center

Portland, Oregon, 97210, United States

Location

MeSH Terms

Conditions

Central Nervous System Neoplasms; Glioblastoma; Gliosarcoma; Brain Neoplasms; Astrocytoma; Ependymoma; Oligodendroglioma; Glioma

Interventions

Temozolomide; veliparib

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Wendy Seiferheld, M.S.
• Organization: NRG Oncology

seiferheldw@nrgoncology.org

Study Officials

• H. Ian Robins, MD, PhD

  University of Wisconsin, Madison

  PRINCIPAL INVESTIGATOR

• Mark R Gilbert, MD

  National Cancer Institute/National Institutes of Health

  PRINCIPAL INVESTIGATOR

• Arnab Chakravarti, MD

  Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, Ohio State University Medical School

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 3, 2009
• First Posted: December 4, 2009
• Study Start: July 1, 2010
• Primary Completion: May 1, 2014
• Study Completion: December 1, 2016
• Last Updated: July 2, 2017
• Results First Posted: July 2, 2017

Record last verified: 2017-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (17)