Brain Metastases From Non-small Cell Lung Cancer
Conditions
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).
Interventions
DRUGVeliparib
Veliparib capsules for oral administration
DRUGPlacebo
Placebo to veliparib capsules for oral administration
RADIATIONWhole brain radiation therapy
30.0 grays (Gy) of WBRT given in 10 daily fractions of 3.0 Gy each, excluding weekends and holidays
Sponsors
AbbVie (prior sponsor, Abbott)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From randomization up to 36 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Tumor Response Rate | From randomization up to 24 months | 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. |
| Time to Intracranial Progression (Radiographic) | From randomization up to 24 months | 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. |
| Time to Clinical Brain Metastasis Progression | From randomization up to 24 months | 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. |
Participant flow
Recruitment details
Participants were enrolled across 87 sites in Argentina, Australia, Belgium, Canada, Chile, Czech Republic, Egypt, Finland, France, Hungary, Korea, Norway, Russia, Spain, Taiwan, Ukraine, and the United States.
Pre-assignment details
Subjects were randomized in a 1:1:1 ratio to one of three treatment groups. Randomization was stratified by graded prognostic assessment (GPA) score (≤ 2.5 versus \> 2.5) and neurological symptoms (symptomatic versus asymptomatic).
Participants by arm
| Arm | Count |
|---|---|
| Placebo BID + WBRT 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. | 102 |
| Veliparib 50 mg BID + WBRT 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. | 103 |
| Veliparib 200 mg BID + WBRT 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. | 102 |
| Total | 307 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event Not Related to Progression | 5 | 4 | 4 |
| Overall Study | Adverse Event Related to progression | 6 | 8 | 12 |
| Overall Study | Disease Progression | 2 | 4 | 4 |
| Overall Study | Lost to Follow-up | 1 | 0 | 1 |
| Overall Study | Other | 52 | 62 | 49 |
| Overall Study | Progressive Disease Clinical | 7 | 4 | 7 |
| Overall Study | Radiographic & Clinical Progression | 16 | 11 | 15 |
| Overall Study | Withdrawal by Subject | 13 | 10 | 10 |
Baseline characteristics
| Characteristic | Placebo BID + WBRT | Veliparib 50 mg BID + WBRT | Veliparib 200 mg BID + WBRT | Total |
|---|---|---|---|---|
| Age, Continuous | 60.0 years STANDARD_DEVIATION 9.71 | 59.8 years STANDARD_DEVIATION 8.74 | 61.8 years STANDARD_DEVIATION 9.08 | 60.6 years STANDARD_DEVIATION 9.2 |
| Age, Customized < 65 years | 68 Participants | 73 Participants | 64 Participants | 205 Participants |
| Age, Customized ≥ 65 years | 34 Participants | 30 Participants | 38 Participants | 102 Participants |
| Graded Prognostic Assessment (GPA) ≤ 2.5 | 91 Participants | 91 Participants | 92 Participants | 274 Participants |
| Graded Prognostic Assessment (GPA) > 2.5 | 11 Participants | 12 Participants | 10 Participants | 33 Participants |
| Race/Ethnicity, Customized Asian | 22 Participants | 16 Participants | 28 Participants | 66 Participants |
| Race/Ethnicity, Customized Black | 0 Participants | 2 Participants | 6 Participants | 8 Participants |
| Race/Ethnicity, Customized Multirace | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 79 Participants | 85 Participants | 66 Participants | 230 Participants |
| Sex: Female, Male Female | 46 Participants | 42 Participants | 36 Participants | 124 Participants |
| Sex: Female, Male Male | 56 Participants | 61 Participants | 66 Participants | 183 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 78 / 101 | 76 / 103 | 77 / 102 |
| serious Total, serious adverse events | 39 / 101 | 31 / 103 | 36 / 102 |
Outcome results
Primary
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.
Time frame: From randomization up to 36 months
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo BID + WBRT | Overall Survival | 185 days |
| Veliparib 50 mg BID + WBRT | Overall Survival | 209 days |
| Veliparib 200 mg BID + WBRT | Overall Survival | 209 days |
Comparison: The primary analysis used a Hochberg testing procedure to preserve the familywise error rate for multiple comparisons, where the larger P-value for the comparisons of veliparib 50 mg BID + WBRT with placebo BID + WBRT and veliparib 200 mg BID + WBRT with placebo BID + WBRT were compared to an α = 0.05. If statistically significant (P ≤ 0.05), both comparisons were considered significant. If the larger P-value was not statistically significant, the smaller P-value was compared to an α = 0.025.p-value: 0.933Log Rank
Comparison: The primary analysis used a Hochberg testing procedure to preserve the familywise error rate for multiple comparisons, where the larger P-value for the comparisons of veliparib 50 mg BID + WBRT with placebo BID + WBRT and veliparib 200 mg BID + WBRT with placebo BID + WBRT were compared to an α = 0.05. If statistically significant (P ≤ 0.05), both comparisons were considered significant. If the larger P-value was not statistically significant, the smaller P-value was compared to an α = 0.025.p-value: 0.909Log Rank
p-value: 0.92795% CI: [0.716, 1.355]Cox proportional hazard model
p-value: 0.90695% CI: [0.71, 1.354]Cox proportional hazard model
Secondary
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.
Time frame: From randomization up to 24 months
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo BID + WBRT | Best Tumor Response Rate | 41.2 percentage of participants |
| Veliparib 50 mg BID + WBRT | Best Tumor Response Rate | 36.9 percentage of participants |
| Veliparib 200 mg BID + WBRT | Best Tumor Response Rate | 42.2 percentage of participants |
p-value: 0.535Cochran-Mantel-Haenszel
p-value: 0.898Cochran-Mantel-Haenszel
Secondary
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.
Time frame: From randomization up to 24 months
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo BID + WBRT | Time to Clinical Brain Metastasis Progression | 348 days |
| Veliparib 50 mg BID + WBRT | Time to Clinical Brain Metastasis Progression | 286 days |
| Veliparib 200 mg BID + WBRT | Time to Clinical Brain Metastasis Progression | 255 days |
p-value: 0.864Log Rank
p-value: 0.301Log Rank
p-value: 0.8695% CI: [0.626, 1.754]Cox proportional hazard model
p-value: 0.28995% CI: [0.803, 2.086]Cox proportional hazard model
Secondary
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.
Time frame: From randomization up to 24 months
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo BID + WBRT | Time to Intracranial Progression (Radiographic) | 259 days |
| Veliparib 50 mg BID + WBRT | Time to Intracranial Progression (Radiographic) | 226 days |
| Veliparib 200 mg BID + WBRT | Time to Intracranial Progression (Radiographic) | 224 days |
p-value: 0.314Log Rank
p-value: 0.536Log Rank
p-value: 0.31395% CI: [0.78, 2.168]Cox proportional hazard model
p-value: 0.53495% CI: [0.698, 1.999]Cox proportional hazard model