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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)

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ClinicalTrials.gov Identifier: NCT02412371
Recruitment Status : Terminated (Phase 2 was not conducted due to a change in the standard of care for newly diagnosed, unresectable Stage III NSCLC)
First Posted : April 9, 2015
Results First Posted : July 22, 2020
Last Update Posted : July 22, 2020
Sponsor:
Information provided by (Responsible Party):
AbbVie

Tracking Information
First Submitted Date  ICMJE November 6, 2014
First Posted Date  ICMJE April 9, 2015
Results First Submitted Date  ICMJE June 9, 2020
Results First Posted Date  ICMJE July 22, 2020
Last Update Posted Date July 22, 2020
Actual Study Start Date  ICMJE April 30, 2015
Actual Primary Completion Date August 5, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 8, 2020)
Number of Participants With Dose-limiting Toxicities (DLTs) [ 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. ]
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
Original Primary Outcome Measures  ICMJE
 (submitted: April 6, 2015)
  • Recommended Phase 2 dose (RPTD) of veliparib (ABT-888) in combination with radiotherapy, paclitaxel and carboplatin [ Time Frame: Approximately 2 years ]
    Recommended Phase 2 dose (RPTD) in combination with radiotherapy, paclitaxel and carboplatin will be determined by dose escalation in phase 1 of the study. Dose limiting toxicity (DLT) events will be collected for each dosing cohort until a new dosing cohort is opened or until the recommended Phase 2 dose is identified.
  • Progression-free survival (PFS) [ Time Frame: Approximately 3 years ]
    Progression-free survival (PFS) is defined as the number of days from the date of enrollment to the date of earliest progression or death. If the participant does not experience disease progression or death, then the data will be censored at the date of the last disease assessment.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 8, 2020)
Objective Response Rate [ 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. ]
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.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 6, 2015)
  • Overall Survival (OS) [ Time Frame: Approximately 3 years ]
    Overall survival is defined as the number of days from the date of participant enrollment to the date of death.
  • Objective Response Rate (ORR) [ Time Frame: Approximately every 8 weeks from first dose until one year after beginning therapy, then every 12 weeks for up to 3 years. ]
    Objective Response Rate (ORR) is defined as the proportion of the participants who have a complete response (CR) or partial response (PR).
  • Duration of Overall Response (DOR) [ Time Frame: Approximately every 8 weeks from first dose until one year after beginning therapy, then every 12 weeks for up to 3 years. ]
    Duration of Overall Response (DOR) is defined as the time from the participant's initial CR or PR to the time of disease progression.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures
 (submitted: April 6, 2015)
  • Quality of Life (QoL) [ Time Frame: Until a participant achieves 1 year on treatment (for participants in phase 2 only) ]
    Two short cancer questionnaires by the European Organization for Research and Treatment of Cancer (EORTC) will be used to measure change in a participant's quality of life.
  • Change in ECOG (Eastern Cooperative Oncology Group) Performance Status of Participants [ Time Frame: Approximately 3 years ]
 
Descriptive Information
Brief Title  ICMJE 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)
Official Title  ICMJE A Phase 1 Dose Escalation and Phase 2 Randomized, Placebo-Controlled Study of the Efficacy and Tolerability of Veliparib in Combination With Paclitaxel/Carboplatin-Based Chemoradiotherapy Followed by Veliparib and Paclitaxel/Carboplatin Consolidation in Subjects With Stage III Non-Small Cell Lung Cancer (NSCLC)
Brief Summary

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.

Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

In the dose escalation phase (Phase 1) of the study participants will be enrolled sequentially to receive ascending dose of veliparib in combination with carboplatin + paclitaxel + thoracic radiotherapy.

In the Phase 2 portion of the study participants were to be randomized in a 1:1:1 ratio to one of three treatment arms.

Masking: None (Open Label)
Masking Description:

All participants will be treated with open-label paclitaxel and carboplatin (Phase 1 and Phase 2).

Participants in Phase 1 will be treated with open-label veliparib. In Phase 2, the Sponsor, Investigator, study site personnel and participant were to be be blinded to each participant's treatment with veliparib or placebo throughout the course of the study.

Primary Purpose: Treatment
Condition  ICMJE Non-small Cell Lung Cancer Stage III
Intervention  ICMJE
  • Drug: Paclitaxel
    Administered via intravenous infusion on Day 1 of each treatment week (concurrent CRT) / cycle (consolidation)
  • Drug: Placebo for Veliparib
    Capsule for oral administration
  • Drug: Carboplatin
    Administered via intravenous infusion on Day 1 of each treatment week (concurrent CRT) / cycle (consolidation)
  • Drug: Veliparib
    Capsule for oral administration
    Other Name: ABT-888
  • Radiation: Radiotherapy
    Radiation treatment with total dose of 60 - 63 Gy administered on Days 1 to 5 of each week for 7 weeks
Study Arms  ICMJE
  • Experimental: Phase 1: Veliparib + Carboplatin + Paclitaxel + Radiotherapy

    Participants in Phase 1 will be sequentially assigned to ascending dose levels of 60 mg, 80 mg, 120 mg, 200 mg, and 240 mg of twice daily (BID) veliparib in combination with carboplatin at an area under the concentration-time curve (AUC) 2 mg/mL/min and paclitaxel 45 mg/m² once a week plus thoracic radiotherapy for 7 weeks.

    After completion of concurrent chemoradiotherapy participants will receive up to 2 cycles of consolidation therapy consisting of veliparib 120 mg or 240 mg BID, carboplatin AUC 6 mg/mL/min and paclitaxel 200 mg/m² administered on Day 1 of each 21-day cycle.

    Interventions:
    • Drug: Paclitaxel
    • Drug: Carboplatin
    • Drug: Veliparib
    • Radiation: Radiotherapy
  • Experimental: Phase 2: Veliparib + CRT -> Paclitaxel/Carboplatin/Veliparib

    Participants will receive veliparib at the recommended phase 2 dose determined in Phase 1 in combination with carboplatin at an AUC 2 mg/mL/min and paclitaxel 45 mg/m² once a week plus thoracic radiotherapy for 7 weeks.

    After completion of concurrent chemoradiotherapy participants will receive up to 2 cycles of consolidation therapy consisting of veliparib 120 mg or 240 mg BID, carboplatin AUC 6 mg/mL/min and paclitaxel 200 mg/m² administered on Day 1 of each 21-day cycle.

    Interventions:
    • Drug: Paclitaxel
    • Drug: Carboplatin
    • Drug: Veliparib
    • Radiation: Radiotherapy
  • Experimental: Phase 2: Veliparib + CRT -> Paclitaxel/Carboplatin/Placebo

    Participants will receive veliparib at the recommended phase 2 dose determined in Phase 1 in combination with carboplatin at an AUC 2 mg/mL/min and paclitaxel 45 mg/m² once a week plus thoracic radiotherapy for 7 weeks.

    After completion of concurrent chemoradiotherapy participants will receive up to 2 cycles of consolidation therapy consisting of placebo to veliparib BID, carboplatin AUC 6 mg/mL/min and paclitaxel 200 mg/m² administered on Day 1 of each 21-day cycle.

    Interventions:
    • Drug: Paclitaxel
    • Drug: Placebo for Veliparib
    • Drug: Carboplatin
    • Drug: Veliparib
    • Radiation: Radiotherapy
  • Active Comparator: Phase 2: Placebo + CRT -> Paclitaxel/Carboplatin/Placebo

    Participants will receive placebo to veliparib with carboplatin at an AUC 2 mg/mL/min and paclitaxel 45 mg/m² once a week plus thoracic radiotherapy for 7 weeks.

    After completion of concurrent chemoradiotherapy participants will receive up to 2 cycles of consolidation therapy consisting of placebo to veliparib BID, carboplatin AUC 6 mg/mL/min and paclitaxel 200 mg/m² administered on Day 1 of each 21-day cycle.

    Interventions:
    • Drug: Paclitaxel
    • Drug: Placebo for Veliparib
    • Drug: Carboplatin
    • Radiation: Radiotherapy
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: June 6, 2018)
48
Original Estimated Enrollment  ICMJE
 (submitted: April 6, 2015)
174
Actual Study Completion Date  ICMJE August 5, 2019
Actual Primary Completion Date August 5, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries Czechia,   Greece,   Spain
 
Administrative Information
NCT Number  ICMJE NCT02412371
Other Study ID Numbers  ICMJE M14-360
2016-001659-32 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information (e.g., protocols and clinical study reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Clinical Study Report (CSR)
Supporting Materials: Analytic Code
Time Frame: Data requests can be submitted at any time and the data will be accessible for 12 months, with possible extensions considered.
Access Criteria: Access to this clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). For more information on the process, or to submit a request, visit the following link.
URL: https://www.abbvie.com/our-science/clinical-trials/clinical-trials-data-and-information-sharing/data-and-information-sharing-with-qualified-researchers.html
Responsible Party AbbVie
Study Sponsor  ICMJE AbbVie
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: AbbVie Inc. AbbVie
PRS Account AbbVie
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP