Anaplastic Astrocytoma, Brain Stem Glioma, Childhood Mixed Glioma, Fibrillary Astrocytoma, Giant Cell Glioblastoma, Glioblastoma, Gliosarcoma, Untreated Childhood Anaplastic Astrocytoma, Untreated Childhood Brain Stem Glioma, Untreated Childhood Fibrillary Astrocytoma, Untreated Childhood Giant Cell Glioblastoma, Untreated Childhood Glioblastoma, Untreated Childhood Gliosarcoma
Conditions
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.
Detailed description
PRIMARY OBJECTIVES: I. 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: I. To estimate the progression-free survival (PFS) distribution and to summarize the best tumor responses observed prior to progression or recurrence. II. 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. IV. 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. V. To explore quantifying PARP activity and deoxyribonucleic acid (DNA)-repair protein levels in biopsied atypical pontine gliomas, if available. VI. To explore associations of molecular parameters from secondary aims III, IV, and V with PFS and overall survival (OS) after conclusion of clinical trial. VII. 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. VIII. 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.
Interventions
RADIATION3-Dimensional Conformal Radiation Therapy
Undergo 3D-CRT
RADIATIONIntensity-Modulated Radiation Therapy
Undergo IMRT
OTHERLaboratory Biomarker Analysis
Optional correlative studies
OTHERPharmacological Study
Correlative studies
DRUGTemozolomide
Given PO
DRUGVeliparib
Given PO
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 21 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
Countries
United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| Phase I, Dose Level 1 (50 mg) 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. | 6 |
| Phase I, Dose Level 2 (65 mg) 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. | 6 |
| Phase I, Dose Level 3 (85 mg) 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. | 6 |
| Phase II (MTD) 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. | 47 |
| Total | 65 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| PHASE II: Maintenance With Veliparib/TMZ | Adverse Event | 0 | 0 | 0 | 4 |
| PHASE II: Maintenance With Veliparib/TMZ | Lack of Efficacy | 0 | 0 | 0 | 22 |
| PHASE II: Maintenance With Veliparib/TMZ | Withdrawal by Subject | 0 | 0 | 0 | 7 |
| PHASE II: Veliparib + Radiation Therapy | Adverse Event | 0 | 0 | 0 | 2 |
| PHASE II: Veliparib + Radiation Therapy | Death | 0 | 0 | 0 | 1 |
| PHASE II: Veliparib + Radiation Therapy | Ineligible | 0 | 0 | 0 | 1 |
| PHASE II: Veliparib + Radiation Therapy | Lack of Efficacy | 0 | 0 | 0 | 2 |
| PHASE II: Veliparib + Radiation Therapy | Withdrawal by Subject | 0 | 0 | 0 | 6 |
| PHASE I: Maintenance With Veliparib/TMZ | Adverse Event | 0 | 1 | 1 | 0 |
| PHASE I: Maintenance With Veliparib/TMZ | Lack of Efficacy | 4 | 4 | 5 | 0 |
| PHASE I: Maintenance With Veliparib/TMZ | Withdrawal by Subject | 1 | 1 | 0 | 0 |
| PHASE I: Veliparib + Radiation Therapy | Lack of Efficacy | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | 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 |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 6 Participants | 6 Participants | 6 Participants | 47 Participants | 65 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 6.3 years | 10.2 years | 9.2 years | 6.5 years | 6.6 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 0 Participants | 0 Participants | 7 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 5 Participants | 5 Participants | 34 Participants | 47 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants | 6 Participants | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 1 Participants | 9 Participants | 12 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 6 Participants | 8 Participants |
| Race (NIH/OMB) White | 3 Participants | 3 Participants | 5 Participants | 29 Participants | 40 Participants |
| Region of Enrollment United States | 6 Participants | 6 Participants | 6 Participants | 47 Participants | 65 Participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 2 Participants | 30 Participants | 37 Participants |
| Sex: Female, Male Male | 4 Participants | 3 Participants | 4 Participants | 17 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 6 | 5 / 6 | 6 / 6 | 40 / 47 |
| other Total, other adverse events | 6 / 6 | 6 / 6 | 6 / 6 | 46 / 47 |
| serious Total, serious adverse events | 5 / 6 | 2 / 6 | 2 / 6 | 19 / 47 |
Outcome results
Primary
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)
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Patients | 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) | 65 mg/m2/dose BID |
Primary
Number of Phase I Patients Who Experienced Dose Limiting Toxicities (DLTs)
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I Patients | Number of Phase I Patients Who Experienced Dose Limiting Toxicities (DLTs) | 1 Participants |
| Dose Level 2 (175 mg/m2) | Number of Phase I Patients Who Experienced Dose Limiting Toxicities (DLTs) | 0 Participants |
| Dose Level 3 (200 mg/m2) | Number of Phase I Patients Who Experienced Dose Limiting Toxicities (DLTs) | 3 Participants |
Primary
Overall Survival
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Patients | Overall Survival | 5.3 Percent probability |
Primary
Percentage of Participants Observed to Have Unacceptable Toxicity During the Intra-patient Dose Escalation of Temozolomide During Maintenance Therapy (Feasibility Analysis Population)
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Patients | Percentage of Participants Observed to Have Unacceptable Toxicity During the Intra-patient Dose Escalation of Temozolomide During Maintenance Therapy (Feasibility Analysis Population) | 9 % of participants |
| Dose Level 2 (175 mg/m2) | Percentage of Participants Observed to Have Unacceptable Toxicity During the Intra-patient Dose Escalation of Temozolomide During Maintenance Therapy (Feasibility Analysis Population) | 40 % of participants |
| Dose Level 3 (200 mg/m2) | Percentage of Participants Observed to Have Unacceptable Toxicity During the Intra-patient Dose Escalation of Temozolomide During Maintenance Therapy (Feasibility Analysis Population) | 67 % of participants |
Comparison: 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.
Secondary
Apparent Volume of Distribution (Vd/F) for Veliparib [Pharmacokinetic Parameter]
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase I Patients | Apparent Volume of Distribution (Vd/F) for Veliparib [Pharmacokinetic Parameter] | 75.4 L/m^2 | Standard Deviation 29.2 |
| Dose Level 2 (175 mg/m2) | Apparent Volume of Distribution (Vd/F) for Veliparib [Pharmacokinetic Parameter] | 56.1 L/m^2 | Standard Deviation 25.4 |
| Dose Level 3 (200 mg/m2) | Apparent Volume of Distribution (Vd/F) for Veliparib [Pharmacokinetic Parameter] | 63.9 L/m^2 | Standard Deviation 10.6 |
| Phase II (MTD) | Apparent Volume of Distribution (Vd/F) for Veliparib [Pharmacokinetic Parameter] | 73.1 L/m^2 | Standard Deviation 109.7 |
Secondary
Maximum Concentration of Veliparib (Cmax) on Day 1 (Measured in μM) [Pharmacokinetic Parameter]
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase I Patients | Maximum Concentration of Veliparib (Cmax) on Day 1 (Measured in μM) [Pharmacokinetic Parameter] | 2.12 μM | Standard Deviation 0.98 |
| Dose Level 2 (175 mg/m2) | Maximum Concentration of Veliparib (Cmax) on Day 1 (Measured in μM) [Pharmacokinetic Parameter] | 3.45 μM | Standard Deviation 1.49 |
| Dose Level 3 (200 mg/m2) | Maximum Concentration of Veliparib (Cmax) on Day 1 (Measured in μM) [Pharmacokinetic Parameter] | 4.40 μM | Standard Deviation 1.52 |
| Phase II (MTD) | Maximum Concentration of Veliparib (Cmax) on Day 1 (Measured in μM) [Pharmacokinetic Parameter] | 3.45 μM | Standard Deviation 1.14 |
Secondary
Maximum Concentration of Veliparib (Cmax) on Days 1 and 4 (Measured in ng/mL) [Pharmacokinetic Parameter]
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I Patients | Maximum Concentration of Veliparib (Cmax) on Days 1 and 4 (Measured in ng/mL) [Pharmacokinetic Parameter] | Day 1, Cmax (ng/mL) | 519 ng/mL | Standard Deviation 241 |
| Phase I Patients | Maximum Concentration of Veliparib (Cmax) on Days 1 and 4 (Measured in ng/mL) [Pharmacokinetic Parameter] | Day 4, Cmax (ng/mL) | 409 ng/mL | Standard Deviation 84 |
| Dose Level 2 (175 mg/m2) | Maximum Concentration of Veliparib (Cmax) on Days 1 and 4 (Measured in ng/mL) [Pharmacokinetic Parameter] | Day 4, Cmax (ng/mL) | 788 ng/mL | Standard Deviation 435 |
| Dose Level 2 (175 mg/m2) | Maximum Concentration of Veliparib (Cmax) on Days 1 and 4 (Measured in ng/mL) [Pharmacokinetic Parameter] | Day 1, Cmax (ng/mL) | 843 ng/mL | Standard Deviation 364 |
| Dose Level 3 (200 mg/m2) | Maximum Concentration of Veliparib (Cmax) on Days 1 and 4 (Measured in ng/mL) [Pharmacokinetic Parameter] | Day 1, Cmax (ng/mL) | 1074 ng/mL | Standard Deviation 372 |
| Dose Level 3 (200 mg/m2) | Maximum Concentration of Veliparib (Cmax) on Days 1 and 4 (Measured in ng/mL) [Pharmacokinetic Parameter] | Day 4, Cmax (ng/mL) | 954 ng/mL | Standard Deviation 348 |
| Phase II (MTD) | Maximum Concentration of Veliparib (Cmax) on Days 1 and 4 (Measured in ng/mL) [Pharmacokinetic Parameter] | Day 1, Cmax (ng/mL) | 844 ng/mL | Standard Deviation 279 |
| Phase II (MTD) | Maximum Concentration of Veliparib (Cmax) on Days 1 and 4 (Measured in ng/mL) [Pharmacokinetic Parameter] | Day 4, Cmax (ng/mL) | 717 ng/mL | Standard Deviation 232 |
Secondary
Mean Apparent Clearance (CL/F) for Veliparib [Pharmacokinetic Parameter]
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase I Patients | Mean Apparent Clearance (CL/F) for Veliparib [Pharmacokinetic Parameter] | 16.1 L/m^2/h | Standard Deviation 8.1 |
| Dose Level 2 (175 mg/m2) | Mean Apparent Clearance (CL/F) for Veliparib [Pharmacokinetic Parameter] | 13.2 L/m^2/h | Standard Deviation 4.3 |
| Dose Level 3 (200 mg/m2) | Mean Apparent Clearance (CL/F) for Veliparib [Pharmacokinetic Parameter] | 15.8 L/m^2/h | Standard Deviation 8.3 |
| Phase II (MTD) | Mean Apparent Clearance (CL/F) for Veliparib [Pharmacokinetic Parameter] | 11.7 L/m^2/h | Standard Deviation 8.8 |
Secondary
Percentage of Patients With Pseudo Progression
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Patients | Percentage of Patients With Pseudo Progression | 33.3 Percentage of participants |
| Dose Level 2 (175 mg/m2) | Percentage of Patients With Pseudo Progression | 16.7 Percentage of participants |
| Dose Level 3 (200 mg/m2) | Percentage of Patients With Pseudo Progression | 0 Percentage of participants |
| Phase II (MTD) | Percentage of Patients With Pseudo Progression | 12.8 Percentage of participants |
Secondary
Progression-free Survival (PFS)
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Patients | Progression-free Survival (PFS) | 2.9 Percent probability |
Secondary
Terminal Half-life (t1/2) for Veliparib [Pharmacokinetic Parameter]
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase I Patients | Terminal Half-life (t1/2) for Veliparib [Pharmacokinetic Parameter] | 5.18 Hour | Standard Deviation 6.34 |
| Dose Level 2 (175 mg/m2) | Terminal Half-life (t1/2) for Veliparib [Pharmacokinetic Parameter] | 2.62 Hour | Standard Deviation 0.76 |
| Dose Level 3 (200 mg/m2) | Terminal Half-life (t1/2) for Veliparib [Pharmacokinetic Parameter] | 4.45 Hour | Standard Deviation 4.8 |
| Phase II (MTD) | Terminal Half-life (t1/2) for Veliparib [Pharmacokinetic Parameter] | 2.18 Hour | Standard Deviation 2.71 |
Secondary
Trough for Veliparib [Pharmacokinetic Parameter]
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase I Patients | Trough for Veliparib [Pharmacokinetic Parameter] | 58 ng/mL | Standard Deviation 19 |
| Dose Level 2 (175 mg/m2) | Trough for Veliparib [Pharmacokinetic Parameter] | 140 ng/mL | Standard Deviation 173 |
| Dose Level 3 (200 mg/m2) | Trough for Veliparib [Pharmacokinetic Parameter] | 163 ng/mL | Standard Deviation 97 |
| Phase II (MTD) | Trough for Veliparib [Pharmacokinetic Parameter] | 84 ng/mL | Standard Deviation 42 |
Other Pre-specified
Change in Level of Gamma-H2A Histone Family, Member X (H2AX) Measured in PBMCs
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
Population: These data were not available as the lab did not perform these analyses. There are no plans to perform these analyses.
Other Pre-specified
Change in Non-homologous End-joining (NHEJ) Activity as Measured in Peripheral Blood Monocytes (PBMCs)
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
Population: These data were not available as the lab did not perform these analyses. There are no plans to perform these analyses.
Other Pre-specified
Levels of Urinary Biomarkers
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
Population: Not all patients had urine samples at each time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase I Patients | Levels of Urinary Biomarkers | MMP3 at pre-study | 2.0 pg/μg |
| Phase I Patients | Levels of Urinary Biomarkers | bFGF at week 10-11 | 3.6 pg/μg |
| Phase I Patients | Levels of Urinary Biomarkers | Netrin-1 at pre-study | 0.1 pg/μg |
| Phase I Patients | Levels of Urinary Biomarkers | TIMP1 at week 18 | 10.7 pg/μg |
| Phase I Patients | Levels of Urinary Biomarkers | bFGF at week 18 | 10.3 pg/μg |
| Phase I Patients | Levels of Urinary Biomarkers | Netrin-1 at week 10-11 | 0.1 pg/μg |
| Phase I Patients | Levels of Urinary Biomarkers | MMP3 at week 18 | 4.3 pg/μg |
| Phase I Patients | Levels of Urinary Biomarkers | TIMP1 at week 26 | 7.3 pg/μg |
| Phase I Patients | Levels of Urinary Biomarkers | TIMP1 at week 10-11 | 6.2 pg/μg |
| Phase I Patients | Levels of Urinary Biomarkers | Netrin-1 at week 18 | 0.3 pg/μg |
| Phase I Patients | Levels of Urinary Biomarkers | TIMP1 at pre-study | 3.4 pg/μg |
| Phase I Patients | Levels of Urinary Biomarkers | MMP3 at week 10-11 | 1.4 pg/μg |
| Phase I Patients | Levels of Urinary Biomarkers | bFGF at pre-study | 3.1 pg/μg |
| Phase I Patients | Levels of Urinary Biomarkers | Netrin-1 at week 26 | 0.4 pg/μg |
| Phase I Patients | Levels of Urinary Biomarkers | MMP3 at week 26 | 2.9 pg/μg |
| Phase I Patients | Levels of Urinary Biomarkers | bFGF at week 26 | 7.7 pg/μg |
| Dose Level 2 (175 mg/m2) | Levels of Urinary Biomarkers | MMP3 at week 10-11 | 1.0 pg/μg |
| Dose Level 2 (175 mg/m2) | Levels of Urinary Biomarkers | TIMP1 at pre-study | 9.9 pg/μg |
| Dose Level 2 (175 mg/m2) | Levels of Urinary Biomarkers | TIMP1 at week 10-11 | 11.9 pg/μg |
| Dose Level 2 (175 mg/m2) | Levels of Urinary Biomarkers | TIMP1 at week 18 | 7.7 pg/μg |
| Dose Level 2 (175 mg/m2) | Levels of Urinary Biomarkers | MMP3 at week 18 | 1.7 pg/μg |
| Dose Level 2 (175 mg/m2) | Levels of Urinary Biomarkers | MMP3 at pre-study | 1.0 pg/μg |
| Dose Level 2 (175 mg/m2) | Levels of Urinary Biomarkers | bFGF at week 18 | 3.5 pg/μg |
| Dose Level 2 (175 mg/m2) | Levels of Urinary Biomarkers | MMP3 at week 26 | 0.4 pg/μg |
| Dose Level 2 (175 mg/m2) | Levels of Urinary Biomarkers | bFGF at week 10-11 | 2.1 pg/μg |
| Dose Level 2 (175 mg/m2) | Levels of Urinary Biomarkers | Netrin-1 at pre-study | 0.1 pg/μg |
| Dose Level 2 (175 mg/m2) | Levels of Urinary Biomarkers | Netrin-1 at week 10-11 | 0.1 pg/μg |
| Dose Level 2 (175 mg/m2) | Levels of Urinary Biomarkers | bFGF at week 26 | 0.9 pg/μg |
| Dose Level 2 (175 mg/m2) | Levels of Urinary Biomarkers | bFGF at pre-study | 1.9 pg/μg |
| Dose Level 2 (175 mg/m2) | Levels of Urinary Biomarkers | Netrin-1 at week 18 | 0.1 pg/μg |
| Dose Level 2 (175 mg/m2) | Levels of Urinary Biomarkers | Netrin-1 at week 26 | 0.2 pg/μg |
| Dose Level 2 (175 mg/m2) | Levels of Urinary Biomarkers | TIMP1 at week 26 | 5.2 pg/μg |
| Dose Level 3 (200 mg/m2) | Levels of Urinary Biomarkers | MMP3 at week 26 | 1.0 pg/μg |
| Dose Level 3 (200 mg/m2) | Levels of Urinary Biomarkers | MMP3 at pre-study | 0.0 pg/μg |
| Dose Level 3 (200 mg/m2) | Levels of Urinary Biomarkers | MMP3 at week 10-11 | 0.8 pg/μg |
| Dose Level 3 (200 mg/m2) | Levels of Urinary Biomarkers | MMP3 at week 18 | 0.7 pg/μg |
| Dose Level 3 (200 mg/m2) | Levels of Urinary Biomarkers | Netrin-1 at pre-study | 0.1 pg/μg |
| Dose Level 3 (200 mg/m2) | Levels of Urinary Biomarkers | Netrin-1 at week 10-11 | 0.1 pg/μg |
| Dose Level 3 (200 mg/m2) | Levels of Urinary Biomarkers | Netrin-1 at week 18 | 0.0 pg/μg |
| Dose Level 3 (200 mg/m2) | Levels of Urinary Biomarkers | Netrin-1 at week 26 | 0.0 pg/μg |
| Dose Level 3 (200 mg/m2) | Levels of Urinary Biomarkers | TIMP1 at pre-study | 10.8 pg/μg |
| Dose Level 3 (200 mg/m2) | Levels of Urinary Biomarkers | TIMP1 at week 10-11 | 12.3 pg/μg |
| Dose Level 3 (200 mg/m2) | Levels of Urinary Biomarkers | TIMP1 at week 18 | 14.8 pg/μg |
| Dose Level 3 (200 mg/m2) | Levels of Urinary Biomarkers | TIMP1 at week 26 | 32.8 pg/μg |
| Dose Level 3 (200 mg/m2) | Levels of Urinary Biomarkers | bFGF at pre-study | 1.2 pg/μg |
| Dose Level 3 (200 mg/m2) | Levels of Urinary Biomarkers | bFGF at week 10-11 | 1.8 pg/μg |
| Dose Level 3 (200 mg/m2) | Levels of Urinary Biomarkers | bFGF at week 18 | 1.3 pg/μg |
| Dose Level 3 (200 mg/m2) | Levels of Urinary Biomarkers | bFGF at week 26 | 1.1 pg/μg |
| Phase II (MTD) | Levels of Urinary Biomarkers | TIMP1 at week 26 | 10.7 pg/μg |
| Phase II (MTD) | Levels of Urinary Biomarkers | Netrin-1 at week 18 | 0.1 pg/μg |
| Phase II (MTD) | Levels of Urinary Biomarkers | Netrin-1 at week 10-11 | 0.0 pg/μg |
| Phase II (MTD) | Levels of Urinary Biomarkers | MMP3 at week 10-11 | 2.6 pg/μg |
| Phase II (MTD) | Levels of Urinary Biomarkers | bFGF at pre-study | 4.5 pg/μg |
| Phase II (MTD) | Levels of Urinary Biomarkers | MMP3 at week 26 | 3.0 pg/μg |
| Phase II (MTD) | Levels of Urinary Biomarkers | Netrin-1 at pre-study | 0.1 pg/μg |
| Phase II (MTD) | Levels of Urinary Biomarkers | MMP3 at pre-study | 1.1 pg/μg |
| Phase II (MTD) | Levels of Urinary Biomarkers | bFGF at week 10-11 | 3.5 pg/μg |
| Phase II (MTD) | Levels of Urinary Biomarkers | MMP3 at week 18 | 2.3 pg/μg |
| Phase II (MTD) | Levels of Urinary Biomarkers | TIMP1 at week 10-11 | 7.5 pg/μg |
| Phase II (MTD) | Levels of Urinary Biomarkers | bFGF at week 26 | 4.5 pg/μg |
| Phase II (MTD) | Levels of Urinary Biomarkers | TIMP1 at week 18 | 7.1 pg/μg |
| Phase II (MTD) | Levels of Urinary Biomarkers | TIMP1 at pre-study | 7.3 pg/μg |
| Phase II (MTD) | Levels of Urinary Biomarkers | Netrin-1 at week 26 | 0.0 pg/μg |
| Phase II (MTD) | Levels of Urinary Biomarkers | bFGF at week 18 | 4.4 pg/μg |
Other Pre-specified
Percentage of Participants With Significant Changes in Poly(ADP-ribose) Polymerase (PARP) Levels Post-Veliparib, as Measured in Peripheral Blood Monocytes (PBMCs)
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Patients | Percentage of Participants With Significant Changes in Poly(ADP-ribose) Polymerase (PARP) Levels Post-Veliparib, as Measured in Peripheral Blood Monocytes (PBMCs) | 100 percentage of participants |
| Dose Level 2 (175 mg/m2) | Percentage of Participants With Significant Changes in Poly(ADP-ribose) Polymerase (PARP) Levels Post-Veliparib, as Measured in Peripheral Blood Monocytes (PBMCs) | 100 percentage of participants |
| Dose Level 3 (200 mg/m2) | Percentage of Participants With Significant Changes in Poly(ADP-ribose) Polymerase (PARP) Levels Post-Veliparib, as Measured in Peripheral Blood Monocytes (PBMCs) | 75 percentage of participants |
| Phase II (MTD) | Percentage of Participants With Significant Changes in Poly(ADP-ribose) Polymerase (PARP) Levels Post-Veliparib, as Measured in Peripheral Blood Monocytes (PBMCs) | 36 percentage of participants |