Veliparib, Radiation Therapy, and Temozolomide in Treating Younger Patients With Newly Diagnosed Diffuse Pontine Gliomas
Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Completed
CT.gov ID
NCT01514201
Collaborator
(none)
66
12
1
73.8
5.5
0.1
Study Details
Study Description
Brief Summary
This phase I/II trial studies the side effects and the best dose of veliparib when given together with radiation therapy and temozolomide and to see how well they work in treating younger patients newly diagnosed with diffuse pontine gliomas. Veliparib 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 veliparib with radiation therapy and temozolomide may kill more tumor cells.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
|
Phase 1/Phase 2 |
Detailed Description
PRIMARY OBJECTIVES:
- To identify the maximum-tolerated dose or recommended Phase II dose of ABT-888 (veliparib) which can be safely administered concurrently with radiation therapy, followed by maintenance therapy with ABT-888 and temozolomide (TMZ), in patients with newly diagnosed diffuse pontine gliomas (DIPG). (Phase I) II. To study the plasma pharmacokinetics (PK) of ABT-888 during ABT-888 and radiation therapy. (Phase I) III. To study the feasibility of intra-patient dose escalation of TMZ during maintenance therapy with ABT-888 and TMZ. (Phase I) IV. To describe the toxicities associated with administering ABT-888 and radiation therapy, followed by ABT-888 and TMZ, in patients with newly diagnosed DIPG. (Phase I) V. To estimate the proportion of newly diagnosed DIPG patients treated on protocol that are determined to have experienced pseudo progression. (Phase I) VI. To estimate the overall survival distribution for newly diagnosed patients with DIPG treated with the combination of ABT-888 and radiation therapy, followed by ABT-888 and TMZ, and compare to Pediatric Brain Tumor Consortium (PBTC) historical controls. (Phase II) VII. To study the feasibility of intra-patient dose escalation of TMZ during maintenance therapy with ABT-888 and TMZ. (Phase II) VIII. To estimate the proportion of newly diagnosed DIPG patients treated on protocol that are determined to have experienced pseudo progression. (Phase II)
SECONDARY OBJECTIVES:
-
To estimate the progression-free survival (PFS) distribution and to summarize the best tumor responses observed prior to progression or recurrence.
-
To explore the plasma PK of ABT-888 during ABT-888 and radiation therapy. III. To explore peripheral blood mononuclear cell (PBMC) poly (ADP-ribose) polymerase 1(PARP) activity before and after treatment with ABT-888.
-
To explore quantifying non-homologous end-joining (NHEJ) activity or gamma-H2A histone family, member X (H2AX) levels (as surrogate markers of unrepaired double-strand breaks (DSBs)) in PBMC before and after treatment with ABT-888.
-
To explore quantifying PARP activity and deoxyribonucleic acid (DNA)-repair protein levels in biopsied atypical pontine gliomas, if available.
-
To explore associations of molecular parameters from secondary aims III, IV, and V with PFS and overall survival (OS) after conclusion of clinical trial.
-
To explore the quantitative magnetic resonance (MR) measures of relative cerebral blood volume (rCBV), vascular permeability (Ktrans, fractional plasma volume [vp], and extravascular extracellular space volume fraction [ve] values), and apparent diffusion coefficient (ADC) within the first six months of initiating protocol treatment to correlate with disease outcome and determine whether such metrics differentiate patients with pseudo progression from those with true early progressive disease.
-
To explore the potential utility of urine biomarkers as a novel, non-invasive method of detecting and tracking changes in the status of pediatric brain stem gliomas.
OUTLINE: This is a phase I, dose-escalation study of veliparib followed by a phase II study.
DOSE-ESCALATION: Patients receive veliparib orally (PO) twice daily (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT) once daily (QD) 5 days a week for 6-7 weeks.
MAINTENANCE THERAPY: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up periodically for up to 3 years.
Study Design
Study Type:
Interventional
Actual Enrollment
:
66 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase I/II Study of ABT-888, An Oral Poly(ADP-ribose) Polymerase Inhibitor, and Concurrent Radiation Therapy, Followed by ABT-888 and Temozolomide, in Children With Newly Diagnosed Diffuse Pontine Gliomas (DIPG)
Actual Study Start Date
:
Feb 1, 2012
Actual Primary Completion Date
:
Mar 28, 2018
Actual Study Completion Date
:
Mar 28, 2018
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Treatment (veliparib, temozolomide, 3D-CRT, IMRT) DOSE-ESCALATION: Patients receive veliparib PO BID 5 days a week for 6-7 weeks. Patients also undergo concurrent 3D-CRT or IMRT QD 5 days a week for 6-7 weeks. MAINTENANCE THERAPY: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. |
Radiation: 3-Dimensional Conformal Radiation Therapy
Undergo 3D-CRT
Other Names:
Radiation: Intensity-Modulated Radiation Therapy
Undergo IMRT
Other Names:
Other: Laboratory Biomarker Analysis
Optional correlative studies
Other: Pharmacological Study
Correlative studies
Drug: Temozolomide
Given PO
Other Names:
Drug: Veliparib
Given PO
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Maximum-tolerated Dose of Veliparib Defined as Highest Dose Level With Fewer Than 2 Dose Limiting Toxicities in 6 Patients as Assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (Phase I) [10 weeks]
The traditional 3+3 dose finding algorithm was used to estimate the maximum-tolerated dose of veliparib given concurrently with radiation therapy. The dose-limiting toxicity observation period was the first 10 weeks of therapy. Dose-limiting toxicities included any grade 4 non-hematologic toxicity, any grade 3 non-hematologic toxicity with a few exceptions (see section 5.2.1.2 of the protocol document), any grade 2 non-hematologic toxicity that persisted for >7 days and considered medically significant that required treatment interruption; grade 3 or higher thrombocytopenia or grade 4 neutropenia; and any Veliparib related adverse event that led to a dose reduction or the permanent cessation of therapy.
- Percentage of Participants Observed to Have Unacceptable Toxicity During the Intra-patient Dose Escalation of Temozolomide During Maintenance Therapy (Feasibility Analysis Population) [28 days per treatment cycle]
Unacceptable toxicities during maintenance included events at least possibly attributable to Veliparib and temozolomide (TMZ) such as any grade 4 non-hematologic toxicity, any grade 3 non-hematologic toxicity with some exceptions (e.g., grade 3 nausea/vomiting <5 days, grade 3 fever or infection <5 days), grade 3+ thrombocytopenia, grade 4 neutropenia, delay >14 days in starting subsequent cycle due to neutrophil <1,000/mm3 or platelet <100,000/mm3. Maintenance therapy was initiated with 25 mg/m2 Veliparib and 135 mg/m2 of TMZ, with the possibility to escalate TMZ to 175 mg/m2 and 200 mg/m2 in courses 2 and 3, respectively, if no unacceptable toxicities occurred following one course of treatment at each of the dose levels to be tested. Intra-patient dose escalation to a given dose (135, 175, or 200 mg/m2) was halted based on rules employed in 3+3 designs. This dose escalation was intended for all patients but was halted early, during the phase I portion, as it was not well tolerated.
- Overall Survival [Time from initiation of therapy to the date of death from any cause or to the date patient was known to be alive for surviving patients, assessed to up to 3 years]
Overall survival was defined as the interval from date on treatment to date of death from any cause or to date of last follow-up. Patients who had not failed (died) at the time of analyses were censored at their last date of contact. The method of Kaplan and Meier was used to estimate overall survival. The 3-year estimate with a 95% confidence interval is reported.
- Number of Phase I Patients Who Experienced Dose Limiting Toxicities (DLTs) [10 weeks]
DLTs were defined as any of the following adverse events that were at least possibly attributable to Veliparib observed during the dose finding phase (the first 10 weeks of therapy). Hematologic dose limiting toxicities included grade 3 and higher thrombocytopenia or grade 4 neutropenia. Non-hematologic dose limiting toxicities included any grade 4 non-hematologic toxicity, any grade 3 non-hematologic toxicity with some exceptions (e.g., nausea and vomiting of <5 days; fever or infection of <5 days; hypophosphatemia, hypokalemia, hypocalcemia or hypomagnesemia responsive to oral supplementation; elevation of transaminases that return to levels meeting eligibility criteria within 7 days), or any grade non-hematologic toxicity that persisted for >7 days and considered medically significant or sufficiently intolerable by patients that required treatment interruption.
Secondary Outcome Measures
- Progression-free Survival (PFS) [Time from initiation of treatment to the earliest date of failure (disease progression, death from any cause, or second malignancy), assessed up to 3 years]
PFS was defined as the interval from date of treatment initiation to date of first event (disease progression or relapse, second malignancy or death from any cause). Patients who had not failed at the time of analyses were censored at their last date of contact. The method of Kaplan and Meier was used to estimate PFS. A 3-year estimate with a 95% confidence interval is reported.
- Percentage of Patients With Pseudo Progression [Up to 6 months]
For participants that showed possible tumor progression (pseudo progression) on magnetic resonance imaging (MRI) during the first 6 months of therapy, treating physicians had the option of allowing patients to remain on therapy and repeating the disease assessment in 4-6 weeks. If the repeat MRI at 4-6 weeks showed disease progression, the patient was noted to have true disease progression (and the progression date corresponded to that of the first MRI). If the repeat MRI at 4-6 weeks did not show disease progression, then the patient was noted to have pseudo progression. The percentage of patients observed to have experienced pseudo progression was provided with a 95% confidence interval.
- Maximum Concentration of Veliparib (Cmax) on Days 1 and 4 (Measured in ng/mL) [Pharmacokinetic Parameter] [Up to day 4]
During course 1, blood samples were collected pre-veliparib on day 1, at 0.5, 1, 2, and 6-8 hours after the first dose, pre-veliparib on day 4 (steady state), and 2 hours after the morning dose. Veliparib concentrations were measured using a liquid chromatography tandem mass spectrometry assay and pharmacokinetic parameters were evaluated using a non-compartmental analysis. Cmax measures the highest concentration of drug.
- Mean Apparent Clearance (CL/F) for Veliparib [Pharmacokinetic Parameter] [Up to day 4]
During course 1, blood samples were collected pre-veliparib on day 1, at 0.5, 1, 2, and 6-8 hours after the first dose, pre-veliparib on day 4 (steady state), and 2 hours after the morning dose. Veliparib concentrations were measured using a liquid chromatography tandem mass spectrometry assay and pharmacokinetic parameters were evaluated using a non-compartmental analysis.
- Maximum Concentration of Veliparib (Cmax) on Day 1 (Measured in μM) [Pharmacokinetic Parameter] [Day 1]
During course 1, blood samples were collected pre-veliparib on day 1, at 0.5, 1, 2, and 6-8 hours after the first dose, pre-veliparib on day 4 (steady state), and 2 hours after the morning dose. Veliparib concentrations were measured using a liquid chromatography tandem mass spectrometry assay and pharmacokinetic parameters were evaluated using a non-compartmental analysis. Cmax measures the highest concentration of drug.
- Apparent Volume of Distribution (Vd/F) for Veliparib [Pharmacokinetic Parameter] [Up to day 4]
During course 1, blood samples were collected pre-veliparib on day 1, at 0.5, 1, 2, and 6-8 hours after the first dose, pre-veliparib on day 4 (steady state), and 2 hours after the morning dose. Veliparib concentrations were measured using a liquid chromatography tandem mass spectrometry assay and pharmacokinetic parameters were evaluated using a non-compartmental analysis.
- Terminal Half-life (t1/2) for Veliparib [Pharmacokinetic Parameter] [Up to day 4]
During course 1, blood samples were collected pre-veliparib on day 1, at 0.5, 1, 2, and 6-8 hours after the first dose, pre-veliparib on day 4 (steady state), and 2 hours after the morning dose. Veliparib concentrations were measured using a liquid chromatography tandem mass spectrometry assay and pharmacokinetic parameters were evaluated using a non-compartmental analysis.
- Trough for Veliparib [Pharmacokinetic Parameter] [Up to day 4]
During course 1, blood samples were collected pre-veliparib on day 1, at 0.5, 1, 2, and 6-8 hours after the first dose, pre-veliparib on day 4 (steady state), and 2 hours after the morning dose. Veliparib concentrations were measured using a liquid chromatography tandem mass spectrometry assay and pharmacokinetic parameters were evaluated using a non-compartmental analysis.
Other Outcome Measures
- Percentage of Participants With Significant Changes in Poly(ADP-ribose) Polymerase (PARP) Levels Post-Veliparib, as Measured in Peripheral Blood Monocytes (PBMCs) [Baseline and up to 11 weeks]
Blood samples were collected from patients and assessed pre- and post-Veliparib to assess treatment-induced changes. A significant change in PBMC PARP level was arbitrarily defined as a >50% increase or decrease from the pre-treatment level, documented at week 6 and/or week 11 after starting protocol therapy.
- Change in Non-homologous End-joining (NHEJ) Activity as Measured in Peripheral Blood Monocytes (PBMCs) [Baseline to up to 3 years]
Levels of non-homologous end-joining (NHEJ) activity were to be calculated. Cox models to explore associations between the levels of NHEJ and outcome (progression-free survival and overall survival) were planned, in addition to looking at associations between Poly(ADP-ribose) polymerase (PARP) activity and NHEJ levels.
- Change in Level of Gamma-H2A Histone Family, Member X (H2AX) Measured in PBMCs [Baseline to up to 3 years]
Levels of gamma-H2A histone family, member X (H2AX) were to be calculated. Cox models to explore associations between the levels of gamma-H2AX and outcome (progression-free survival and overall survival) were planned, in addition to looking at associations between Poly(ADP-ribose) polymerase (PARP) activity and gamma-H2AX levels.
- Levels of Urinary Biomarkers [Baseline to up to 3 years]
Urine samples were analyzed for a panel of biomarkers. Netrin-1 levels were determined by ELISA. Levels of matrix metalloproteinase 3 (MMP3) and basic fibroblast growth factor (bFGF) were analyzed using custom Luminex® screening assays. Tissue inhibitor of metalloproteinase 1 (TIMP1) levels were analyzed using a Luminex® performance assay. Protein concentrations are given in picograms per microgram (pg/μg), and were determined by dividing the concentration of the target protein in the sample (pg/mL) by the concentration of total protein in the sample (μg/mL) as a normalization measure.
Eligibility Criteria
Criteria
Ages Eligible for Study:
N/A
to 21 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Patients with newly diagnosed diffuse intrinsic pontine gliomas (DIPGs), defined as tumors with a pontine epicenter and diffuse intrinsic involvement of the pons, are eligible without histologic confirmation; patients with brainstem tumors that do not meet these criteria or not considered to be typical intrinsic pontine gliomas will only be eligible if the tumors are biopsied and proven to be an anaplastic astrocytoma, glioblastoma multiforme, gliosarcoma, anaplastic mixed glioma, or fibrillary astrocytoma
-
Patients with juvenile pilocytic astrocytoma, pilomyxoid astrocytoma, fibrillary astrocytoma, gangliogliomas, or other mixed gliomas without anaplasia are not eligible;
-
Patients with disseminated disease are not eligible, and magnetic resonance imaging (MRI) of spine must be performed if disseminated disease is suspected by the treating physician
-
Patient must be able to swallow oral medications to be eligible for study enrollment
-
Karnofsky >= 50% for patients > 16 years of age or Lansky >= 50% for patients =< 16 years of age; 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
-
Patients must have not received any prior therapy other than surgery and/or steroids
-
Absolute neutrophil count >= 1,000/mm^3
-
Platelets >= 100,000/mm^3 (unsupported)
-
Hemoglobin >= 10 g/dL (unsupported)
-
Total bilirubin =< 1.5 times upper limit of normal (ULN) for age
-
Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase (SGPT)) =< 5 x institutional upper limit of normal for age
-
Albumin >= 2 g/dL
-
Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
-
0.6 mg/dL (1 to < 2 years of age)
-
0.8 mg/dL (2 to < 6 years of age)
-
1.0 mg/dL (6 to < 10 years of age)
-
1.2 mg/dL (10 to < 13 years of age)
-
1.5 mg/dL (male) or 1.4 mg/dL (female) (13 to < 16 years of age)
-
1.7 mg/dL (male) or 1.4 mg/dL (female) (>= 16 years of age)
-
Female patients of childbearing potential must not be pregnant or breast-feeding; female patients of childbearing potential must have a negative serum or urine pregnancy test
-
Patients of childbearing or child-fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study
-
Signed informed consent according to institutional guidelines must be obtained; assent, when appropriate, will be obtained according to institutional guidelines
Exclusion Criteria:
-
Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that would compromise the patient's ability to tolerate protocol therapy or would likely interfere with the study procedures or results
-
Patients with inability to return for follow-up visits or obtain follow-up studies required to assess toxicity to therapy
-
Patients with active seizures or a history of seizure are not eligible for study entry, with the exception of patients with documented febrile seizure
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Children's Hospital Los Angeles | Los Angeles | California | United States | 90027 |
| 2 | Lucile Packard Children's Hospital Stanford University | Palo Alto | California | United States | 94304 |
| 3 | Children's National Medical Center | Washington | District of Columbia | United States | 20010 |
| 4 | Lurie Children's Hospital-Chicago | Chicago | Illinois | United States | 60611 |
| 5 | National Institutes of Health Clinical Center | Bethesda | Maryland | United States | 20892 |
| 6 | Memorial Sloan Kettering Cancer Center | New York | New York | United States | 10065 |
| 7 | Duke University Medical Center | Durham | North Carolina | United States | 27710 |
| 8 | Cincinnati Children's Hospital Medical Center | Cincinnati | Ohio | United States | 45229 |
| 9 | Children's Hospital of Pittsburgh of UPMC | Pittsburgh | Pennsylvania | United States | 15224 |
| 10 | Pediatric Brain Tumor Consortium | Memphis | Tennessee | United States | 38105 |
| 11 | St. Jude Children's Research Hospital | Memphis | Tennessee | United States | 38105 |
| 12 | Texas Children's Hospital | Houston | Texas | United States | 77030 |
Sponsors and Collaborators
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Patricia Baxter, Pediatric Brain Tumor Consortium
Study Documents (Full-Text)
More Information
Publications
None provided.Responsible Party:
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01514201
Other Study ID Numbers:
- NCI-2012-00082
- NCI-2012-00082
- PBTC-033
- 12-C-0213
- CDR0000717423
- P12978
- PBTC-033
- PBTC-033
- U01CA081457
- UM1CA081457
- NCT01507324
First Posted:
Jan 23, 2012
Last Update Posted:
Aug 13, 2019
Last Verified:
Jul 1, 2019
Study Results
Participant Flow
| Recruitment Details | Patients up to 21 years of age with newly diagnosed diffuse intrinsic pontine gliomas (DIPGs) were enrolled at Pediatric Brain Tumor Consortium (PBTC) member institutions. The first patient was enrolled on 2/1/2012 and the last patient was enrolled on 01/20/2016. |
|---|---|
| Pre-assignment Detail | Of the 66 patients enrolled, 1 phase II patient was deemed ineligible due to an elevated alanine aminotransferase (ALT). Of note, the 6 phase I patients who were treated at the established maximum tolerated dose (MTD) during the phase I portion of the trial were also counted as phase II patients in analyses of phase II objectives. |
| Arm/Group Title | Phase I, Dose Level 1 (50 mg) | Phase I, Dose Level 2 (65 mg) | Phase I, Dose Level 3 (85 mg) | Phase II (MTD) |
|---|---|---|---|---|
| Arm/Group Description | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Patients receive veliparib at the maximum tolerated dose (MTD) orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early (before the phase II study was initiated) as it was not well tolerated. |
| Period Title: PHASE I: Veliparib + Radiation Therapy | ||||
| STARTED | 6 | 6 | 6 | 0 |
| COMPLETED | 5 | 6 | 6 | 0 |
| NOT COMPLETED | 1 | 0 | 0 | 0 |
| Period Title: PHASE I: Veliparib + Radiation Therapy | ||||
| STARTED | 5 | 6 | 6 | 0 |
| COMPLETED | 0 | 0 | 0 | 0 |
| NOT COMPLETED | 5 | 6 | 6 | 0 |
| Period Title: PHASE I: Veliparib + Radiation Therapy | ||||
| STARTED | 0 | 0 | 0 | 47 |
| COMPLETED | 0 | 0 | 0 | 35 |
| NOT COMPLETED | 0 | 0 | 0 | 12 |
| Period Title: PHASE I: Veliparib + Radiation Therapy | ||||
| STARTED | 0 | 0 | 0 | 35 |
| COMPLETED | 0 | 0 | 0 | 2 |
| NOT COMPLETED | 0 | 0 | 0 | 33 |
Baseline Characteristics
| Arm/Group Title | Phase I, Dose Level 1 (50 mg) | Phase I, Dose Level 2 (65 mg) | Phase I, Dose Level 3 (85 mg) | Phase II (MTD) | Total |
|---|---|---|---|---|---|
| Arm/Group Description | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Patients receive veliparib at the maximum tolerated dose (MTD) orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early (before the phase II study was initiated) as it was not well tolerated. | Total of all reporting groups |
| Overall Participants | 6 | 6 | 6 | 47 | 65 |
| Age (Count of Participants) | |||||
| <=18 years |
6
100%
|
6
100%
|
6
100%
|
47
100%
|
65
100%
|
| Between 18 and 65 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| >=65 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Age (years) [Median (Full Range) ] | |||||
| Median (Full Range) [years] |
6.3
|
10.2
|
9.2
|
6.5
|
6.6
|
| Sex: Female, Male (Count of Participants) | |||||
| Female |
2
33.3%
|
3
50%
|
2
33.3%
|
30
63.8%
|
37
56.9%
|
| Male |
4
66.7%
|
3
50%
|
4
66.7%
|
17
36.2%
|
28
43.1%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||||
| Hispanic or Latino |
3
50%
|
0
0%
|
0
0%
|
7
14.9%
|
10
15.4%
|
| Not Hispanic or Latino |
3
50%
|
5
83.3%
|
5
83.3%
|
34
72.3%
|
47
72.3%
|
| Unknown or Not Reported |
0
0%
|
1
16.7%
|
1
16.7%
|
6
12.8%
|
8
12.3%
|
| Race (NIH/OMB) (Count of Participants) | |||||
| American Indian or Alaska Native |
1
16.7%
|
0
0%
|
0
0%
|
1
2.1%
|
2
3.1%
|
| Asian |
1
16.7%
|
0
0%
|
0
0%
|
1
2.1%
|
2
3.1%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
1
2.1%
|
1
1.5%
|
| Black or African American |
0
0%
|
2
33.3%
|
1
16.7%
|
9
19.1%
|
12
18.5%
|
| White |
3
50%
|
3
50%
|
5
83.3%
|
29
61.7%
|
40
61.5%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
1
16.7%
|
1
16.7%
|
0
0%
|
6
12.8%
|
8
12.3%
|
| Region of Enrollment (Count of Participants) | |||||
| United States |
6
100%
|
6
100%
|
6
100%
|
47
100%
|
65
100%
|
Outcome Measures
| Title | Maximum-tolerated Dose of Veliparib Defined as Highest Dose Level With Fewer Than 2 Dose Limiting Toxicities in 6 Patients as Assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (Phase I) |
|---|---|
| Description | The traditional 3+3 dose finding algorithm was used to estimate the maximum-tolerated dose of veliparib given concurrently with radiation therapy. The dose-limiting toxicity observation period was the first 10 weeks of therapy. Dose-limiting toxicities included any grade 4 non-hematologic toxicity, any grade 3 non-hematologic toxicity with a few exceptions (see section 5.2.1.2 of the protocol document), any grade 2 non-hematologic toxicity that persisted for >7 days and considered medically significant that required treatment interruption; grade 3 or higher thrombocytopenia or grade 4 neutropenia; and any Veliparib related adverse event that led to a dose reduction or the permanent cessation of therapy. |
| Time Frame | 10 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| The first 18 patients enrolled on the study were phase I patients used to determine the maximum tolerated dose or the recommended phase II dose and to address other objectives of the phase I component of this trial. |
| Arm/Group Title | Phase I Patients |
|---|---|
| Arm/Group Description | The first 18 patients enrolled on the study were phase I patients used to determine the maximum tolerated dose or the recommended phase II dose and to address other objectives of the phase I component of this trial. The starting dose level was 50 mg/m2/dose twice a day (BID) and other dose levels to be studied were 65 and 85 mg/m2/dose BID. If the 85 mg/m2 dose level was tolerated, there was a plan to study a higher dose level (110 mg/m2/dose BID) but only if supported by clinical data. |
| Measure Participants | 18 |
| Number [mg/m2/dose BID] |
65
|
| Title | Percentage of Participants Observed to Have Unacceptable Toxicity During the Intra-patient Dose Escalation of Temozolomide During Maintenance Therapy (Feasibility Analysis Population) |
|---|---|
| Description | Unacceptable toxicities during maintenance included events at least possibly attributable to Veliparib and temozolomide (TMZ) such as any grade 4 non-hematologic toxicity, any grade 3 non-hematologic toxicity with some exceptions (e.g., grade 3 nausea/vomiting <5 days, grade 3 fever or infection <5 days), grade 3+ thrombocytopenia, grade 4 neutropenia, delay >14 days in starting subsequent cycle due to neutrophil <1,000/mm3 or platelet <100,000/mm3. Maintenance therapy was initiated with 25 mg/m2 Veliparib and 135 mg/m2 of TMZ, with the possibility to escalate TMZ to 175 mg/m2 and 200 mg/m2 in courses 2 and 3, respectively, if no unacceptable toxicities occurred following one course of treatment at each of the dose levels to be tested. Intra-patient dose escalation to a given dose (135, 175, or 200 mg/m2) was halted based on rules employed in 3+3 designs. This dose escalation was intended for all patients but was halted early, during the phase I portion, as it was not well tolerated. |
| Time Frame | 28 days per treatment cycle |
Outcome Measure Data
| Analysis Population Description |
|---|
| Patients were combined across dose levels since they received the same maintenance therapy. Though this objective was intended for all patients, only the first 12 enrolled were included as the dose-escalation stopped early. 1 of the first 12 patients did not start maintenance due to early progression, so 11 patients started dose level 1. |
| Arm/Group Title | Dose Level 1 (135 mg/m2) | Dose Level 2 (175 mg/m2) | Dose Level 3 (200 mg/m2) |
|---|---|---|---|
| Arm/Group Description | Participants in the feasibility analysis population that started dose level 1 of the intra-patient dose escalation during maintenance (Veliparib 25 mg/m2 twice a day (BID) + temozolomide 135 mg/m2/day) | Participants in the feasibility analysis population that started dose level 2 of the intra-patient dose escalation during maintenance (Veliparib 25 mg/m2 twice a day (BID) + temozolomide 175 mg/m2/day) | Participants in the feasibility analysis population that started dose level 1 of the intra-patient dose escalation during maintenance (Veliparib 25 mg/m2 twice a day (BID) + temozolomide 200 mg/m2/day) |
| Measure Participants | 11 | 5 | 3 |
| Number [% of participants] |
9
150%
|
40
666.7%
|
67
1116.7%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Phase I Patients, Dose Level 2 (175 mg/m2), Dose Level 3 (200 mg/m2) |
|---|---|---|
| Comments | Intra-patient dose escalation of temozolomide during maintenance was assessed based on similar rules employed in traditional 3+3 designs. For example intra-patient dose escalation would be halted if at any time 2 out of first 2-6 patients experienced dose-modifying toxicities at a given dose level or if 4 out of first 12 patients experienced dose-modifying toxicities at a given dose level. | |
| Type of Statistical Test | Other | |
| Comments | This was descriptive in nature. Two of the first 5 patients who were escalated to 175 mg/m2 of temozolomide during the maintenance intra-patient dose escalation had dose-modifying toxicities (DMTs). Since the ad hoc stopping rule was met, intra-patient dose escalation was halted and all subsequent patients were to receive 135 mg/m2 of temozolomide during maintenance. | |
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Percentage of patients with DMTs |
| Estimated Value | 40 | |
| Confidence Interval |
(2-Sided) % to |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Overall Survival |
|---|---|
| Description | Overall survival was defined as the interval from date on treatment to date of death from any cause or to date of last follow-up. Patients who had not failed (died) at the time of analyses were censored at their last date of contact. The method of Kaplan and Meier was used to estimate overall survival. The 3-year estimate with a 95% confidence interval is reported. |
| Time Frame | Time from initiation of therapy to the date of death from any cause or to the date patient was known to be alive for surviving patients, assessed to up to 3 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| 53 patients were evaluable for outcome analyses (47 phase II patients + 6 phase I patients treated at the MTD). 50 patients were evaluable; 1 patient withdrew prior to beginning protocol therapy and 2 patients did not receive adequate study drug to be evaluable for efficacy. To be evaluable patients had to receive at least one dose of Veliparib. |
| Arm/Group Title | Phase II Patients + Phase I MTD Patients |
|---|---|
| Arm/Group Description | Phase II patients were those enrolled after the maximum tolerated dose was established in the phase I portion of this trial. Six patients enrolled as phase I patients but who were treated with the established maximum tolerated dose of 65 mg/m2/day twice a day (BID) were also considered phase II patients. There were 53 eligible phase II patients (including the latter six patients). Fifty (50) of these patients were evaluable for outcome analyses as 1 patient withdrew prior to beginning protocol therapy and 2 other patients did not receive adequate study drug to be evaluable for efficacy. To be evaluable for assessing overall survival, patients had to receive at least one dose of Veliparib. |
| Measure Participants | 50 |
| Number (95% Confidence Interval) [Percent probability] |
5.3
|
| Title | Number of Phase I Patients Who Experienced Dose Limiting Toxicities (DLTs) |
|---|---|
| Description | DLTs were defined as any of the following adverse events that were at least possibly attributable to Veliparib observed during the dose finding phase (the first 10 weeks of therapy). Hematologic dose limiting toxicities included grade 3 and higher thrombocytopenia or grade 4 neutropenia. Non-hematologic dose limiting toxicities included any grade 4 non-hematologic toxicity, any grade 3 non-hematologic toxicity with some exceptions (e.g., nausea and vomiting of <5 days; fever or infection of <5 days; hypophosphatemia, hypokalemia, hypocalcemia or hypomagnesemia responsive to oral supplementation; elevation of transaminases that return to levels meeting eligibility criteria within 7 days), or any grade non-hematologic toxicity that persisted for >7 days and considered medically significant or sufficiently intolerable by patients that required treatment interruption. |
| Time Frame | 10 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Phase I, Dose Level 1 (50 mg) | Phase I, Dose Level 2 (65 mg) | Phase I, Dose Level 3 (85 mg) |
|---|---|---|---|
| Arm/Group Description | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. |
| Measure Participants | 6 | 6 | 6 |
| Count of Participants [Participants] |
1
16.7%
|
0
0%
|
3
50%
|
| Title | Progression-free Survival (PFS) |
|---|---|
| Description | PFS was defined as the interval from date of treatment initiation to date of first event (disease progression or relapse, second malignancy or death from any cause). Patients who had not failed at the time of analyses were censored at their last date of contact. The method of Kaplan and Meier was used to estimate PFS. A 3-year estimate with a 95% confidence interval is reported. |
| Time Frame | Time from initiation of treatment to the earliest date of failure (disease progression, death from any cause, or second malignancy), assessed up to 3 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| 53 patients were evaluable for outcome analyses (47 phase II patients + 6 phase I patients treated at the MTD). 50 patients were evaluable; 1 patient withdrew prior to beginning protocol therapy and 2 patients did not receive adequate study drug to be evaluable for efficacy. To be evaluable patients had to receive at least one dose of Veliparib. |
| Arm/Group Title | Phase II Patients + Phase I MTD Patients |
|---|---|
| Arm/Group Description | Phase II patients were those enrolled after the maximum tolerated dose was established in the phase I portion of this trial. Six patients enrolled as phase I patients but who were treated with the established maximum tolerated dose of 65 mg/m2/day twice a day (BID) were also considered phase II patients. There were 53 eligible phase II patients (including the latter six patients). Fifty (50) of these patients were evaluable for outcome analyses as 1 patient withdrew prior to beginning protocol therapy and 2 other patients did not receive adequate study drug to be evaluable for efficacy. To be evaluable for assessing PFS, patients had to receive at least one dose of Veliparib. |
| Measure Participants | 50 |
| Number (95% Confidence Interval) [Percent probability] |
2.9
|
| Title | Percentage of Patients With Pseudo Progression |
|---|---|
| Description | For participants that showed possible tumor progression (pseudo progression) on magnetic resonance imaging (MRI) during the first 6 months of therapy, treating physicians had the option of allowing patients to remain on therapy and repeating the disease assessment in 4-6 weeks. If the repeat MRI at 4-6 weeks showed disease progression, the patient was noted to have true disease progression (and the progression date corresponded to that of the first MRI). If the repeat MRI at 4-6 weeks did not show disease progression, then the patient was noted to have pseudo progression. The percentage of patients observed to have experienced pseudo progression was provided with a 95% confidence interval. |
| Time Frame | Up to 6 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Phase I, Dose Level 1 (50 mg) | Phase I, Dose Level 2 (65 mg) | Phase I, Dose Level 3 (85 mg) | Phase II (MTD) |
|---|---|---|---|---|
| Arm/Group Description | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Patients receive veliparib at the maximum tolerated dose (MTD) orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early (before the phase II study was initiated) as it was not well tolerated. |
| Measure Participants | 6 | 6 | 6 | 47 |
| Number (95% Confidence Interval) [Percentage of participants] |
33.3
555%
|
16.7
278.3%
|
0
0%
|
12.8
27.2%
|
| Title | Maximum Concentration of Veliparib (Cmax) on Days 1 and 4 (Measured in ng/mL) [Pharmacokinetic Parameter] |
|---|---|
| Description | During course 1, blood samples were collected pre-veliparib on day 1, at 0.5, 1, 2, and 6-8 hours after the first dose, pre-veliparib on day 4 (steady state), and 2 hours after the morning dose. Veliparib concentrations were measured using a liquid chromatography tandem mass spectrometry assay and pharmacokinetic parameters were evaluated using a non-compartmental analysis. Cmax measures the highest concentration of drug. |
| Time Frame | Up to day 4 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic studies were optional for the phase II portion of the study. Pharmacokinetic data were not available for all patients as indicated in the outcome measure data table below. |
| Arm/Group Title | Phase I, Dose Level 1 (50 mg) | Phase I, Dose Level 2 (65 mg) | Phase I, Dose Level 3 (85 mg) | Phase II (MTD) |
|---|---|---|---|---|
| Arm/Group Description | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Patients receive veliparib at the maximum tolerated dose (MTD) orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early (before the phase II study was initiated) as it was not well tolerated. |
| Measure Participants | 6 | 6 | 6 | 47 |
| Day 1, Cmax (ng/mL) |
519
(241)
|
843
(364)
|
1074
(372)
|
844
(279)
|
| Day 4, Cmax (ng/mL) |
409
(84)
|
788
(435)
|
954
(348)
|
717
(232)
|
| Title | Mean Apparent Clearance (CL/F) for Veliparib [Pharmacokinetic Parameter] |
|---|---|
| Description | During course 1, blood samples were collected pre-veliparib on day 1, at 0.5, 1, 2, and 6-8 hours after the first dose, pre-veliparib on day 4 (steady state), and 2 hours after the morning dose. Veliparib concentrations were measured using a liquid chromatography tandem mass spectrometry assay and pharmacokinetic parameters were evaluated using a non-compartmental analysis. |
| Time Frame | Up to day 4 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic studies were optional for the phase II portion of the study. 6/6 phase I dose level 1 patients, 6/6 phase I dose level 2 patients, 4/6 phase I dose level 3 patients, and 25/47 phase II patients had this data available. |
| Arm/Group Title | Phase I, Dose Level 1 (50 mg) | Phase I, Dose Level 2 (65 mg) | Phase I, Dose Level 3 (85 mg) | Phase II (MTD) |
|---|---|---|---|---|
| Arm/Group Description | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Patients receive veliparib at the maximum tolerated dose (MTD) orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early (before the phase II study was initiated) as it was not well tolerated. |
| Measure Participants | 6 | 6 | 4 | 25 |
| Mean (Standard Deviation) [L/m^2/h] |
16.1
(8.1)
|
13.2
(4.3)
|
15.8
(8.3)
|
11.7
(8.8)
|
| Title | Maximum Concentration of Veliparib (Cmax) on Day 1 (Measured in μM) [Pharmacokinetic Parameter] |
|---|---|
| Description | During course 1, blood samples were collected pre-veliparib on day 1, at 0.5, 1, 2, and 6-8 hours after the first dose, pre-veliparib on day 4 (steady state), and 2 hours after the morning dose. Veliparib concentrations were measured using a liquid chromatography tandem mass spectrometry assay and pharmacokinetic parameters were evaluated using a non-compartmental analysis. Cmax measures the highest concentration of drug. |
| Time Frame | Day 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic studies were optional for the phase II portion of the study. Pharmacokinetic data were not available for all patients. 6/6 phase I dose level 1, 6/6 phase I dose level 2, 4/6 phase I dose level 3, and 25/47 phase II patients had day 4 Cmax data available. |
| Arm/Group Title | Phase I, Dose Level 1 (50 mg) | Phase I, Dose Level 2 (65 mg) | Phase I, Dose Level 3 (85 mg) | Phase II (MTD) |
|---|---|---|---|---|
| Arm/Group Description | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Patients receive veliparib at the maximum tolerated dose (MTD) orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early (before the phase II study was initiated) as it was not well tolerated. |
| Measure Participants | 6 | 6 | 4 | 25 |
| Mean (Standard Deviation) [μM] |
2.12
(0.98)
|
3.45
(1.49)
|
4.40
(1.52)
|
3.45
(1.14)
|
| Title | Percentage of Participants With Significant Changes in Poly(ADP-ribose) Polymerase (PARP) Levels Post-Veliparib, as Measured in Peripheral Blood Monocytes (PBMCs) |
|---|---|
| Description | Blood samples were collected from patients and assessed pre- and post-Veliparib to assess treatment-induced changes. A significant change in PBMC PARP level was arbitrarily defined as a >50% increase or decrease from the pre-treatment level, documented at week 6 and/or week 11 after starting protocol therapy. |
| Time Frame | Baseline and up to 11 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| Only 27 patients had pre- and post-Veliparib samples available in order to assess treatment-related changes. Two of the patients had inconsistent changes in post-Veliparib PARP levels and therefore were excluded from the analysis, leaving 25 patients for this objective. |
| Arm/Group Title | Phase I, Dose Level 1 (50 mg) | Phase I, Dose Level 2 (65 mg) | Phase I, Dose Level 3 (85 mg) | Phase II (MTD) |
|---|---|---|---|---|
| Arm/Group Description | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3D conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3D conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3D conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Patients receive veliparib at the maximum tolerated dose (MTD) orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo 3D conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early (before the phase II study was initiated) as it was not well tolerated. |
| Measure Participants | 3 | 4 | 4 | 14 |
| Number (95% Confidence Interval) [percentage of participants] |
100
1666.7%
|
100
1666.7%
|
75
1250%
|
36
76.6%
|
| Title | Change in Non-homologous End-joining (NHEJ) Activity as Measured in Peripheral Blood Monocytes (PBMCs) |
|---|---|
| Description | Levels of non-homologous end-joining (NHEJ) activity were to be calculated. Cox models to explore associations between the levels of NHEJ and outcome (progression-free survival and overall survival) were planned, in addition to looking at associations between Poly(ADP-ribose) polymerase (PARP) activity and NHEJ levels. |
| Time Frame | Baseline to up to 3 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| These data were not available as the lab did not perform these analyses. There are no plans to perform these analyses. |
| Arm/Group Title | Phase I, Dose Level 1 (50 mg) | Phase I, Dose Level 2 (65 mg) | Phase I, Dose Level 3 (85 mg) | Phase II (MTD) |
|---|---|---|---|---|
| Arm/Group Description | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3D conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3D conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3D conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Patients receive veliparib at the maximum tolerated dose (MTD) orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo 3D conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early (before the phase II study was initiated) as it was not well tolerated. |
| Measure Participants | 0 | 0 | 0 | 0 |
| Title | Change in Level of Gamma-H2A Histone Family, Member X (H2AX) Measured in PBMCs |
|---|---|
| Description | Levels of gamma-H2A histone family, member X (H2AX) were to be calculated. Cox models to explore associations between the levels of gamma-H2AX and outcome (progression-free survival and overall survival) were planned, in addition to looking at associations between Poly(ADP-ribose) polymerase (PARP) activity and gamma-H2AX levels. |
| Time Frame | Baseline to up to 3 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| These data were not available as the lab did not perform these analyses. There are no plans to perform these analyses. |
| Arm/Group Title | Phase I, Dose Level 1 (50 mg) | Phase I, Dose Level 2 (65 mg) | Phase I, Dose Level 3 (85 mg) | Phase II (MTD) |
|---|---|---|---|---|
| Arm/Group Description | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3D conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3D conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3D conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Patients receive veliparib at the maximum tolerated dose (MTD) orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo 3D conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early (before the phase II study was initiated) as it was not well tolerated. |
| Measure Participants | 0 | 0 | 0 | 0 |
| Title | Levels of Urinary Biomarkers |
|---|---|
| Description | Urine samples were analyzed for a panel of biomarkers. Netrin-1 levels were determined by ELISA. Levels of matrix metalloproteinase 3 (MMP3) and basic fibroblast growth factor (bFGF) were analyzed using custom Luminex® screening assays. Tissue inhibitor of metalloproteinase 1 (TIMP1) levels were analyzed using a Luminex® performance assay. Protein concentrations are given in picograms per microgram (pg/μg), and were determined by dividing the concentration of the target protein in the sample (pg/mL) by the concentration of total protein in the sample (μg/mL) as a normalization measure. |
| Time Frame | Baseline to up to 3 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| Not all patients had urine samples at each time point. |
| Arm/Group Title | Phase I, Dose Level 1 (50 mg) | Phase I, Dose Level 2 (65 mg) | Phase I, Dose Level 3 (85 mg) | Phase II (MTD) |
|---|---|---|---|---|
| Arm/Group Description | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3D conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3D conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3D conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Patients receive veliparib at the maximum tolerated dose (MTD) orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo 3D conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early (before the phase II study was initiated) as it was not well tolerated. |
| Measure Participants | 6 | 6 | 6 | 47 |
| MMP3 at pre-study |
2.0
|
1.0
|
0.0
|
1.1
|
| MMP3 at week 10-11 |
1.4
|
1.0
|
0.8
|
2.6
|
| MMP3 at week 18 |
4.3
|
1.7
|
0.7
|
2.3
|
| MMP3 at week 26 |
2.9
|
0.4
|
1.0
|
3.0
|
| Netrin-1 at pre-study |
0.1
|
0.1
|
0.1
|
0.1
|
| Netrin-1 at week 10-11 |
0.1
|
0.1
|
0.1
|
0.0
|
| Netrin-1 at week 18 |
0.3
|
0.1
|
0.0
|
0.1
|
| Netrin-1 at week 26 |
0.4
|
0.2
|
0.0
|
0.0
|
| TIMP1 at pre-study |
3.4
|
9.9
|
10.8
|
7.3
|
| TIMP1 at week 10-11 |
6.2
|
11.9
|
12.3
|
7.5
|
| TIMP1 at week 18 |
10.7
|
7.7
|
14.8
|
7.1
|
| TIMP1 at week 26 |
7.3
|
5.2
|
32.8
|
10.7
|
| bFGF at pre-study |
3.1
|
1.9
|
1.2
|
4.5
|
| bFGF at week 10-11 |
3.6
|
2.1
|
1.8
|
3.5
|
| bFGF at week 18 |
10.3
|
3.5
|
1.3
|
4.4
|
| bFGF at week 26 |
7.7
|
0.9
|
1.1
|
4.5
|
| Title | Apparent Volume of Distribution (Vd/F) for Veliparib [Pharmacokinetic Parameter] |
|---|---|
| Description | During course 1, blood samples were collected pre-veliparib on day 1, at 0.5, 1, 2, and 6-8 hours after the first dose, pre-veliparib on day 4 (steady state), and 2 hours after the morning dose. Veliparib concentrations were measured using a liquid chromatography tandem mass spectrometry assay and pharmacokinetic parameters were evaluated using a non-compartmental analysis. |
| Time Frame | Up to day 4 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic studies were optional for the phase II portion of the study. 6/6 phase I dose level 1 patients, 6/6 phase I dose level 2 patients, 4/6 phase I dose level 3 patients, and 25/47 phase II patients had this data available. |
| Arm/Group Title | Phase I, Dose Level 1 (50 mg) | Phase I, Dose Level 2 (65 mg) | Phase I, Dose Level 3 (85 mg) | Phase II (MTD) |
|---|---|---|---|---|
| Arm/Group Description | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Patients receive veliparib at the maximum tolerated dose (MTD) orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early (before the phase II study was initiated) as it was not well tolerated. |
| Measure Participants | 6 | 6 | 4 | 25 |
| Mean (Standard Deviation) [L/m^2] |
75.4
(29.2)
|
56.1
(25.4)
|
63.9
(10.6)
|
73.1
(109.7)
|
| Title | Terminal Half-life (t1/2) for Veliparib [Pharmacokinetic Parameter] |
|---|---|
| Description | During course 1, blood samples were collected pre-veliparib on day 1, at 0.5, 1, 2, and 6-8 hours after the first dose, pre-veliparib on day 4 (steady state), and 2 hours after the morning dose. Veliparib concentrations were measured using a liquid chromatography tandem mass spectrometry assay and pharmacokinetic parameters were evaluated using a non-compartmental analysis. |
| Time Frame | Up to day 4 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic studies were optional for the phase II portion of the study. 6/6 phase I dose level 1 patients, 6/6 phase I dose level 2 patients, 4/6 phase I dose level 3 patients, and 25/47 phase II patients had this data available. |
| Arm/Group Title | Phase I, Dose Level 1 (50 mg) | Phase I, Dose Level 2 (65 mg) | Phase I, Dose Level 3 (85 mg) | Phase II (MTD) |
|---|---|---|---|---|
| Arm/Group Description | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Patients receive veliparib at the maximum tolerated dose (MTD) orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early (before the phase II study was initiated) as it was not well tolerated. |
| Measure Participants | 6 | 6 | 4 | 25 |
| Mean (Standard Deviation) [Hour] |
5.18
(6.34)
|
2.62
(0.76)
|
4.45
(4.80)
|
2.18
(2.71)
|
| Title | Trough for Veliparib [Pharmacokinetic Parameter] |
|---|---|
| Description | During course 1, blood samples were collected pre-veliparib on day 1, at 0.5, 1, 2, and 6-8 hours after the first dose, pre-veliparib on day 4 (steady state), and 2 hours after the morning dose. Veliparib concentrations were measured using a liquid chromatography tandem mass spectrometry assay and pharmacokinetic parameters were evaluated using a non-compartmental analysis. |
| Time Frame | Up to day 4 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic studies were optional for the phase II portion of the study. 6/6 phase I dose level 1 patients, 5/6 phase I dose level 2 patients, 4/6 phase I dose level 3 patients, and 20/47 phase II patients had this data available. |
| Arm/Group Title | Phase I, Dose Level 1 (50 mg) | Phase I, Dose Level 2 (65 mg) | Phase I, Dose Level 3 (85 mg) | Phase II (MTD) |
|---|---|---|---|---|
| Arm/Group Description | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Patients receive veliparib at the maximum tolerated dose (MTD) orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo 3-dimensional conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early (before the phase II study was initiated) as it was not well tolerated. |
| Measure Participants | 6 | 5 | 4 | 20 |
| Mean (Standard Deviation) [ng/mL] |
58
(19)
|
140
(173)
|
163
(97)
|
84
(42)
|
Adverse Events
| Time Frame | Approximately 1 year after starting treatment | |||||||
|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | Adverse events (AEs) were graded according to CTCAE v4.0. AEs collected per protocol included: a) grade 1 and 2 AEs if attribution was at least possibly related to veliparib and b) all grade 3+ AEs on treatment and within 30 days off treatment. All AEs collected are reported. As the intra-patient escalation of TMZ during maintenance was by course (rather than patient) and was halted early (only 5(3) patients escalated to 175(200) mg/m2), AEs were not reported separately by course-specific doses. | |||||||
| Arm/Group Title | Phase I, Dose Level 1 (50 mg/m2) | Phase I, Dose Level 2 (65 mg/m2) | Phase I, Dose Level 3 (85 mg/m2) | Phase II (MTD) | ||||
| Arm/Group Description | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent radiation (3D-CRT or IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent radiation (3D-CRT or IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Dose Escalation: Patients receive veliparib orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent radiation (3D-CRT or IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide (TMZ) PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early as it was not well tolerated. | Patients receive veliparib at the maximum tolerated dose (MTD) orally (PO) twice a day (BID) 5 days a week for 6-7 weeks. Patients also undergo concurrent radiation (3D-CRT or IMRT) once a day (QD) 5 days a week for 6-7 weeks. Maintenance Therapy: Beginning 3-4 weeks later, patients receive veliparib PO BID on days 1-5 and temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 10 courses in the absence of disease progression or unacceptable toxicity. All patients start maintenance with 25 mg/m2 BID of veliparib and 135 mg/m2/day of TMZ. Intra-patient escalation of TMZ to 175 mg/m2/day and 200 mg/m2/day in subsequent courses was allowed for patients with minimal toxicities. However this intra-patient dose escalation was halted early (before the phase II study was initiated) as it was not well tolerated. | ||||
All Cause Mortality |
||||||||
| Phase I, Dose Level 1 (50 mg/m2) | Phase I, Dose Level 2 (65 mg/m2) | Phase I, Dose Level 3 (85 mg/m2) | Phase II (MTD) | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 6/6 (100%) | 5/6 (83.3%) | 6/6 (100%) | 40/47 (85.1%) | ||||
Serious Adverse Events |
||||||||
| Phase I, Dose Level 1 (50 mg/m2) | Phase I, Dose Level 2 (65 mg/m2) | Phase I, Dose Level 3 (85 mg/m2) | Phase II (MTD) | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 5/6 (83.3%) | 2/6 (33.3%) | 2/6 (33.3%) | 19/47 (40.4%) | ||||
| Ear and labyrinth disorders | ||||||||
| Hearing impaired | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/47 (0%) | 0 |
| Endocrine disorders | ||||||||
| Cushingoid | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/47 (2.1%) | 1 |
| Eye disorders | ||||||||
| Papilledema | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/47 (2.1%) | 1 |
| Gastrointestinal disorders | ||||||||
| Abdominal pain | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/47 (0%) | 0 |
| Constipation | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 2/47 (4.3%) | 2 |
| Abdominal distension | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/47 (0%) | 0 |
| Dysphagia | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 3/47 (6.4%) | 3 |
| Pancreatitis | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/47 (2.1%) | 1 |
| Vomiting | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 4/47 (8.5%) | 4 |
| General disorders | ||||||||
| Fever | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 2 | 1/47 (2.1%) | 1 |
| Death NOS | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/47 (2.1%) | 1 |
| Fatigue | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 5/47 (10.6%) | 5 |
| Gait disturbance | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/47 (2.1%) | 1 |
| Pain | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/47 (2.1%) | 1 |
| Infections and infestations | ||||||||
| Catheter related infection | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/47 (0%) | 0 |
| Infections and infestations - Other, specify | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/47 (2.1%) | 1 |
| Lung infection | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/47 (4.3%) | 2 |
| Urinary tract infection | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/47 (4.3%) | 2 |
| Injury, poisoning and procedural complications | ||||||||
| Postoperative hemorrhage | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/47 (0%) | 0 |
| Investigations | ||||||||
| Neutrophil count decreased | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/47 (0%) | 0 |
| Platelet count decreased | 2/6 (33.3%) | 2 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/47 (0%) | 0 |
| Weight loss | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/47 (0%) | 0 |
| Lipase increased | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/47 (2.1%) | 1 |
| Lymphocyte count decreased | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/47 (4.3%) | 2 |
| Serum amylase increased | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/47 (2.1%) | 1 |
| Metabolism and nutrition disorders | ||||||||
| Anorexia | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/47 (0%) | 0 |
| Hyponatremia | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 1/47 (2.1%) | 1 |
| Acidosis | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/47 (2.1%) | 1 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 4/47 (8.5%) | 4 |
| Nervous system disorders | ||||||||
| Headache | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 3/47 (6.4%) | 3 |
| Hydrocephalus | 3/6 (50%) | 3 | 1/6 (16.7%) | 1 | 1/6 (16.7%) | 1 | 8/47 (17%) | 9 |
| Intracranial hemorrhage | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/47 (2.1%) | 1 |
| Nervous system disorders - Other, specify | 1/6 (16.7%) | 3 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 1/47 (2.1%) | 1 |
| Depressed level of consciousness | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/6 (33.3%) | 2 | 2/47 (4.3%) | 2 |
| Encephalopathy | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/47 (0%) | 0 |
| Lethargy | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/47 (0%) | 0 |
| Seizure | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 2/47 (4.3%) | 2 |
| Ataxia | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/47 (4.3%) | 2 |
| Cerebrospinal fluid leakage | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/47 (2.1%) | 1 |
| Cognitive disturbance | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/47 (2.1%) | 1 |
| Dizziness | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/47 (2.1%) | 1 |
| Dysarthria | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 4/47 (8.5%) | 4 |
| Hypoglossal nerve disorder | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/47 (2.1%) | 1 |
| Reversible posterior leukoencephalopathy syndrome | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/47 (2.1%) | 1 |
| Somnolence | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 3/47 (6.4%) | 3 |
| Renal and urinary disorders | ||||||||
| Hematuria | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/47 (2.1%) | 1 |
| Renal calculi | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/47 (0%) | 0 |
| Urinary incontinence | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/47 (2.1%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||||||||
| Atelectasis | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/47 (0%) | 0 |
| Respiratory failure | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 4/47 (8.5%) | 4 |
| Hypoxia | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/47 (4.3%) | 2 |
| Respiratory, thoracic and mediastinal disorders - Other, specify | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/47 (2.1%) | 1 |
| Vascular disorders | ||||||||
| Hypertension | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 3/47 (6.4%) | 3 |
| Thromboembolic event | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/47 (2.1%) | 1 |
Other (Not Including Serious) Adverse Events |
||||||||
| Phase I, Dose Level 1 (50 mg/m2) | Phase I, Dose Level 2 (65 mg/m2) | Phase I, Dose Level 3 (85 mg/m2) | Phase II (MTD) | |||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 6/6 (100%) | 6/6 (100%) | 6/6 (100%) | 46/47 (97.9%) | ||||
| Blood and lymphatic system disorders | ||||||||
| Anemia | 4/6 (66.7%) | 11 | 4/6 (66.7%) | 20 | 6/6 (100%) | 13 | 27/47 (57.4%) | 59 |
| Febrile neutropenia | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/47 (0%) | 0 |
| Cardiac disorders | ||||||||
| Palpitations | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/47 (0%) | 0 |
| Sinus bradycardia | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/47 (0%) | 0 |
| Sinus tachycardia | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/47 (0%) | 0 |
| Ear and labyrinth disorders | ||||||||
| Ear pain | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/47 (0%) | 0 |
| External ear inflammation | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/47 (0%) | 0 |
| Endocrine disorders | ||||||||
| Cushingoid | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/47 (2.1%) | 1 |
| Eye disorders | ||||||||
| Blurred vision | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/47 (2.1%) | 1 |
| Eye disorders - Other, specify | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 1/47 (2.1%) | 1 |
| Eye pain | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/47 (2.1%) | 1 |
| Gastrointestinal disorders | ||||||||
| Abdominal pain | 0/6 (0%) | 0 | 2/6 (33.3%) | 3 | 1/6 (16.7%) | 1 | 4/47 (8.5%) | 4 |
| Constipation | 3/6 (50%) | 4 | 5/6 (83.3%) | 6 | 1/6 (16.7%) | 1 | 14/47 (29.8%) | 19 |
| Diarrhea | 2/6 (33.3%) | 3 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 1/47 (2.1%) | 1 |
| Dry mouth | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/47 (0%) | 0 |
| Dysphagia | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 5/47 (10.6%) | 5 |
| Mucositis oral | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/47 (0%) | 0 |
| Nausea | 5/6 (83.3%) | 7 | 5/6 (83.3%) | 7 | 4/6 (66.7%) | 7 | 14/47 (29.8%) | 23 |
| Rectal pain | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/47 (0%) | 0 |
| Stomach pain | 1/6 (16.7%) | 4 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/47 (4.3%) | 3 |
| Vomiting | 2/6 (33.3%) | 3 | 4/6 (66.7%) | 11 | 4/6 (66.7%) | 12 | 21/47 (44.7%) | 35 |
| General disorders | ||||||||
| Fatigue | 4/6 (66.7%) | 4 | 4/6 (66.7%) | 5 | 3/6 (50%) | 7 | 15/47 (31.9%) | 26 |
| Fever | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 2/6 (33.3%) | 2 | 0/47 (0%) | 0 |
| Gait disturbance | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/47 (0%) | 0 |
| Hypothermia | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/47 (0%) | 0 |
| Infusion related reaction | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/47 (0%) | 0 |
| Non-cardiac chest pain | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/47 (0%) | 0 |
| Infections and infestations | ||||||||
| Infections and infestations - Other, specify | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/47 (0%) | 0 |
| Urinary tract infection | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 2/47 (4.3%) | 3 |
| Injury, poisoning and procedural complications | ||||||||
| Dermatitis radiation | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/47 (0%) | 0 |
| Fall | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/47 (0%) | 0 |
| Investigations | ||||||||
| Alanine aminotransferase increased | 3/6 (50%) | 3 | 2/6 (33.3%) | 2 | 0/6 (0%) | 0 | 23/47 (48.9%) | 33 |
| Alkaline phosphatase increased | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/47 (4.3%) | 2 |
| Aspartate aminotransferase increased | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 12/47 (25.5%) | 22 |
| Blood bilirubin increased | 1/6 (16.7%) | 1 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 3/47 (6.4%) | 3 |
| Creatinine increased | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 1/6 (16.7%) | 1 | 2/47 (4.3%) | 3 |
| GGT increased | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/47 (0%) | 0 |
| Hemoglobin increased | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 5/47 (10.6%) | 11 |
| Lymphocyte count decreased | 5/6 (83.3%) | 15 | 6/6 (100%) | 34 | 6/6 (100%) | 27 | 44/47 (93.6%) | 260 |
| Neutrophil count decreased | 3/6 (50%) | 8 | 4/6 (66.7%) | 17 | 5/6 (83.3%) | 24 | 19/47 (40.4%) | 66 |
| Platelet count decreased | 5/6 (83.3%) | 14 | 5/6 (83.3%) | 30 | 4/6 (66.7%) | 18 | 23/47 (48.9%) | 72 |
| Weight gain | 2/6 (33.3%) | 2 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 3/47 (6.4%) | 4 |
| Weight loss | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 2/6 (33.3%) | 3 | 4/47 (8.5%) | 4 |
| White blood cell decreased | 5/6 (83.3%) | 17 | 5/6 (83.3%) | 36 | 5/6 (83.3%) | 22 | 36/47 (76.6%) | 131 |
| Metabolism and nutrition disorders | ||||||||
| Anorexia | 1/6 (16.7%) | 1 | 2/6 (33.3%) | 3 | 4/6 (66.7%) | 4 | 10/47 (21.3%) | 14 |
| Dehydration | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/47 (0%) | 0 |
| Hypercalcemia | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/47 (0%) | 0 |
| Hyperglycemia | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 3/47 (6.4%) | 4 |
| Hyperkalemia | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 5/47 (10.6%) | 7 |
| Hypermagnesemia | 3/6 (50%) | 3 | 2/6 (33.3%) | 2 | 1/6 (16.7%) | 2 | 8/47 (17%) | 11 |
| Hypernatremia | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 2/47 (4.3%) | 4 |
| Hypoalbuminemia | 1/6 (16.7%) | 1 | 2/6 (33.3%) | 3 | 0/6 (0%) | 0 | 18/47 (38.3%) | 33 |
| Hypocalcemia | 2/6 (33.3%) | 2 | 2/6 (33.3%) | 6 | 2/6 (33.3%) | 2 | 9/47 (19.1%) | 21 |
| Hypokalemia | 4/6 (66.7%) | 8 | 0/6 (0%) | 0 | 3/6 (50%) | 4 | 14/47 (29.8%) | 22 |
| Hyponatremia | 1/6 (16.7%) | 1 | 1/6 (16.7%) | 1 | 2/6 (33.3%) | 3 | 6/47 (12.8%) | 6 |
| Hypophosphatemia | 2/6 (33.3%) | 2 | 1/6 (16.7%) | 1 | 4/6 (66.7%) | 5 | 14/47 (29.8%) | 20 |
| Metabolism and nutrition disorders - Other, specify | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/47 (4.3%) | 2 |
| Musculoskeletal and connective tissue disorders | ||||||||
| Arthralgia | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/47 (0%) | 0 |
| Flank pain | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/47 (0%) | 0 |
| Muscle weakness left-sided | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 3/47 (6.4%) | 6 |
| Muscle weakness lower limb | 1/6 (16.7%) | 2 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/47 (0%) | 0 |
| Muscle weakness right-sided | 0/6 (0%) | 0 | 1/6 (16.7%) | 2 | 0/6 (0%) | 0 | 1/47 (2.1%) | 1 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 2/47 (4.3%) | 2 |
| Nervous system disorders | ||||||||
| Abducens nerve disorder | 1/6 (16.7%) | 1 | 1/6 (16.7%) | 1 | 1/6 (16.7%) | 1 | 5/47 (10.6%) | 5 |
| Ataxia | 4/6 (66.7%) | 4 | 3/6 (50%) | 4 | 1/6 (16.7%) | 1 | 5/47 (10.6%) | 9 |
| Dizziness | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 1/47 (2.1%) | 1 |
| Dysarthria | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 4/47 (8.5%) | 5 |
| Dysgeusia | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/47 (0%) | 0 |
| Facial nerve disorder | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 2/47 (4.3%) | 2 |
| Glossopharyngeal nerve disorder | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/47 (0%) | 0 |
| Headache | 2/6 (33.3%) | 3 | 3/6 (50%) | 4 | 4/6 (66.7%) | 5 | 7/47 (14.9%) | 12 |
| IVth nerve disorder | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 1/6 (16.7%) | 1 | 1/47 (2.1%) | 1 |
| Oculomotor nerve disorder | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/47 (2.1%) | 1 |
| Paresthesia | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/47 (2.1%) | 1 |
| Somnolence | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/47 (0%) | 0 |
| Spasticity | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/47 (2.1%) | 1 |
| Tremor | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/47 (2.1%) | 1 |
| Psychiatric disorders | ||||||||
| Anxiety | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/47 (0%) | 0 |
| Depression | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/47 (0%) | 0 |
| Insomnia | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 4/47 (8.5%) | 5 |
| Personality change | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/47 (0%) | 0 |
| Renal and urinary disorders | ||||||||
| Hematuria | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/47 (2.1%) | 1 |
| Urinary frequency | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/47 (0%) | 0 |
| Urinary retention | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/47 (0%) | 0 |
| Urinary tract pain | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/47 (2.1%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||||||||
| Cough | 3/6 (50%) | 3 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 4/47 (8.5%) | 5 |
| Dyspnea | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/47 (0%) | 0 |
| Epistaxis | 1/6 (16.7%) | 1 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/47 (2.1%) | 1 |
| Skin and subcutaneous tissue disorders | ||||||||
| Alopecia | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 5/47 (10.6%) | 5 |
| Dry skin | 2/6 (33.3%) | 2 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/47 (2.1%) | 1 |
| Pruritus | 1/6 (16.7%) | 1 | 1/6 (16.7%) | 1 | 1/6 (16.7%) | 1 | 2/47 (4.3%) | 2 |
| Rash maculo-papular | 1/6 (16.7%) | 1 | 2/6 (33.3%) | 2 | 2/6 (33.3%) | 2 | 5/47 (10.6%) | 6 |
| Skin hyperpigmentation | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/47 (2.1%) | 2 |
| Vascular disorders | ||||||||
| Hypertension | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/47 (4.3%) | 5 |
| Hypotension | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/47 (0%) | 0 |
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
Results Point of Contact
| Name/Title | Catherine Billups |
|---|---|
| Organization | St. Jude Children's Research Hospital |
| Phone | 901-595-3709 |
| catherine.billups@stjude.org |
Responsible Party:
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01514201
Other Study ID Numbers:
- NCI-2012-00082
- NCI-2012-00082
- PBTC-033
- 12-C-0213
- CDR0000717423
- P12978
- PBTC-033
- PBTC-033
- U01CA081457
- UM1CA081457
- NCT01507324
First Posted:
Jan 23, 2012
Last Update Posted:
Aug 13, 2019
Last Verified:
Jul 1, 2019