Small Cell Lung Cancer
Conditions
Keywords
Extensive Stage Smal Cell Lung Cancer, ABT-888, Veliparib, PARP - Poly (ADP) ribose polymerase
Brief summary
The study seeks to assess the efficacy of veliparib (ABT-888) in combination with carboplatin and etoposide in participants with extensive disease small cell lung cancer (ED SCLC).
Detailed description
This is a Phase 1, open-label, dose-escalation/Phase 2 randomized double-blind study of veliparib in combination with carboplatin and etoposide and maintenance veliparib monotherapy. Participants in Phase 1 will be sequentially assigned to ascending dose levels of veliparib in combination with standard carboplatin/etoposide regimen for up to four 21-day cycles based on the observed toxicities. The study design for Phase 1 will follow a traditional 3 + 3 dose-escalation protocol. Once the veliparib recommended Phase 2 dose (RPTD) and schedule is determined, enrollment into Phase 2 will begin. Participants from the Phase 1 dose-escalation portion of the study are not eligible for enrollment into the Phase 2 portion. Participants in Phase 2 will be randomized in a 1:1:1 ratio to carboplatin, etoposide, placebo followed by placebo maintenance (Arm C), or carboplatin, etoposide, veliparib followed by either veliparib (Arm A) or placebo (Arm B) maintenance. Randomization for Phase 2 will be stratified by baseline lactate dehydrogenase (LDH) level (\> upper limit of normal \[ULN\] vs. ≤ ULN), and gender.
Interventions
DRUGVeliparib
Capsules administered orally twice a day according to the dosing schedule.
DRUGCarboplatin
Administered by intravenous infusion on Day 1 of each 21-day cycle over approximately 30 minutes at a target area under the curve (AUC) 5 mg/mL\*minute.
DRUGEtoposide
Administered by intravenous infusion on Days 1 to 3 of every 21-day cycle over approximately 60 minutes at 100 mg/m².
DRUGPlacebo
Placebo to veliparib administered orally twice a day according to the dosing schedule.
Sponsors
AbbVie
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Phase 1 was open-label, phase 2 was conducted in a double-blind manner.
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
1. Subject with histologically or cytologically confirmed extensive-stage disease SCLC which is newly diagnosed and chemotherapy naive 2. Phase 1 ONLY: histologically or cytologically confirmed advanced/metastatic solid tumors for which carboplatin/etoposide treatment is considered appropriate. 3. Subject in Phase 2 only: must have measurable disease per RECIST 1.1. 4. Subjects with ED SCLC must consent to provide available archived formalin fixed paraffin embedded (FFPE) tissue sample of SCLC lesion (primary or metastatic) for central review and biomarker analysis. 5. Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 1. 6. Subject must have adequate hematologic, renal and hepatic function.
Exclusion criteria
1. Phase 1 ONLY: Subject has had any prior anti-cancer therapy other than: Hormonal, non-myelosuppressive, biologic, targeted, or immune therapy (must be completed ≥ 4 weeks prior to Cycle 1 Day -2). One line of cytotoxic chemotherapy (must be completed ≥ 4 weeks prior to Cycle 1 Day -2). Adjuvant/neoadjuvant radiotherapy (must be completed ≥ 12 months prior to Cycle 1 Day -2, with field not involving \> 10% of bone marrow reserve). 2. Phase 2 ONLY: Subject has had any prior chemotherapy, radiotherapy, investigational anti-cancer agents or biologic therapy for the disease under study. Single non-target lesion irradiation with intent of symptom palliation is allowed if ≥ 4 weeks prior Cycle 1 Day -2. 3. Subject has current central nervous system (CNS) or leptomeningeal metastases or history of CNS or leptomeningeal metastases. 4. Subject has a history of seizures within 12 months of Cycle 1 Day-2 or diagnosed neurological condition placing subject at the increased risk of seizures. 5. Subject has received anti-cancer Chinese medicine or anti-cancer herbal remedies within 14 days prior to Cycle 1 Day-2. 6. Subject has had major surgery within 6 weeks prior to Cycle 1 Day-2 (subjects must have completely recovered from any previous surgery prior Cycle 1 Day-2). 7. Subject has clinically significant and uncontrolled major medical condition(s) including but not limited to: * Uncontrolled nausea/vomiting/diarrhea; * Active uncontrolled infection; * History of hepatitis B (HBV) with surface antigen (HBsAg) positivity within 3 months prior to the date of informed consent for this study (if no test has been performed within 3 months, it must be done at screening); * History of hepatitis C (HCV) with HCV ribonucleic acid (RNA) positivity within 3 months prior to the date of informed consent for this study (if no test has been performed within 3 months it must be done at screening); * Symptomatic congestive heart failure (Yew York Heart Association \[NYHA\] class ≥ II); * Unstable angina pectoris or cardiac arrhythmia (except atrial fibrillation); * Psychiatric illness/social situation that would limit compliance with study requirements; * Any other medical condition, which in the opinion of the Investigator, places the subject at an unacceptably high risk for toxicities. 8. The subject has a history of another active cancer within the past 3 years except cervical cancer in situ, in situ carcinoma of the bladder, squamous or basal cell carcinoma of the skin or another in situ cancer that is considered cured by the investigator (e.g., in situ prostate cancer, breast DCIS).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: Progression-free Survival | From randomization up to the date the 126th PFS event was reached; Median time on follow-up was 7.3, 7.1, and 8.9 months in each treatment group respectively. | Progression-free survival (PFS) is defined as the time from the date of randomization to the date of earliest radiographic disease progression or death provided no radiographic disease progression occurred. If a participant did not have an event of disease progression and had not died on or prior to the cutoff for PFS analysis, the participant's data was censored at the date of their last disease assessment or randomization date provided participant did not have any post-baseline disease assessment. Disease assessments were performed using computed tomography according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. Progressive Disease (PD) was defined as at least a 20% increase in the size of target lesions and an absolute increase of at least 5 mm taking as reference the smallest lesion size recorded since the treatment started (baseline or after), or the appearance of one or more new lesions. |
| Phase 1: Dose-normalized Maximum Observed Plasma Concentration (Cmax) of Etoposide With and Without Veliparib | Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose. | Etoposide plasma concentrations were determined using liquid chromatography with tandem mass spectrometric detection with a lower limit of quantitation 160 ng/mL. Dose normalized Cmax is calculated as Cmax / etoposide dose in mg/m². |
| Phase 1: Dose-normalized Area Under the Concentration-time Curve From Time 0 to Time of Last Measurable Concentration (AUC[0-t]) of Etoposide With and Without Veliparib | Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose. | The area under the plasma concentration-time curve from 0 to the last measurable concentration (24 hours) of etoposide was estimated using using non-compartmental methods. Dose normalized AUC(0-t) is calculated as AUC(0-t) / etoposide dose in mg/m². |
| Phase 1: Dose-normalized Area Under the Concentration-time Curve From Time 0 to Infinity (AUC[0-∞]) of Etoposide With and Without Veliparib | Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose. | The area under the plasma concentration-time curve from 0 to infinity for etoposide was estimated using using non-compartmental methods. Dose normalized AUC(0-∞) is calculated as AUC(0-∞) / etoposide dose in mg/m². |
| Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) | Cycle 1 Day -2 to pre-dose on Cycle 2 Day 1 (23 days) | A DLT was defined as any of the following drug-related toxicities, graded according to the Common Toxicity Criteria for Adverse Events (CTCAE), V.4.0: 1. Events associated with treatment delay \>14 days in initiating Cycle 2 therapy: Grade 4 thrombocytopenia, neutropenia, or febrile neutropenia, or Grade 3 febrile neutropenia with fever for \> 7 days 2. Grade ≥ 3 non-hematologic toxicity with ≥ 2 grade increase from baseline and attributed to veliparib treatment, excluding nausea or vomiting for ≤ 48 hours or inadequately treated, electrolyte abnormalities resolving in ≤ 24 hours, hypersensitivity reactions or alopecia 3. Grade 2 non-hematologic toxicity of ≥ 2 grade increase from baseline, attributed to veliparib treatment requiring delay of \>14 days in initiation of Cycle 2 4. Any toxicity of ≥ 2-grade increase from baseline, attributed to veliparib and requiring a dose modification in Cycle 1 or omission of carboplatin, \>1 daily etoposide dose, or \>30% veliparib doses in Cycle 1 |
| Phase 1: Maximum Observed Plasma Concentration (Cmax) of Veliparib | Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose | Plasma concentrations of veliparib were determined using a validated online solid-phase extraction followed by high-performance liquid chromatography with tandem mass spectrometric detection (HPLC LC-MS/MS). The lower limit of quantitation (LLOQ) for veliparib was established at ≥ 1.05 ng/mL. |
| Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Veliparib | Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose | Plasma concentrations of veliparib were determined using a validated online solid-phase extraction followed by high-performance liquid chromatography with tandem mass spectrometric detection (HPLC LC-MS/MS). The lower limit of quantitation (LLOQ) for veliparib was established at ≥ 1.05 ng/mL. |
| Phase 1: Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose (AUC[0-8]) of Veliparib | Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose | The area under the plasma concentration-time curve from time 0 to 8 hours post-dose for veliparib was estimated using non-compartmental methods. |
| Phase 1: Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours Post-dose (AUC[0-12]) of Veliparib | Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose | The area under the plasma concentration-time curve from time 0 to 12 hours post-dose for veliparib was estimated using non-compartmental methods. AUC(0-12) was calculated by assuming the concentration at 12 hours post-dose was the same as the pre-dose concentration. |
| Phase 1: Dose-normalized Maximum Observed Plasma Concentration of Veliparib | Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose | Plasma concentrations of veliparib were determined using a validated online solid-phase extraction followed by high-performance liquid chromatography with tandem mass spectrometric detection (HPLC LC-MS/MS). The lower limit of quantitation (LLOQ) for veliparib was established at ≥ 1.05 ng/mL. Dose normalized Cmax is calculated as Cmax / veliparib dose in mg. |
| Phase 1: Dose-normalized Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose of Veliparib | Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose | The area under the plasma concentration-time curve from time 0 to 8 hours post-dose for veliparib was estimated using non-compartmental methods. Dose normalized AUC(0-8) is calculated as AUC(0-8) / veliparib dose in mg. |
| Phase 1: Dose-normalized Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours Post-dose of Veliparib | Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose | The area under the plasma concentration-time curve from time 0 to 12 hours post-dose for veliparib was estimated using non-compartmental methods. AUC(0-12) was calculated by assuming the concentration at 12 hours post-dose was the same as the pre-dose concentration. Dose normalized AUC(0-12) is calculated as AUC(0-12) / veliparib dose in mg. |
| Phase 1: Maximum Observed Plasma Concentration (Cmax) of Etoposide With and Without Veliparib | Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose. | Etoposide plasma concentrations were determined using liquid chromatography with tandem mass spectrometric detection with a lower limit of quantitation 160 ng/mL. |
| Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Etoposide With and Without Veliparib | Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose. | Etoposide plasma concentrations were determined using liquid chromatography with tandem mass spectrometric detection with a lower limit of quantitation 160 ng/mL. |
| Phase 1: Area Under the Concentration-time Curve From Time 0 to Time of Last Measurable Concentration (AUC[0-t]) of Etoposide With and Without Veliparib | Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose. | The area under the plasma concentration-time curve from 0 to the last measurable concentration (24 hours) of etoposide was estimated using using non-compartmental methods. |
| Phase 1: Area Under the Concentration-time Curve From Time 0 to Infinity (AUC[0-∞]) of Etoposide With and Without Veliparib | Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose. | The area under the plasma concentration-time curve from 0 to infinity for etoposide was estimated using using non-compartmental methods. |
| Phase 1: Terminal Phase Elimination Half-life (t1/2) of Etoposide With and Without Veliparib | Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose. | The terminal half-life of etoposide was estimated using using non-compartmental methods. Values reported represent the harmonic mean ± pseudo-standard deviation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: Objective Response Rate | Tumor assessments were performed every 6 weeks for the first 30 weeks and every 9 weeks thereafter until disease progression; median time on follow-up was 7.3, 7.1, and 8.9 months in each group respectively. | Objective response rate (ORR) is defined as the percentage of participants with objective response (confirmed) as assessed by the investigator using RECIST version 1.1. Objective response includes both complete response (CR) and partial response (PR). Response must be confirmed at a subsequent tumor assessment at least 28 days apart. Participants with no post-baseline confirmed response were counted as non-responders. CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. No new lesions. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, and no new lesions. |
| Phase 1: Number of Participants With Adverse Events | From first dose of any study drug to 30 days after the last dose; the median duration of treatment with veliparib across all groups in Phase 1 was 127.5 days. | The intensity of each adverse event (AE) was assessed utilizing the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0, and according to the following: Grade 1 (Mild): AE is transient and easily tolerated by the participant; Grade 2 (Moderate): AE causes the participant discomfort and interrupts the participant's usual activities; Grade 3/4 (Severe): The adverse event causes considerable interference with the participant's usual activities and may be incapacitating or life-threatening; Grade 5: Death. Serious adverse events were those that resulted in death, were life-threatening, required hospitalization or prolongation of hospitalization, resulted in congenital anomaly, or persistent or significant disability/incapacity. |
| Phase 2: Overall Survival | From randomization until the end of study; median time on follow-up was 10.0, 8.6, and 11.7 months in each treatment group respectively. | Overall survival (OS) is defined as the time from the date of randomization to the date of death. If a participant did not die on or prior to the cut-off for OS analysis, the participant's data were censored at the date of their last known alive date, which is defined as the last date of the last survival follow-up visit, the start date of the last AE, the start date or end date of the last dose of any study drugs, the last lab and vital sign collection date, or the last disease assessment date, whichever occurred last. |
Countries
Australia, Belgium, Canada, Czechia, France, Hungary, Netherlands, Romania, Russia, South Korea, Spain, United States
Participant flow
Recruitment details
The study was conducted at 52 study sites located in 12 countries (Australia, Belgium, Canada, Czech Republic, France, Hungary, Korea, the Netherlands, Romania, Russian Federation, Spain, United States).
Pre-assignment details
Participants in Phase 1 were sequentially assigned to ascending dose levels of veliparib in combination with standard carboplatin/etoposide regimen. Participants in Phase 2 were randomized equally to placebo, carboplatin/etoposide followed by placebo maintenance, or to veliparib, carboplatin/etoposide followed by veliparib or placebo maintenance.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide Participants received 80 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 5 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered intravenously (IV) on Day 1 at a target AUC 5 mg/mL\*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle.
Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | 4 |
| Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide Participants received 120 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 5 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL\*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle.
Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | 3 |
| Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide Participants received 160 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 5 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL\*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle.
Participants without evidence of disease pParticipants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | 4 |
| Phase 1: Veliparib 200 mg BID 7 Days + Carboplatin/Etoposide Participants received 200 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 5 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL\*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle.
Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | 3 |
| Phase 1: Veliparib 240 mg BID 7 Days + Carboplatin/Etoposide Participants received 240 mg veliparib orally BID on Days -2 to 5 (7 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 5 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL\*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle.
Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | 8 |
| Phase 1: Veliparib 240 mg BID 14 Days + Carboplatin/Etoposide Participants received 240 mg veliparib orally BID on Days -2 to 12 (14 days) in combination with carboplatin/etoposide for up to four 21-day cycles, with the exception of Cycle 2, when veliparib was administered on Days 2 to 12 to allow for evaluation of potential impact of veliparib on etoposide pharmacokinetics. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL\*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle.
Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | 14 |
| Phase 1: Veliparib 240 mg BID 21 Days + Carboplatin/Etoposide Participants received 240 mg veliparib orally BID on Days -2 to Day 19 (continuous schedule) in combination with carboplatin/etoposide for up to four 21-day cycles. Carboplatin was administered IV on Day 1 at a target AUC 5 mg/mL\*minute and etoposide 100 mg/m² IV on Days 1 to 3 of every 21-day cycle.
Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | 4 |
| Phase 2: Veliparib + Carboplatin/Etoposide -> Veliparib Participants received veliparib 240 mg BID on Day -2 to 12 (14-day schedule), carboplatin AUC 5 mg/mL\*min administered on Day 1, and etoposide 100 mg/m² administered on Days 1 to 3 of each 21-day cycle for up to 6 cycles.
Participants without evidence of disease progression continued on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | 61 |
| Phase 2: Veliparib + Carboplatin/Etoposide -> Placebo Participants received veliparib 240 mg BID on Day -2 to 12 (14-day schedule), carboplatin AUC 5 mg/mL\*min administered on Day 1, and etoposide 100 mg/m² administered on Days 1 to 3 of each 21-day cycle for up to 6 cycles.
Participants without evidence of disease progression received placebo monotherapy BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | 59 |
| Phase 2: Placebo + Carboplatin/Etoposide -> Placebo Participants received placebo BID on Day -2 to 12 (14-day schedule), carboplatin AUC 5 mg/mL\*min on Day 1, and etoposide 100 mg/m² on Days 1 to 3 of each 21-day cycle for up to 6 cycles.
Participants without evidence of disease progression received placebo monotherapy BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. | 61 |
| Total | 221 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event Related to Progression | 0 | 1 | 1 | 0 | 1 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 49 | 45 | 41 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 2 |
| Overall Study | Other | 0 | 0 | 0 | 1 | 1 | 0 | 1 | 2 | 3 | 1 |
| Overall Study | Progressive Disease, Per Protocol | 3 | 2 | 3 | 2 | 5 | 13 | 2 | 0 | 0 | 0 |
| Overall Study | Sponsor Discontinued Study | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 9 | 7 | 15 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 4 | 2 |
Baseline characteristics
| Characteristic | Phase 1: Veliparib 200 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID 14 Days + Carboplatin/Etoposide | Phase 1: Veliparib 240 mg BID 21 Days + Carboplatin/Etoposide | Total | Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide | Phase 2: Veliparib + Carboplatin/Etoposide -> Veliparib | Phase 2: Veliparib + Carboplatin/Etoposide -> Placebo | Phase 2: Placebo + Carboplatin/Etoposide -> Placebo |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous Phase 1 | 54.0 years | 52.0 years | 69.0 years | 74.0 years | 66.0 years | 59.0 years | 62.5 years | 62.5 years | — | — | — |
| Age, Continuous Phase 2 | — | — | — | — | — | — | 63.0 years | — | 62.0 years | 64.0 years | 63.0 years |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 - Fully active | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 3 Participants | 2 Participants | 71 Participants | 1 Participants | 21 Participants | 16 Participants | 23 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 - Restricted but ambulatory | 2 Participants | 5 Participants | 2 Participants | 3 Participants | 11 Participants | 1 Participants | 145 Participants | 3 Participants | 39 Participants | 42 Participants | 37 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Missing | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 5 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 18 Participants | 0 Participants | 4 Participants | 7 Participants | 7 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Missing | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 3 Participants | 8 Participants | 3 Participants | 4 Participants | 14 Participants | 4 Participants | 198 Participants | 4 Participants | 55 Participants | 51 Participants | 52 Participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 0 Participants | 3 Participants | 5 Participants | 1 Participants | 79 Participants | 2 Participants | 21 Participants | 21 Participants | 23 Participants |
| Sex: Female, Male Male | 2 Participants | 6 Participants | 3 Participants | 1 Participants | 9 Participants | 3 Participants | 142 Participants | 2 Participants | 40 Participants | 38 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 3 | 1 / 4 | 1 / 3 | 0 / 8 | 0 / 14 | 0 / 4 | 50 / 61 | 45 / 59 | 41 / 61 |
| other Total, other adverse events | 4 / 4 | 3 / 3 | 4 / 4 | 3 / 3 | 8 / 8 | 14 / 14 | 4 / 4 | 57 / 60 | 53 / 58 | 53 / 60 |
| serious Total, serious adverse events | 3 / 4 | 1 / 3 | 3 / 4 | 2 / 3 | 3 / 8 | 6 / 14 | 3 / 4 | 33 / 60 | 39 / 58 | 27 / 60 |
Outcome results
Primary
Phase 1: Area Under the Concentration-time Curve From Time 0 to Infinity (AUC[0-∞]) of Etoposide With and Without Veliparib
The area under the plasma concentration-time curve from 0 to infinity for etoposide was estimated using using non-compartmental methods.
Time frame: Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose.
Population: Phase 1 participants who received at least 1 dose of study drug, had at least 1 reported PK concentration for each time point and for whom AUC could be calculated. Participants in the Veliparib 240 mg BID 21-day (continuous) dosing group and participants whose etoposide dose was reduced in Cycle 2 are not included in the Cycle 2 Day 1 analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Area Under the Concentration-time Curve From Time 0 to Infinity (AUC[0-∞]) of Etoposide With and Without Veliparib | 112 μg*h/mL | Geometric Coefficient of Variation 56 |
| Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Area Under the Concentration-time Curve From Time 0 to Infinity (AUC[0-∞]) of Etoposide With and Without Veliparib | 99.5 μg*h/mL | Geometric Coefficient of Variation 18 |
Primary
Phase 1: Area Under the Concentration-time Curve From Time 0 to Time of Last Measurable Concentration (AUC[0-t]) of Etoposide With and Without Veliparib
The area under the plasma concentration-time curve from 0 to the last measurable concentration (24 hours) of etoposide was estimated using using non-compartmental methods.
Time frame: Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose.
Population: Phase 1 participants who received at least 1 dose of study drug, had at least 1 reported PK concentration for each time point and for whom AUC could be calculated. Participants in the Veliparib 240 mg BID 21-day (continuous) dosing group and participants whose etoposide dose was reduced in Cycle 2 are not included in the Cycle 2 Day 1 analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Area Under the Concentration-time Curve From Time 0 to Time of Last Measurable Concentration (AUC[0-t]) of Etoposide With and Without Veliparib | 102 μg*h/mL | Geometric Coefficient of Variation 23 |
| Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Area Under the Concentration-time Curve From Time 0 to Time of Last Measurable Concentration (AUC[0-t]) of Etoposide With and Without Veliparib | 94.7 μg*h/mL | Geometric Coefficient of Variation 18 |
Primary
Phase 1: Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours Post-dose (AUC[0-12]) of Veliparib
The area under the plasma concentration-time curve from time 0 to 12 hours post-dose for veliparib was estimated using non-compartmental methods. AUC(0-12) was calculated by assuming the concentration at 12 hours post-dose was the same as the pre-dose concentration.
Time frame: Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose
Population: Phase 1 participants who were administered at least 1 dose of study drug, had at least 1 reported PK sample concentration and for whom AUC(0-12) could be calculated.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours Post-dose (AUC[0-12]) of Veliparib | 4.07 μg*h/mL | Geometric Coefficient of Variation 15 |
| Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours Post-dose (AUC[0-12]) of Veliparib | 5.25 μg*h/mL | Geometric Coefficient of Variation 27 |
| Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours Post-dose (AUC[0-12]) of Veliparib | 9.71 μg*h/mL | Geometric Coefficient of Variation 31 |
| Phase 1: Veliparib 200 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours Post-dose (AUC[0-12]) of Veliparib | 8.35 μg*h/mL | Geometric Coefficient of Variation 6 |
| Phase 1: Veliparib 240 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours Post-dose (AUC[0-12]) of Veliparib | 11.6 μg*h/mL | Geometric Coefficient of Variation 40 |
Primary
Phase 1: Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose (AUC[0-8]) of Veliparib
The area under the plasma concentration-time curve from time 0 to 8 hours post-dose for veliparib was estimated using non-compartmental methods.
Time frame: Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose
Population: Phase 1 participants who were administered at least 1 dose of study drug, had at least 1 reported PK sample concentration and for whom AUC(0-8) could be calculated.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose (AUC[0-8]) of Veliparib | 3.18 μg*h/mL | Geometric Coefficient of Variation 14 |
| Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose (AUC[0-8]) of Veliparib | 4.24 μg*h/mL | Geometric Coefficient of Variation 25 |
| Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose (AUC[0-8]) of Veliparib | 7.51 μg*h/mL | Geometric Coefficient of Variation 28 |
| Phase 1: Veliparib 200 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose (AUC[0-8]) of Veliparib | 6.66 μg*h/mL | Geometric Coefficient of Variation 4 |
| Phase 1: Veliparib 240 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose (AUC[0-8]) of Veliparib | 9.29 μg*h/mL | Geometric Coefficient of Variation 37 |
Primary
Phase 1: Dose-normalized Area Under the Concentration-time Curve From Time 0 to Infinity (AUC[0-∞]) of Etoposide With and Without Veliparib
The area under the plasma concentration-time curve from 0 to infinity for etoposide was estimated using using non-compartmental methods. Dose normalized AUC(0-∞) is calculated as AUC(0-∞) / etoposide dose in mg/m².
Time frame: Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose.
Population: Phase 1 participants who received at least 1 dose of study drug, had at least 1 reported PK concentration for each time point and for whom AUC could be calculated. Participants in the Veliparib 240 mg BID 21-day (continuous) dosing group are not included in the Cycle 2 Day 1 analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Dose-normalized Area Under the Concentration-time Curve From Time 0 to Infinity (AUC[0-∞]) of Etoposide With and Without Veliparib | 1120 (ng*h/mL)/(mg/m²) | Geometric Coefficient of Variation 56 |
| Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Dose-normalized Area Under the Concentration-time Curve From Time 0 to Infinity (AUC[0-∞]) of Etoposide With and Without Veliparib | 1020 (ng*h/mL)/(mg/m²) | Geometric Coefficient of Variation 20 |
Primary
Phase 1: Dose-normalized Area Under the Concentration-time Curve From Time 0 to Time of Last Measurable Concentration (AUC[0-t]) of Etoposide With and Without Veliparib
The area under the plasma concentration-time curve from 0 to the last measurable concentration (24 hours) of etoposide was estimated using using non-compartmental methods. Dose normalized AUC(0-t) is calculated as AUC(0-t) / etoposide dose in mg/m².
Time frame: Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose.
Population: Phase 1 participants who received at least 1 dose of study drug, had at least 1 reported PK concentration for each time point and for whom AUC could be calculated. Participants in the Veliparib 240 mg BID 21-day (continuous) dosing group are not included in the Cycle 2 Day 1 analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Dose-normalized Area Under the Concentration-time Curve From Time 0 to Time of Last Measurable Concentration (AUC[0-t]) of Etoposide With and Without Veliparib | 1020 (ng*h/mL)/(mg/m²) | Geometric Coefficient of Variation 23 |
| Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Dose-normalized Area Under the Concentration-time Curve From Time 0 to Time of Last Measurable Concentration (AUC[0-t]) of Etoposide With and Without Veliparib | 952 (ng*h/mL)/(mg/m²) | Geometric Coefficient of Variation 21 |
Primary
Phase 1: Dose-normalized Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours Post-dose of Veliparib
The area under the plasma concentration-time curve from time 0 to 12 hours post-dose for veliparib was estimated using non-compartmental methods. AUC(0-12) was calculated by assuming the concentration at 12 hours post-dose was the same as the pre-dose concentration. Dose normalized AUC(0-12) is calculated as AUC(0-12) / veliparib dose in mg.
Time frame: Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose
Population: Phase 1 participants who were administered at least 1 dose of study drug, had at least 1 reported PK sample concentration and for whom AUC(0-12) could be calculated.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Dose-normalized Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours Post-dose of Veliparib | 50.9 (ng*h/mL)/mg | Geometric Coefficient of Variation 15 |
| Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Dose-normalized Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours Post-dose of Veliparib | 43.8 (ng*h/mL)/mg | Geometric Coefficient of Variation 27 |
| Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Dose-normalized Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours Post-dose of Veliparib | 60.7 (ng*h/mL)/mg | Geometric Coefficient of Variation 31 |
| Phase 1: Veliparib 200 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Dose-normalized Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours Post-dose of Veliparib | 41.7 (ng*h/mL)/mg | Geometric Coefficient of Variation 6 |
| Phase 1: Veliparib 240 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Dose-normalized Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours Post-dose of Veliparib | 48.5 (ng*h/mL)/mg | Geometric Coefficient of Variation 40 |
Primary
Phase 1: Dose-normalized Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose of Veliparib
The area under the plasma concentration-time curve from time 0 to 8 hours post-dose for veliparib was estimated using non-compartmental methods. Dose normalized AUC(0-8) is calculated as AUC(0-8) / veliparib dose in mg.
Time frame: Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose
Population: Phase 1 participants who were administered at least 1 dose of study drug, had at least 1 reported PK sample concentration and for whom AUC(0-8) could be calculated.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Dose-normalized Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose of Veliparib | 39.8 (ng*h/mL)/mg | Geometric Coefficient of Variation 14 |
| Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Dose-normalized Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose of Veliparib | 35.3 (ng*h/mL)/mg | Geometric Coefficient of Variation 25 |
| Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Dose-normalized Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose of Veliparib | 46.9 (ng*h/mL)/mg | Geometric Coefficient of Variation 28 |
| Phase 1: Veliparib 200 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Dose-normalized Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose of Veliparib | 33.3 (ng*h/mL)/mg | Geometric Coefficient of Variation 4 |
| Phase 1: Veliparib 240 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Dose-normalized Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose of Veliparib | 38.7 (ng*h/mL)/mg | Geometric Coefficient of Variation 37 |
Primary
Phase 1: Dose-normalized Maximum Observed Plasma Concentration (Cmax) of Etoposide With and Without Veliparib
Etoposide plasma concentrations were determined using liquid chromatography with tandem mass spectrometric detection with a lower limit of quantitation 160 ng/mL. Dose normalized Cmax is calculated as Cmax / etoposide dose in mg/m².
Time frame: Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose.
Population: Phase 1 participants who received at least 1 dose of study drug, had at least 1 reported PK concentration for each time point and for whom Cmax could be calculated. Participants in the Veliparib 240 mg BID 21-day (continuous) dosing group are not included in the Cycle 2 Day 1 analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Dose-normalized Maximum Observed Plasma Concentration (Cmax) of Etoposide With and Without Veliparib | 169 (ng/mL)/(mg/m²) | Geometric Coefficient of Variation 18 |
| Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Dose-normalized Maximum Observed Plasma Concentration (Cmax) of Etoposide With and Without Veliparib | 170 (ng/mL)/(mg/m²) | Geometric Coefficient of Variation 20 |
Primary
Phase 1: Dose-normalized Maximum Observed Plasma Concentration of Veliparib
Plasma concentrations of veliparib were determined using a validated online solid-phase extraction followed by high-performance liquid chromatography with tandem mass spectrometric detection (HPLC LC-MS/MS). The lower limit of quantitation (LLOQ) for veliparib was established at ≥ 1.05 ng/mL. Dose normalized Cmax is calculated as Cmax / veliparib dose in mg.
Time frame: Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose
Population: Phase 1 participants who were administered at least 1 dose of study drug, had at least 1 reported PK sample concentration and for whom Cmax could be calculated.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Dose-normalized Maximum Observed Plasma Concentration of Veliparib | 7.75 (ng/mL)/mg | Geometric Coefficient of Variation 16 |
| Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Dose-normalized Maximum Observed Plasma Concentration of Veliparib | 8.35 (ng/mL)/mg | Geometric Coefficient of Variation 31 |
| Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Dose-normalized Maximum Observed Plasma Concentration of Veliparib | 8.66 (ng/mL)/mg | Geometric Coefficient of Variation 29 |
| Phase 1: Veliparib 200 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Dose-normalized Maximum Observed Plasma Concentration of Veliparib | 7.19 (ng/mL)/mg | Geometric Coefficient of Variation 10 |
| Phase 1: Veliparib 240 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Dose-normalized Maximum Observed Plasma Concentration of Veliparib | 8.31 (ng/mL)/mg | Geometric Coefficient of Variation 25 |
Primary
Phase 1: Maximum Observed Plasma Concentration (Cmax) of Etoposide With and Without Veliparib
Etoposide plasma concentrations were determined using liquid chromatography with tandem mass spectrometric detection with a lower limit of quantitation 160 ng/mL.
Time frame: Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose.
Population: Phase 1 participants who received at least 1 dose of study drug, had at least 1 reported PK concentration for each time point and for whom Cmax could be calculated. Participants in the Veliparib 240 mg BID 21-day (continuous) dosing group and participants whose etoposide dose was reduced in Cycle 2 are not included in the Cycle 2 Day 1 analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Maximum Observed Plasma Concentration (Cmax) of Etoposide With and Without Veliparib | 16.9 μg/mL | Geometric Coefficient of Variation 18 |
| Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Maximum Observed Plasma Concentration (Cmax) of Etoposide With and Without Veliparib | 16.4 μg/mL | Geometric Coefficient of Variation 21 |
Primary
Phase 1: Maximum Observed Plasma Concentration (Cmax) of Veliparib
Plasma concentrations of veliparib were determined using a validated online solid-phase extraction followed by high-performance liquid chromatography with tandem mass spectrometric detection (HPLC LC-MS/MS). The lower limit of quantitation (LLOQ) for veliparib was established at ≥ 1.05 ng/mL.
Time frame: Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose
Population: Phase 1 participants who were administered at least 1 dose of study drug, had at least 1 reported PK sample concentration and for whom Cmax could be calculated.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Maximum Observed Plasma Concentration (Cmax) of Veliparib | 0.620 μg/mL | Geometric Coefficient of Variation 17 |
| Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Maximum Observed Plasma Concentration (Cmax) of Veliparib | 1.00 μg/mL | Geometric Coefficient of Variation 31 |
| Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Maximum Observed Plasma Concentration (Cmax) of Veliparib | 1.39 μg/mL | Geometric Coefficient of Variation 29 |
| Phase 1: Veliparib 200 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Maximum Observed Plasma Concentration (Cmax) of Veliparib | 1.44 μg/mL | Geometric Coefficient of Variation 10 |
| Phase 1: Veliparib 240 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Maximum Observed Plasma Concentration (Cmax) of Veliparib | 1.99 μg/mL | Geometric Coefficient of Variation 25 |
Primary
Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs)
A DLT was defined as any of the following drug-related toxicities, graded according to the Common Toxicity Criteria for Adverse Events (CTCAE), V.4.0: 1. Events associated with treatment delay \>14 days in initiating Cycle 2 therapy: Grade 4 thrombocytopenia, neutropenia, or febrile neutropenia, or Grade 3 febrile neutropenia with fever for \> 7 days 2. Grade ≥ 3 non-hematologic toxicity with ≥ 2 grade increase from baseline and attributed to veliparib treatment, excluding nausea or vomiting for ≤ 48 hours or inadequately treated, electrolyte abnormalities resolving in ≤ 24 hours, hypersensitivity reactions or alopecia 3. Grade 2 non-hematologic toxicity of ≥ 2 grade increase from baseline, attributed to veliparib treatment requiring delay of \>14 days in initiation of Cycle 2 4. Any toxicity of ≥ 2-grade increase from baseline, attributed to veliparib and requiring a dose modification in Cycle 1 or omission of carboplatin, \>1 daily etoposide dose, or \>30% veliparib doses in Cycle 1
Time frame: Cycle 1 Day -2 to pre-dose on Cycle 2 Day 1 (23 days)
Population: Phase 1 participants who received at least 1 dose of study drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) | 0 Participants |
| Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) | 0 Participants |
| Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) | 0 Participants |
| Phase 1: Veliparib 200 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) | 0 Participants |
| Phase 1: Veliparib 240 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) | 1 Participants |
| Phase 1: Veliparib 240 mg BID 14 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) | 0 Participants |
| Phase 1: Veliparib 240 mg BID 21 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Dose-limiting Toxicities (DLTs) | 1 Participants |
Comparison: A primary objective of Phase 1 was to establish the recommended phase 2 dose (RP2D) for veliparib combined with carboplatin and etoposide. The RP2D was determined by the rate of DLTs and overall tolerability of veliparib plus carboplatin and etoposide.
Primary
Phase 1: Terminal Phase Elimination Half-life (t1/2) of Etoposide With and Without Veliparib
The terminal half-life of etoposide was estimated using using non-compartmental methods. Values reported represent the harmonic mean ± pseudo-standard deviation.
Time frame: Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose.
Population: Participants in Phase 1 who received at least 1 dose of study drug and had at least 1 reported PK sample concentration for each time point and for whom t1/2 could be calculated. Participants in the Veliparib 240 mg BID 21-day (continuous) dosing group are not included in the Cycle 2 Day 1 analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Terminal Phase Elimination Half-life (t1/2) of Etoposide With and Without Veliparib | 5.7 hours | Standard Deviation 1.5 |
| Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Terminal Phase Elimination Half-life (t1/2) of Etoposide With and Without Veliparib | 5.0 hours | Standard Deviation 1.2 |
Primary
Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Etoposide With and Without Veliparib
Etoposide plasma concentrations were determined using liquid chromatography with tandem mass spectrometric detection with a lower limit of quantitation 160 ng/mL.
Time frame: Cycle 1 Day 1 (coadministered with veliparib and carboplatin), and on Cycle 2 Day 1 (co-administered with carboplatin but in the absence of veliparib) at 55 minutes (5 minutes before the end of infusion) and 3, 5, 8, and 24 hours post-dose.
Population: Phase 1 participants who received at least 1 dose of study drug, had at least 1 reported PK concentration for each time point and for whom Tmax could be calculated. Participants in the Veliparib 240 mg BID 21-day (continuous) dosing group are not included in the Cycle 2 Day 1 analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Etoposide With and Without Veliparib | 0.9 hours |
| Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Etoposide With and Without Veliparib | 0.9 hours |
Primary
Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Veliparib
Plasma concentrations of veliparib were determined using a validated online solid-phase extraction followed by high-performance liquid chromatography with tandem mass spectrometric detection (HPLC LC-MS/MS). The lower limit of quantitation (LLOQ) for veliparib was established at ≥ 1.05 ng/mL.
Time frame: Cycle 1 Day 1 predose and at 1, 2, 3, 5, 8, and 24 hours post-dose
Population: Phase 1 participants who were administered at least 1 dose of study drug, had at least 1 reported PK sample concentration and for whom Tmax could be calculated.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Veliparib | 2.0 hours |
| Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Veliparib | 1.0 hours |
| Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Veliparib | 1.5 hours |
| Phase 1: Veliparib 200 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Veliparib | 2.0 hours |
| Phase 1: Veliparib 240 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Veliparib | 1.0 hours |
Primary
Phase 2: Progression-free Survival
Progression-free survival (PFS) is defined as the time from the date of randomization to the date of earliest radiographic disease progression or death provided no radiographic disease progression occurred. If a participant did not have an event of disease progression and had not died on or prior to the cutoff for PFS analysis, the participant's data was censored at the date of their last disease assessment or randomization date provided participant did not have any post-baseline disease assessment. Disease assessments were performed using computed tomography according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. Progressive Disease (PD) was defined as at least a 20% increase in the size of target lesions and an absolute increase of at least 5 mm taking as reference the smallest lesion size recorded since the treatment started (baseline or after), or the appearance of one or more new lesions.
Time frame: From randomization up to the date the 126th PFS event was reached; Median time on follow-up was 7.3, 7.1, and 8.9 months in each treatment group respectively.
Population: All participants randomized in Phase 2
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide | Phase 2: Progression-free Survival | 5.8 months |
| Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide | Phase 2: Progression-free Survival | 5.7 months |
| Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide | Phase 2: Progression-free Survival | 5.6 months |
Comparison: The primary efficacy analysis in the Phase 2 portion of the study was the comparison of PFS among participants who received veliparib in combination with carboplatin and etoposide followed by veliparib maintenance monotherapy (Arm A) vs. placebo in combination with carboplatin and etoposide followed by placebo maintenance monotherapy (Arm C).~Statistical significance was determined by a two-sided p-value ≤ 0.2p-value: 0.05980% CI: [0.503, 0.88]Log Rank
Comparison: If the primary analysis of PFS (Arm A vs Arm C) was statistically significant a fixed sequence testing procedure was to be performed with a 2-sided significance level of 0.2 for the following key secondary endpoints:~1. OS (Arm A vs Arm C)~2. PFS (Arms B vs Arm C)~3. OS (Arm B vs Arm C)~4. ORR (Arm A vs Arm C)~5. ORR (Arm B vs Arm C)~If significance versus Arm C was not demonstrated, all endpoints later in the testing hierarchy were to be considered exploratory.p-value: 0.92480% CI: [0.744, 1.288]Log Rank
Secondary
Phase 1: Number of Participants With Adverse Events
The intensity of each adverse event (AE) was assessed utilizing the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0, and according to the following: Grade 1 (Mild): AE is transient and easily tolerated by the participant; Grade 2 (Moderate): AE causes the participant discomfort and interrupts the participant's usual activities; Grade 3/4 (Severe): The adverse event causes considerable interference with the participant's usual activities and may be incapacitating or life-threatening; Grade 5: Death. Serious adverse events were those that resulted in death, were life-threatening, required hospitalization or prolongation of hospitalization, resulted in congenital anomaly, or persistent or significant disability/incapacity.
Time frame: From first dose of any study drug to 30 days after the last dose; the median duration of treatment with veliparib across all groups in Phase 1 was 127.5 days.
Population: Participants in Phase 1 who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Adverse Events | Any adverse event | 4 Participants |
| Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Adverse Events | Any AE Grade 3/4 | 4 Participants |
| Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Adverse Events | Any serious adverse event | 3 Participants |
| Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Adverse Events | Any fatal adverse event | 0 Participants |
| Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Adverse Events | Any fatal adverse event | 0 Participants |
| Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Adverse Events | Any serious adverse event | 1 Participants |
| Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Adverse Events | Any AE Grade 3/4 | 3 Participants |
| Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Adverse Events | Any adverse event | 3 Participants |
| Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Adverse Events | Any fatal adverse event | 1 Participants |
| Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Adverse Events | Any serious adverse event | 3 Participants |
| Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Adverse Events | Any AE Grade 3/4 | 4 Participants |
| Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Adverse Events | Any adverse event | 4 Participants |
| Phase 1: Veliparib 200 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Adverse Events | Any adverse event | 3 Participants |
| Phase 1: Veliparib 200 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Adverse Events | Any fatal adverse event | 1 Participants |
| Phase 1: Veliparib 200 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Adverse Events | Any AE Grade 3/4 | 3 Participants |
| Phase 1: Veliparib 200 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Adverse Events | Any serious adverse event | 2 Participants |
| Phase 1: Veliparib 240 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Adverse Events | Any fatal adverse event | 0 Participants |
| Phase 1: Veliparib 240 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Adverse Events | Any AE Grade 3/4 | 7 Participants |
| Phase 1: Veliparib 240 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Adverse Events | Any serious adverse event | 3 Participants |
| Phase 1: Veliparib 240 mg BID 7 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Adverse Events | Any adverse event | 8 Participants |
| Phase 1: Veliparib 240 mg BID 14 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Adverse Events | Any fatal adverse event | 0 Participants |
| Phase 1: Veliparib 240 mg BID 14 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Adverse Events | Any serious adverse event | 6 Participants |
| Phase 1: Veliparib 240 mg BID 14 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Adverse Events | Any AE Grade 3/4 | 14 Participants |
| Phase 1: Veliparib 240 mg BID 14 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Adverse Events | Any adverse event | 14 Participants |
| Phase 1: Veliparib 240 mg BID 21 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Adverse Events | Any serious adverse event | 3 Participants |
| Phase 1: Veliparib 240 mg BID 21 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Adverse Events | Any adverse event | 4 Participants |
| Phase 1: Veliparib 240 mg BID 21 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Adverse Events | Any AE Grade 3/4 | 4 Participants |
| Phase 1: Veliparib 240 mg BID 21 Days + Carboplatin/Etoposide | Phase 1: Number of Participants With Adverse Events | Any fatal adverse event | 0 Participants |
Secondary
Phase 2: Objective Response Rate
Objective response rate (ORR) is defined as the percentage of participants with objective response (confirmed) as assessed by the investigator using RECIST version 1.1. Objective response includes both complete response (CR) and partial response (PR). Response must be confirmed at a subsequent tumor assessment at least 28 days apart. Participants with no post-baseline confirmed response were counted as non-responders. CR: Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. No new lesions. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, and no new lesions.
Time frame: Tumor assessments were performed every 6 weeks for the first 30 weeks and every 9 weeks thereafter until disease progression; median time on follow-up was 7.3, 7.1, and 8.9 months in each group respectively.
Population: All participants randomized in Phase 2
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide | Phase 2: Objective Response Rate | 77.0 percentage of participants |
| Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide | Phase 2: Objective Response Rate | 59.3 percentage of participants |
| Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide | Phase 2: Objective Response Rate | 63.9 percentage of participants |
Comparison: If the primary analysis of PFS (Arm A vs Arm C) was statistically significant a fixed sequence testing procedure was to be performed with a 2-sided significance level of 0.2 for the following key secondary endpoints:~1. OS (Arm A vs Arm C)~2. PFS (Arms B vs Arm C)~3. OS (Arm B vs Arm C)~4. ORR (Arm A vs Arm C)~5. ORR (Arm B vs Arm C)~If significance versus Arm C was not demonstrated, all endpoints later in the testing hierarchy were to be considered exploratory.p-value: 0.11580% CI: [1.1, 3.2]Cochran-Mantel-Haenszel
Comparison: If the primary analysis of PFS (Arm A vs Arm C) was statistically significant a fixed sequence testing procedure was to be performed with a 2-sided significance level of 0.2 for the following key secondary endpoints:~1. OS (Arm A vs Arm C)~2. PFS (Arms B vs Arm C)~3. OS (Arm B vs Arm C)~4. ORR (Arm A vs Arm C)~5. ORR (Arm B vs Arm C)~If significance versus Arm C was not demonstrated, all endpoints later in the testing hierarchy were to be considered exploratory.p-value: 0.60480% CI: [0.5, 1.3]Cochran-Mantel-Haenszel
Secondary
Phase 2: Overall Survival
Overall survival (OS) is defined as the time from the date of randomization to the date of death. If a participant did not die on or prior to the cut-off for OS analysis, the participant's data were censored at the date of their last known alive date, which is defined as the last date of the last survival follow-up visit, the start date of the last AE, the start date or end date of the last dose of any study drugs, the last lab and vital sign collection date, or the last disease assessment date, whichever occurred last.
Time frame: From randomization until the end of study; median time on follow-up was 10.0, 8.6, and 11.7 months in each treatment group respectively.
Population: All participants randomized in Phase 2
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Veliparib 80 mg BID 7 Days + Carboplatin/Etoposide | Phase 2: Overall Survival | 10.1 months |
| Phase 1: Veliparib 120 mg BID 7 Days + Carboplatin/Etoposide | Phase 2: Overall Survival | 10.0 months |
| Phase 1: Veliparib 160 mg BID 7 Days + Carboplatin/Etoposide | Phase 2: Overall Survival | 12.4 months |
Comparison: If the primary analysis of PFS (Arm A vs Arm C) was statistically significant a fixed sequence testing procedure was to be performed with a 2-sided significance level of 0.2 for the following key secondary endpoints:~1. OS (Arm A vs Arm C)~2. PFS (Arms B vs Arm C)~3. OS (Arm B vs Arm C)~4. ORR (Arm A vs Arm C)~5. ORR (Arm B vs Arm C)~If significance versus Arm C was not demonstrated, all endpoints later in the testing hierarchy were to be considered exploratory.p-value: 0.08880% CI: [1.092, 1.879]Log Rank
Comparison: If the primary analysis of PFS (Arm A vs Arm C) was statistically significant a fixed sequence testing procedure was to be performed with a 2-sided significance level of 0.2 for the following key secondary endpoints:~1. OS (Arm A vs Arm C)~2. PFS (Arms B vs Arm C)~3. OS (Arm B vs Arm C)~4. ORR (Arm A vs Arm C)~5. ORR (Arm B vs Arm C)~If significance versus Arm C was not demonstrated, all endpoints later in the testing hierarchy were to be considered exploratory.p-value: 0.08380% CI: [1.104, 1.931]Log Rank