Dose Escalation and Double-blind Study of Veliparib in Combination With Carboplatin and Etoposide in Treatment-naive Extensive Stage Disease Small Cell Lung Cancer

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:

• 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

• 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
• 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
• 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

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.

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.

The area under the plasma concentration-time curve from time 0 to 8 hours post-dose for veliparib was estimated using non-compartmental methods.

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.

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.

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.

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.

Etoposide plasma concentrations were determined using liquid chromatography with tandem mass spectrometric detection with a lower limit of quantitation 160 ng/mL.

Etoposide plasma concentrations were determined using liquid chromatography with tandem mass spectrometric detection with a lower limit of quantitation 160 ng/mL.

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.

The area under the plasma concentration-time curve from 0 to infinity for etoposide was estimated using using non-compartmental methods.

The terminal half-life of etoposide was estimated using using non-compartmental methods. Values reported represent the harmonic mean ± pseudo-standard deviation.

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.

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.

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.

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.

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.

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.

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.