NSCLC (Non-small Cell Lung Carcinoma)
Conditions
Keywords
Non small cell lung cancer
Brief summary
The purpose of this study was to determine if ruxolitinib, in combination with Pemetrexed/Cisplatin and Pemetrexed Maintenance, is safe and effective in the treatment of nonsquamous non-small cell lung cancer (NSCLC) that is Stage IIIB, Stage IV, or recurrent.
Detailed description
The study consisted of an open-label, safety run-in (consisting of 1 to 4 cohorts of 9 participants each), to confirm the safety of ruxolitinib in combination with pemetrexed/cisplatin in participants with nonsquamous non-small cell lung cancer (NSCLC) that is Stage IIIB, Stage IV, or recurrent. Participants in the safety run-in received open-label ruxolitinib and pemetrexed and cisplatin. In the second part of the study, participants enrolled and randomized and received pemetrexed and cisplatin (open-label) and either ruxolitinib or placebo in a blinded manner. The dose of ruxolitinib administered was determined from the data produced in the safety run-in phase. Treatment consisted of repeating 21-day cycles. Participants received infusions of pemetrexed and cisplatin on Day 1 of each cycle and ruxolitinib/placebo was self-administered during the entire cycle. Maintenance therapy with ruxolitinib or placebo in combination with pemetrexed, based on the original treatment assignment, was allowed for participants eligible for maintenance therapy.
Interventions
DRUGRuxolitinib
5 mg tablets to be administered by mouth at dose selected from safety run-in phase (Ruxolitinib 15 mg twice daily (BID))
DRUGPlacebo
5 mg matching placebo tablets to be administered by mouth
DRUGPemetrexed
500 mg/m\^2 administered as an intravenous infusion over 10 minutes
DRUGCisplatin
75 mg/m\^2 infused over 2 hours beginning 30 ± 5 minutes after the end of the pemetrexed infusion
Sponsors
Incyte Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed diagnosis of nonsquamous NSCLC that is Stage IIIB Stage IV, or recurrent after prior definitive intervention (radiation, surgery, or chemoradiation therapy, with or without adjuvant or neoadjuvant chemotherapy). * Radiographically measurable or evaluable disease. * Life expectancy of at least 12 weeks. * Tumor without activating driver mutations for which there is available therapy (eg, tumor without mutations in epidermal growth factor receptor or anaplastic lymphoma). * An modified Glasgow Prognostic Score (mGPS) of 1 or 2 as defined below: * Criteria: * C-reactive protein \>10 mg/L AND albumin ≥35 g/L; Score = 1 * C-reactive protein \>10 mg L AND albumin \<35 g/L; Score = 2 * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. * Adequate renal, hepatic, and bone marrow function demonstrated by protocol-specified laboratory parameters at the screening visit.
Exclusion criteria
* Squamous or mixed histology (eg, adenosquamous) NSCLC * Previous systemic therapy for advanced or metastatic disease. * Known active central nervous system (CNS) metastases. * Current or previous other malignancy within 2 years of study entry, except cured basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in situ of the cervix, or other noninvasive or indolent malignancy without sponsor approval. * Current uncontrolled cardiac disease such as angina or myocardial infarction, congestive heart failure including New York Heart Association functional classification of 3, or arrhythmia requiring treatment. * Uncontrolled concomitant medical conditions, including, but not limited to, renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, neurological, cerebral, or psychiatric diseases.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Randomization until death due to any cause; up to 16 months or data cutoff 11FEB2016. | Overall survival is defined as the time from randomization to death due to any cause. Participants without death observed at the time of the analysis were censored at last date known to be alive. The median overall survival time was estimated using the Kaplan-Meier method. Overall survival was compared between treatment groups using log-rank test. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Randomization to disease progression, or death due to any cause if sooner; up to 16 months or to the data cutoff 11FEB2016. | PFS is defined as the time from randomization until the earliest date of disease progression determined by investigator assessment of objective radiographic disease assessments per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or death due to any cause if sooner. Progressive Disease (PD) is defined using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum Longest Diameter (LD) recorded since the treatment started or the appearance of one or more new lesions, unequivocal progression of non-target lesions or increase in disease burden for subjects with only nonmeasurable disease. |
| Objective Response Rate (ORR) | Baseline through end of study; up to 16 months or to the data cutoff 11FEB2016. | Objective response rate determined by radiographic disease assessments per RECIST (v1.1), by investigator assessment and was defined as the percentage of participants with Complete Response (CR) or Partial Response (PR) by Response Evaluation Criteria in Solid Tumours (RECIST) at any post baseline visit. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) for target lesions and assessed by computed tomography (CT) and/or magnetic resonance imaging (MRI) : Complete Response (CR), Disappearance of all target and non-target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions with no worsening of non-target lesions and no new lesions; Overall Response (OR) = CR + PR. |
| Duration of Response | From the start of response to the end of response; up to 16 months or to the data cutoff 11FEB2016. | For objective responders, the duration of response is defined as the difference of the end of response and the start of response. The start of a response was the first visit where the subject achieves PR or better based on RECIST v1.1 criteria. The end of response was the first visit after PD based on RECIST v1.1 criteria. |
| Participants With Treatment-emergent Adverse Events (TEAEs) | Baseline through approximately 30 days post treatment discontinuation; up to 16 months or to the data cutoff 11FEB2016. | A treatment-emergent AE was defined as an event occurring (or worsening of any pre-existing) after exposure to at least 1 dose of study drug. A treatment-related AE was defined as an event with a definite, probable, or possible causality to study medication. A serious AE is an event resulting in death, hospitalization, persistent or significant disability/incapacity, or is life threatening, a congenital anomaly/birth defect or requires medical or surgical intervention to prevent 1 of the outcomes above. The intensity of an AE was graded according to the National Cancer Institute common terminology criteria for adverse events (NCI-CTCAE) version 4.03: Grade 1 (Mild); Grade 2 (Moderate); Grade 3 (Severe); Grade 4 (life-threatening). |
Countries
United States
Participant flow
Recruitment details
This study was conducted at 42 study centers (25 in the United States, 4 in Spain, 3 in France, 3 in Portugal, 2 in Denmark, 2 in Germany, 2 in Italy, 1 in the Netherlands).
Participants by arm
| Arm | Count |
|---|---|
| Double-Blind Treatment: Ruxolitinib + Pemetrexed/Cisplatin Ruxolitinib was self-administered as a 15 mg BID oral treatment during the randomized, double-blind treatment, without regard to food. Pemetrexed 500 mg/m\^2 was administered as an intravenous infusion over 10 minutes, and 75 mg/m\^2 Cisplatin was infused over 2 hours beginning 30 ± 5 minutes after the end of the pemetrexed infusion on Day 1 of each 21-day cycle (Treatment Cycles). | 39 |
| Double-Blind Treatment: Placebo Plus Pemetrexed/Cisplatin Matching placebo was self-administered as a 15 mg BID oral treatment during the randomized, double-blind treatment, without regard to food. Pemetrexed 500 mg/m\^2 was administered as an intravenous infusion over 10 minutes, and 75 mg/m\^2 Cisplatin was infused over 2 hours beginning 30 ± 5 minutes after the end of the pemetrexed infusion on Day 1 of each 21-day cycle (Treatment Cycles). | 37 |
| Total | 76 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 4 |
| Overall Study | Death | 5 | 1 |
| Overall Study | Disease progression | 11 | 14 |
| Overall Study | Multiple reasons for termination | 2 | 1 |
| Overall Study | Noncompliance with study treatment | 1 | 1 |
| Overall Study | Physician Decision | 0 | 2 |
| Overall Study | Study terminated by the sponsor | 1 | 0 |
| Overall Study | Subject decision | 2 | 3 |
Baseline characteristics
| Characteristic | Double-Blind Treatment: Ruxolitinib + Pemetrexed/Cisplatin | Double-Blind Treatment: Placebo Plus Pemetrexed/Cisplatin | Total |
|---|---|---|---|
| Age, Continuous | 61.6 years STANDARD_DEVIATION 8.85 | 62.0 years STANDARD_DEVIATION 8.55 | 61.8 years STANDARD_DEVIATION 8.65 |
| Body Mass Index (BMI) | 27.67 kg/m^2 STANDARD_DEVIATION 6.402 | 27.65 kg/m^2 STANDARD_DEVIATION 7.26 | 27.66 kg/m^2 STANDARD_DEVIATION 6.787 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) White | 36 Participants | 33 Participants | 69 Participants |
| Sex: Female, Male Female | 15 Participants | 14 Participants | 29 Participants |
| Sex: Female, Male Male | 24 Participants | 23 Participants | 47 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 37 / 39 | 36 / 37 |
| serious Total, serious adverse events | 19 / 39 | 16 / 37 |
Outcome results
Primary
Overall Survival (OS)
Overall survival is defined as the time from randomization to death due to any cause. Participants without death observed at the time of the analysis were censored at last date known to be alive. The median overall survival time was estimated using the Kaplan-Meier method. Overall survival was compared between treatment groups using log-rank test.
Time frame: Randomization until death due to any cause; up to 16 months or data cutoff 11FEB2016.
Population: The intent-to-treat (ITT) population consisted of participants that were randomized in the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Double-Blind Treatment: Ruxolitinib + Pemetrexed/Cisplatin | Overall Survival (OS) | 7.5 months |
| Double-Blind Treatment: Placebo Plus Pemetrexed/Cisplatin | Overall Survival (OS) | 5.9 months |
p-value: 0.756280% CI: [0.509, 1.51]Log Rank
Secondary
Duration of Response
For objective responders, the duration of response is defined as the difference of the end of response and the start of response. The start of a response was the first visit where the subject achieves PR or better based on RECIST v1.1 criteria. The end of response was the first visit after PD based on RECIST v1.1 criteria.
Time frame: From the start of response to the end of response; up to 16 months or to the data cutoff 11FEB2016.
Population: The intent-to-treat (ITT) population consisted of participants that were randomized in the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Double-Blind Treatment: Ruxolitinib + Pemetrexed/Cisplatin | Duration of Response | 20.14 weeks |
| Double-Blind Treatment: Placebo Plus Pemetrexed/Cisplatin | Duration of Response | 12.14 weeks |
Secondary
Objective Response Rate (ORR)
Objective response rate determined by radiographic disease assessments per RECIST (v1.1), by investigator assessment and was defined as the percentage of participants with Complete Response (CR) or Partial Response (PR) by Response Evaluation Criteria in Solid Tumours (RECIST) at any post baseline visit. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) for target lesions and assessed by computed tomography (CT) and/or magnetic resonance imaging (MRI) : Complete Response (CR), Disappearance of all target and non-target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions with no worsening of non-target lesions and no new lesions; Overall Response (OR) = CR + PR.
Time frame: Baseline through end of study; up to 16 months or to the data cutoff 11FEB2016.
Population: The intent-to-treat (ITT) population consisted of participants that were randomized in the study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Double-Blind Treatment: Ruxolitinib + Pemetrexed/Cisplatin | Objective Response Rate (ORR) | Partial Response | 12 Participants |
| Double-Blind Treatment: Ruxolitinib + Pemetrexed/Cisplatin | Objective Response Rate (ORR) | Progressive Disease | 6 Participants |
| Double-Blind Treatment: Ruxolitinib + Pemetrexed/Cisplatin | Objective Response Rate (ORR) | Complete Response | 0 Participants |
| Double-Blind Treatment: Ruxolitinib + Pemetrexed/Cisplatin | Objective Response Rate (ORR) | Unable to Evaluate | 2 Participants |
| Double-Blind Treatment: Ruxolitinib + Pemetrexed/Cisplatin | Objective Response Rate (ORR) | Stable Disease | 4 Participants |
| Double-Blind Treatment: Ruxolitinib + Pemetrexed/Cisplatin | Objective Response Rate (ORR) | Not Assessed | 15 Participants |
| Double-Blind Treatment: Ruxolitinib + Pemetrexed/Cisplatin | Objective Response Rate (ORR) | Overall Response | 12 Participants |
| Double-Blind Treatment: Placebo Plus Pemetrexed/Cisplatin | Objective Response Rate (ORR) | Not Assessed | 12 Participants |
| Double-Blind Treatment: Placebo Plus Pemetrexed/Cisplatin | Objective Response Rate (ORR) | Overall Response | 13 Participants |
| Double-Blind Treatment: Placebo Plus Pemetrexed/Cisplatin | Objective Response Rate (ORR) | Complete Response | 0 Participants |
| Double-Blind Treatment: Placebo Plus Pemetrexed/Cisplatin | Objective Response Rate (ORR) | Partial Response | 13 Participants |
| Double-Blind Treatment: Placebo Plus Pemetrexed/Cisplatin | Objective Response Rate (ORR) | Stable Disease | 5 Participants |
| Double-Blind Treatment: Placebo Plus Pemetrexed/Cisplatin | Objective Response Rate (ORR) | Progressive Disease | 4 Participants |
| Double-Blind Treatment: Placebo Plus Pemetrexed/Cisplatin | Objective Response Rate (ORR) | Unable to Evaluate | 3 Participants |
Secondary
Participants With Treatment-emergent Adverse Events (TEAEs)
A treatment-emergent AE was defined as an event occurring (or worsening of any pre-existing) after exposure to at least 1 dose of study drug. A treatment-related AE was defined as an event with a definite, probable, or possible causality to study medication. A serious AE is an event resulting in death, hospitalization, persistent or significant disability/incapacity, or is life threatening, a congenital anomaly/birth defect or requires medical or surgical intervention to prevent 1 of the outcomes above. The intensity of an AE was graded according to the National Cancer Institute common terminology criteria for adverse events (NCI-CTCAE) version 4.03: Grade 1 (Mild); Grade 2 (Moderate); Grade 3 (Severe); Grade 4 (life-threatening).
Time frame: Baseline through approximately 30 days post treatment discontinuation; up to 16 months or to the data cutoff 11FEB2016.
Population: The safety evaluable population consisted of all participants exposed to at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Double-Blind Treatment: Ruxolitinib + Pemetrexed/Cisplatin | Participants With Treatment-emergent Adverse Events (TEAEs) | Participants with any serious TEAE | 19 Participants |
| Double-Blind Treatment: Ruxolitinib + Pemetrexed/Cisplatin | Participants With Treatment-emergent Adverse Events (TEAEs) | Participants who discontinued drug due to TEAEs | 2 Participants |
| Double-Blind Treatment: Ruxolitinib + Pemetrexed/Cisplatin | Participants With Treatment-emergent Adverse Events (TEAEs) | Participants with a fatal TEAE | 4 Participants |
| Double-Blind Treatment: Ruxolitinib + Pemetrexed/Cisplatin | Participants With Treatment-emergent Adverse Events (TEAEs) | Participants who interrupted drug due to TEAEs | 11 Participants |
| Double-Blind Treatment: Ruxolitinib + Pemetrexed/Cisplatin | Participants With Treatment-emergent Adverse Events (TEAEs) | Participants who had treatment-related TEAEs | 16 Participants |
| Double-Blind Treatment: Ruxolitinib + Pemetrexed/Cisplatin | Participants With Treatment-emergent Adverse Events (TEAEs) | Discontinued reference therapy due to TEAEs | 4 Participants |
| Double-Blind Treatment: Ruxolitinib + Pemetrexed/Cisplatin | Participants With Treatment-emergent Adverse Events (TEAEs) | TEAEs related to reference therapy | 30 Participants |
| Double-Blind Treatment: Ruxolitinib + Pemetrexed/Cisplatin | Participants With Treatment-emergent Adverse Events (TEAEs) | Interrupted reference therapy due to TEAEs | 8 Participants |
| Double-Blind Treatment: Ruxolitinib + Pemetrexed/Cisplatin | Participants With Treatment-emergent Adverse Events (TEAEs) | Participants who had Grade 3 or higher TEAEs | 25 Participants |
| Double-Blind Treatment: Ruxolitinib + Pemetrexed/Cisplatin | Participants With Treatment-emergent Adverse Events (TEAEs) | Participants given concomitant meds due to TEAEs | 36 Participants |
| Double-Blind Treatment: Ruxolitinib + Pemetrexed/Cisplatin | Participants With Treatment-emergent Adverse Events (TEAEs) | Participants who were hospitalized due to TEAEs | 16 Participants |
| Double-Blind Treatment: Ruxolitinib + Pemetrexed/Cisplatin | Participants With Treatment-emergent Adverse Events (TEAEs) | Procedure/nondrug therapy due to TEAEs | 17 Participants |
| Double-Blind Treatment: Ruxolitinib + Pemetrexed/Cisplatin | Participants With Treatment-emergent Adverse Events (TEAEs) | Participants who had any TEAEs | 39 Participants |
| Double-Blind Treatment: Placebo Plus Pemetrexed/Cisplatin | Participants With Treatment-emergent Adverse Events (TEAEs) | Procedure/nondrug therapy due to TEAEs | 12 Participants |
| Double-Blind Treatment: Placebo Plus Pemetrexed/Cisplatin | Participants With Treatment-emergent Adverse Events (TEAEs) | Participants who had any TEAEs | 36 Participants |
| Double-Blind Treatment: Placebo Plus Pemetrexed/Cisplatin | Participants With Treatment-emergent Adverse Events (TEAEs) | Participants who had treatment-related TEAEs | 28 Participants |
| Double-Blind Treatment: Placebo Plus Pemetrexed/Cisplatin | Participants With Treatment-emergent Adverse Events (TEAEs) | Participants with any serious TEAE | 16 Participants |
| Double-Blind Treatment: Placebo Plus Pemetrexed/Cisplatin | Participants With Treatment-emergent Adverse Events (TEAEs) | Participants who had Grade 3 or higher TEAEs | 22 Participants |
| Double-Blind Treatment: Placebo Plus Pemetrexed/Cisplatin | Participants With Treatment-emergent Adverse Events (TEAEs) | Participants with a fatal TEAE | 4 Participants |
| Double-Blind Treatment: Placebo Plus Pemetrexed/Cisplatin | Participants With Treatment-emergent Adverse Events (TEAEs) | TEAEs related to reference therapy | 35 Participants |
| Double-Blind Treatment: Placebo Plus Pemetrexed/Cisplatin | Participants With Treatment-emergent Adverse Events (TEAEs) | Participants who were hospitalized due to TEAEs | 15 Participants |
| Double-Blind Treatment: Placebo Plus Pemetrexed/Cisplatin | Participants With Treatment-emergent Adverse Events (TEAEs) | Participants who discontinued drug due to TEAEs | 4 Participants |
| Double-Blind Treatment: Placebo Plus Pemetrexed/Cisplatin | Participants With Treatment-emergent Adverse Events (TEAEs) | Participants who interrupted drug due to TEAEs | 15 Participants |
| Double-Blind Treatment: Placebo Plus Pemetrexed/Cisplatin | Participants With Treatment-emergent Adverse Events (TEAEs) | Discontinued reference therapy due to TEAEs | 7 Participants |
| Double-Blind Treatment: Placebo Plus Pemetrexed/Cisplatin | Participants With Treatment-emergent Adverse Events (TEAEs) | Interrupted reference therapy due to TEAEs | 7 Participants |
| Double-Blind Treatment: Placebo Plus Pemetrexed/Cisplatin | Participants With Treatment-emergent Adverse Events (TEAEs) | Participants given concomitant meds due to TEAEs | 32 Participants |
Secondary
Progression-free Survival (PFS)
PFS is defined as the time from randomization until the earliest date of disease progression determined by investigator assessment of objective radiographic disease assessments per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or death due to any cause if sooner. Progressive Disease (PD) is defined using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum Longest Diameter (LD) recorded since the treatment started or the appearance of one or more new lesions, unequivocal progression of non-target lesions or increase in disease burden for subjects with only nonmeasurable disease.
Time frame: Randomization to disease progression, or death due to any cause if sooner; up to 16 months or to the data cutoff 11FEB2016.
Population: The intent-to-treat (ITT) population consisted of participants that were randomized in the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Double-Blind Treatment: Ruxolitinib + Pemetrexed/Cisplatin | Progression-free Survival (PFS) | NA Months |
| Double-Blind Treatment: Placebo Plus Pemetrexed/Cisplatin | Progression-free Survival (PFS) | NA Months |