Comparison of Veliparib and Whole Brain Radiation Therapy (WBRT) Versus Placebo and WBRT in Adults With Brain Metastases From Non-Small Cell Lung Cancer

Study Overview
=================
Brief Summary
-----------------
The primary objective of this study is to evaluate the efficacy and safety of veliparib and whole brain radiation therapy in adults with brain metastases from non-small cell lung cancer (NSCLC).

Official Title
-----------------
A Randomized, Double-Blind, Phase 2, Dose-Ranging Study to Evaluate the Safety and Efficacy of Veliparib and Whole Brain Radiation Therapy Versus Placebo and Whole Brain Radiation Therapy in Subjects With Brain Metastases From Non-Small Cell Lung Cancer

Conditions
-----------------
Brain Metastases From Non-small Cell Lung Cancer

Intervention / Treatment
-----------------
* Drug: Veliparib
* Drug: Placebo
* Radiation: Whole brain radiation therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subject must have cytologically or histologically confirmed non-small cell lung cancer Subject must have brain metastases demonstrated on a magnetic resonance imaging (MRI) brain scan. Subject must be eligible for treatment with WBRT Subject must have had adequate hematologic, renal, and hepatic function. Exclusion Criteria: Subject is diagnosed with brain metastases greater than 28 days prior to Day 1 Subject received any prior form of cranial radiation and/or neurosurgery for their brain metastases Subject's last dose of anti-cancer therapy or investigational therapy was less than or equal to 7 days prior to Day 1 Subject has a Karnofsky Performance Score of less than 70 Subject has significant dyspnea requiring supplemental oxygen therapy Subject has liver metastases (restaging is not required for known liver metastases) Subject has more than 2 sites (organ systems) of metastases from non-small cell lung cancer with the exception of intra-cranial sites of metastases from non-small cell lung cancer, thoracic sites of metastases from non-small cell lung cancer and bone metastases Subject has leptomeningeal metastases or subarachnoid spread of tumor Subject has unresolved or unstable, serious toxicity from prior administration of another investigational drug and/or prior anti-cancer treatment Subject has a known seizure disorder that is uncontrolled, or has seizures occurring greater than or equal to 3 times a week over the past month. Subjects presenting with symptoms of seizures from the brain metastases are eligible; however he/she should receive adequate anti-seizure medication prior to study treatment Subject is pregnant or lactating Subject has previously been treated with a poly-(ADP-ribose)-polymerase inhibitor as an investigational agent Subject has clinically significant and uncontrolled major medical condition(s) Subject has a history of another active cancer within the past 5 years except: cervical cancer in situ, in situ carcinoma of the bladder, basal or squamous cell carcinoma of the skin or other cancer in situ that is considered cured

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Veliparib 200 mg BID + WBRT<br>Participants received veliparib 200 mg twice a day (BID) orally concomitantly with whole brain radiation therapy (WBRT). Participants received a total of 30.0 Gy of WBRT given in 10 daily fractions of 3.0 Gy, excluding weekends and holidays. | Drug: Veliparib<br>* Veliparib capsules for oral administration<br>* Other names: ABT-888;Radiation: Whole brain radiation therapy<br>* 30.0 grays (Gy) of WBRT given in 10 daily fractions of 3.0 Gy each, excluding weekends and holidays<br>|
| Experimental: Veliparib 50 mg BID + WBRT<br>Participants received veliparib 50 mg twice a day (BID) orally concomitantly with whole brain radiation therapy (WBRT). Participants received a total of 30.0 Gy of WBRT given in 10 daily fractions of 3.0 Gy, excluding weekends and holidays. | Drug: Veliparib<br>* Veliparib capsules for oral administration<br>* Other names: ABT-888;Radiation: Whole brain radiation therapy<br>* 30.0 grays (Gy) of WBRT given in 10 daily fractions of 3.0 Gy each, excluding weekends and holidays<br>|
| Placebo Comparator: Placebo BID + WBRT<br>Participants received placebo twice a day (BID) orally concomitantly with whole brain radiation therapy (WBRT). Participants received a total of 30.0 Gy of WBRT given in 10 daily fractions of 3.0 Gy, excluding weekends and holidays. | Drug: Placebo<br>* Placebo to veliparib capsules for oral administration<br>Radiation: Whole brain radiation therapy<br>* 30.0 grays (Gy) of WBRT given in 10 daily fractions of 3.0 Gy each, excluding weekends and holidays<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival was defined as the number of days from the date of randomization to the date of death. All events of death were included, regardless of whether the event occurred while the participant was still taking study treatment or after treatment was discontinued. If a participant had not died, the data were censored at the date the participant was last known to be alive. | From randomization up to 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Tumor Response Rate | Best tumor response rate was calculated as the percentage of participants with a complete response or partial response, as determined by brain scan imaging (magnetic resonance image or computed tomography) by a central imaging vendor. Response was assessed according to the modified bidimensional criteria: Complete response required all of the following: complete disappearance of all target and non-target lesions sustained for at least 4 weeks; no new lesions, including no new leptomeningeal disease; no systemic corticosteroid dose. Partial response required all of the following: ≥ 50% decrease compared with baseline in the size of all target lesions sustained for at least 4 weeks; no new lesions, including no new leptomeningeal disease and no unequivocal progression of non-target lesions, which, even in presence of stable disease or progressive disease in target lesions, was significant enough to qualify as progression; stable or reduced daily total systemic corticosteroid dose. | From randomization up to 24 months | 
| Time to Intracranial Progression (Radiographic) | Time to intracranial progression (radiographic) was defined as the number of days from the date of randomization to the date of the first intracranial progression, as determined by brain scan imaging (magnetic resonance image [MRI]/ computed tomography [CT] scan) by a central imaging vendor. All confirmed events of intracranial progression were included, regardless of whether the event occurred while the participant was still taking study treatment or had previously discontinued study treatment. If the participant did not have a confirmed event of intracranial progression, their data were censored at the date of the last available intracranial progression assessment. Time to intracranial progression (radiographic) was estimated for each treatment group using Kaplan-Meier methodology. | From randomization up to 24 months | 
| Time to Clinical Brain Metastasis Progression | Time to clinical brain metastases progression was defined as the number of days from randomization to the date of the first experience of clinical brain metastases progression, as assessed by a team of neuro-oncology experts (Event Review Board). All events of clinical brain metastasis progression were included, regardless of whether the event occurred while the participant was still receiving study treatment or had previously discontinued study treatment. If a participant did not have an event of clinical brain metastases progression, their data were censored at the date of the last available clinical disease progression assessment. Time to clinical brain metastasis progression was estimated for each treatment group using Kaplan-Meier methodology. | From randomization up to 24 months |