A Study Evaluating the Efficacy and Tolerability of Veliparib in Combination With Paclitaxel/Carboplatin-Based Chemoradiotherapy Followed by Veliparib and Paclitaxel/Carboplatin Consolidation in Adults With Stage III Non-Small Cell Lung Cancer (NSCLC)

Phase 2TerminatedNCT02412371

AbbVie48 enrolled

Overview

This study seeks to establish * the recommended Phase 2 dose (RPTD) of veliparib in combination with concurrent paclitaxel/carboplatin-based chemoradiotherapy (CRT) and consolidation with paclitaxel/carboplatin-based chemotherapy (Phase 1 portion), and * to assess whether the addition of oral veliparib versus placebo to paclitaxel/carboplatin-based chemoradiotherapy with paclitaxel/carboplatin consolidation will improve progression-free survival (PFS) in adults with Stage III non-small cell lung cancer (Phase 2 portion). A strategy decision was made not to proceed to Phase 2 portion of this study due to change in standard of care.

This was to be a 2-phase study consisting of 1. A Phase 1, dose escalation study of veliparib to determine a RPTD for combination with concurrent paclitaxel/carboplatin-based CRT and paclitaxel/carboplatin-based consolidation chemotherapy; followed by 2. A Phase 2, randomized, double-blinded study to determine whether veliparib improved outcome relative to placebo when added to paclitaxel/carboplatin based CRT followed by consolidation paclitaxel/carboplatin in adults with previously untreated Stage III NSCLC. In the dose escalation phase (Phase 1) of the study participants will be assigned to ascending doses of veliparib in combination with carboplatin, paclitaxel, and thoracic radiotherapy for 7 weeks following a traditional "3 + 3" design. The first cohort of at least 3 - 6 participants will receive veliparib 60 mg twice a day (BID) throughout CRT. Dose limiting toxicity (DLT) events will be collected for each dosing cohort until a new dosing cohort is opened or until the RPTD is identified. Participants will also receive a consolidation dose of veliparib of 120 mg BID + carboplatin and paclitaxel for up to two 21-day cycles. Once the concurrent CRT RPTD is identified, an additional cohort will be enrolled to explore the tolerability of a consolidation dose of veliparib at 240 mg BID + carboplatin + paclitaxel for up to two 21-day cycles. Following the dose escalation portion of the study, the RPTD will be determined by the sponsor and the Phase 2 portion of the study will begin with patient randomization in a 1:1:1 ratio to concurrent paclitaxel/carboplatin/radiotherapy/veliparib followed by consolidation paclitaxel/carboplatin/veliparib, concurrent paclitaxel/carboplatin/radiotherapy/veliparib followed by consolidation paclitaxel/carboplatin/placebo, or concurrent paclitaxel/carboplatin/radiotherapy/placebo followed by consolidation paclitaxel/carboplatin/placebo. Randomization will be stratified by tumor volume (≤ 90 versus \> 90 cm³) and smoking history (current smoker versus former smoker versus never smoked). Phase 2 was not carried out since during the study there was a change in standard of care for patients with newly diagnosed, unresectable Stage III NSCLC.

Interventions

PaclitaxelDRUG

Administered via intravenous infusion on Day 1 of each treatment week (concurrent CRT) / cycle (consolidation)

Placebo for VeliparibDRUG

Capsule for oral administration

CarboplatinDRUG

Administered via intravenous infusion on Day 1 of each treatment week (concurrent CRT) / cycle (consolidation)

VeliparibDRUG

Capsule for oral administration

RadiotherapyRADIATION

Radiation treatment with total dose of 60 - 63 Gy administered on Days 1 to 5 of each week for 7 weeks

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Participants with histologically or cytologically confirmed Stage III non-small cell lung cancer (NSCLC). 2. Participants in the randomized portion of the study must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 criteria. 3. Participants must have V20 (volume of lung to receive 20 Gy radiotherapy according to simulation) \< 35%. 4. Participant must have an Eastern Cooperative Oncology Group (ECOG) performance score of 0 - 1. 5. Participant must have adequate hematologic, renal, hepatic, and lung function. 6. Participant must consent to provide archived tissue or cytology sample of NSCLC lesion for analysis. Exclusion Criteria: 1. Participants with prior chemotherapy or radiotherapy (RT) for current NSCLC. Participants curatively treated for past early stage NSCLC greater than 3 years ago may be included. 2. Participants with prior exposure to poly-adenosine diphosphate (ADP)-ribose polymerase (PARP) inhibitors. 3. Participants with known hypersensitivity to carboplatin, paclitaxel, or formulations containing polyethoxylated castor oil (Cremophor). 4. Participants with prior mediastinal or thoracic radiotherapy. Prior tangential radiotherapy to prior breast cancer is acceptable. 5. Participants with major surgery in the 4 weeks prior to randomization (Video-assisted thoracoscopic surgery (VATS) and/or mediastinoscopy is not considered major surgery). 6. Participants with a previous or concurrent malignancy except for treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient received potentially curative treatment and has been disease-free for 3 years or is considered cured by the investigator if has been disease-free for less than 3 years. 7. Participant is pregnant or lactating. 8. Participant with sensory peripheral neuropathy of ≥ Grade 2 at baseline, unable to swallow medication, or participants with prior history of seizure within the prior 12 months.

Locations (12)

Ucsd /Id# 133037

La Jolla, California, United States

Christiana Care Health Service /ID# 133486

Newark, Delaware, United States

University of Chicago /ID# 133828

Chicago, Illinois, United States

Univ Maryland School Medicine /ID# 132944

Baltimore, Maryland, United States

Dana-Farber Cancer Institute /ID# 133494

Boston, Massachusetts, United States

SUNY Upstate Medical University - Downtown /ID# 133492

Syracuse, New York, United States

Unc /Id# 133496

Chapel Hill, North Carolina, United States

Duke University Medical Center /ID# 133497

Durham, North Carolina, United States

Wake Forest Univ HS /ID# 134608

Winston-Salem, North Carolina, United States

Rhode Island Hospital /ID# 133493

Providence, Rhode Island, United States

...and 2 more locations

Outcomes

Primary Outcomes

Number of Participants With Dose-limiting Toxicities (DLTs)

DLTs were defined as the following events considered treatment-related by the Investigator, graded per Common Terminology Criteria for Adverse Events (CTCAE) v4.0. * Radiation-induced myelopathy/myelitis or ≥ Grade (G) 3 cardiac toxicity * Radiation-related pneumonitis resulting in delay in RT, CT, or veliparib of \>3 weeks or early discontinuation (DC) of RT (total dose \<50 Gy) * ≥G4 esophagitis or esophagitis, dysphagia, and odynophagia requiring treatment interruption of \>7 days despite medical management, neutropenia for \>7 days or neutropenic fever or thrombocytopenia * ≥G2 seizure * G4 diarrhea or nausea/vomiting despite antiemetic therapy for \>48 hours * Any other toxicity resulting in delay in RT, CT or veliparib \>14 days or early DC of RT * Other nonhematologic toxicities ≥G3, except anorexia, fatigue, G3 infection, G3 aspartate/alanine transferase (AST/ALT) elevations ≤7 days, infusion reactions, G3/4 lymphopenia or electrolyte abnormalities corrected to ≤G2 in \<48 hours

Time frame: For Cohorts 1 - 5, from the start of veliparib dosing through 28 days after RT completion or until initiation of consolidation CT, approx. 10 weeks; For Cohort 6, 21 days from start of consolidation CT or until the start of cycle 2 consolidation therapy.

Secondary Outcomes

Objective Response Rate

Objective response rate (ORR) is defined as the percentage of participants who have a confirmed complete response (CR) or partial response (PR) as assessed by the investigator using RECIST v1.1. Participants who did not meet complete response or partial response, including those who did not have post-baseline radiological assessments were considered as non-responders. Complete Response (CR): The 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. Normalization of tumor marker level. All lymph nodes must be non-pathological in size (\< 10 mm short axis). Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Response must have been confirmed 4 weeks after the first documentation.

Time frame: Tumor assessments were performed prior to consolidation chemotherapy, 24 weeks after start of treatment, every 8 weeks until 1 year after start of treatment, and then every 12 weeks until disease progression; median time on follow-up was 11 months.