Objective/Outcomes
The primary objective of this phase 1, dose-finding trial was to determine the maximum tolerated dose of veliparib in patients with newly diagnosed glioblastoma when given daily along with standard radiotherapy and temozolomide. Given the potential for excess myelosuppression, a six patient safety cohort was enrolled to first confirm tolerability of administering six weeks of daily veliparib and temozolomide. If this was well tolerated, the second part of the phase I study would be initiated to determine the maximally tolerated dose of veliparib daily when it is combined with concurrent radiation and temozolomide. Secondary objectives were to assess and describe the plasma pharmacokinetics of veliparib and to describe the toxicity. The primary objective for the planned phase 2 was to estimate overall survival.
Eligibility Criteria
Eligible patients were ≥ 18 years of age with newly diagnosed, histologically-confirmed supratentorial grade IV astrocytoma (GBM), Karnofosky performance status (KPS) ≥ 60%, absolute neutrophil count > 1,500/µL, platelet count > 100,000/µL, hemoglobin ≥ 9.0 g/dL, serum creatinine ≤ 2.0 mg/dL or creatinine clearance ≥ 60 mL/min, total bilirubin ≤ 1.5 mg/dl, and serum transaminases ≤ 2.5-times above the upper limits of institutional normal. Patients in the initial safety cohort of this study were required to have completed standard concurrent RT/TMZ (within 28–42 days of study treatment) including 90% of planned doses of temozolomide without grade ≥ 3 toxicities. Exclusion criteria included pregnancy/breast-feeding; other antineoplastic therapies, life expectancy < 3 months, uncontrolled seizure disorder, inability to swallow/retain oral medication, concurrent cytochrome-P450-inducing anticonvulsants, and comorbidities jeopardizing the ability to receive treatment with reasonable safety.
All subjects provided written informed consent to participate in the trial. The study was reviewed and approved by CTEP and the institutional review boards at each participating ABTC institution.
Study Design
This was an open-label, multi-center, phase 1 study. The maximum tolerated dose (MTD) was a dose producing a dose-limiting-toxicity (DLT) rate at 33% or less. A modified 3 + 3 design with 6 patients per dose cohort was used due to 10 weeks long safety evaluation period that potentially 40–50% patient might drop-out study for early disease progression.
The initial safety group of up to 6 patients included patients who had recently completed standard concurrent RT/TMZ) were then treated with one cycle of low-dose veliparib 10 mg BID along with 6 weeks of once-a day (QD) temozolomide 75 mg/m2/d (no RT). Once this one cycle was complete, patients were permitted to transition to monthly cycles of standard adjuvant temozolomide 150–200 mg/m2/d for five consecutive days each month.
If safety was confirmed, then the phase I component including radiotherapy would proceed enrolling cohorts of 6 patients to pre-specified escalating dose levels of daily veliparib, ranging from 10 mg BID to 100 mg twice-daily BID daily along with TMZ (75 mg/m2/d) for 6 weeks in conjunction with standard radiation 60 Gy in 30 fractions.The protocol specified that if excessive toxicity occurred, de-escalation could be introduced by joint decision of study PI, sponsor, and ABTC leadership to a choice of veliparib 10 mg daily, 10 mg every other day or 10 mg BID 1 week on/1 week off for the 6-week period.
Patients received a single dose of veliparib one day prior to starting combination therapy with TMZ or RT/TMZ for PK testing after the first single dose as described below. Patients without disease progression, as evaluated by MRI 10-weeks after the initiation of veliparib therapy, received up to four maintenance cycles of the same dose of veliparib in the initial safety cohort or six cycles in phase I veliparib/RT/TMZ cohort. Veliparib was to be given BID for 7 days and TMZ 150–200 mg/m2 QD for 5 days, repeated every 28 days, with an imaging evaluation after completing every second maintenance cycle.
All subjects were followed until death, and survival from the date of study enrollment was reported to evaluate for any unexpected adverse results.
A single arm phase II efficacy test at the MTD was planned to include 78 patients with 80% power to detect an observed hazard ratio for death of 0.75 (0.45–0.6) at an alpha level of 0.1 (one-sided) when compared with the reference hazard ratio of 0.6 observed in the phase III trial of RT/TMZ reported by Stupp [19]
Dose-Limiting Toxicities (DLTs)
DLTs were events considered possible or probably related to veliparib alone, veliparibib/TMZ or Veliparib/RT per CTCAE v.3.0 including: ≥ grade 3 nonhematological toxicities not resolving with anticonvulsants or steroid treatment excluding grade 3 nausea and dermatitis. Hematologic toxicity was considered dose limiting if there was 1) ANC ≤ 500/mm3; 2) Platelets ≤ 25,000/mm3; 3) Grade 3 toxicity that prevents administration of > 75% of the planned temozolomide doses for the first cycle; 4) interruption of treatment for > 14 days. All subjects were monitored for safety throughout the trial.
Pharmacokinetics
Plasma samples were collected to define plasma concentration-time profiles. Samples were collected shortly before dosing and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours after the first dose of six weeks of TMZ and again after achieving steady-state conditions on any day of week 3 of the six weeks (omitting the 24 hour specimen). Samples were analyzed by liquid chromatography-mass spectrometry (LC-MS)/mass spectrometry (MS), Agilent 410B Triple Quadrupole LC/MS system (Agilent Technologies, Inc., Santa Clara, CA).
The plasma concentration-time data for veliparib was analyzed by noncompartmental methods using model 200 for extravascular input in WinNonlin Professional version 5.0.1. Samples with concentrations below the LLQ of the assay were excluded. The maximum concentration of the drug achieved in plasma (Cmax) and the time that it occurred (tmax) were based upon the observed values following a given dose. Area under the plasma concentration-time curves for 8 h (AUC8) and 24 h (AUC24) after dosing were estimated using the log- linear trapezoidal algorithm. Routines provided in the Data Analysis ToolPak of Microsoft Excel 2003 (11.8231.8221) SP3, Professional Edition (Redmond, WA), were used for the descriptive statistics and statistical tests. Arithmetic averages and standard deviations were calculated for the time of the maximum drug concentration in plasma (tmax). Geometric means were calculated for all other pharmacokinetic variables. The jackknife technique was used to estimate the standard deviation of geometric means.