Ruxolitinib in Combination With Pemetrexed/Cisplatin in Non Small Cell Lung Cancer

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomized, Double-Blind Phase 2 Study of Ruxolitinib or Placebo in Combination With Pemetrexed/Cisplatin and Pemetrexed Maintenance for Initial Treatment of Subjects With Nonsquamous Non-Small Cell Lung Cancer That Is Stage IIIB, Stage IV, or Recurrent

Conditions
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NSCLC (Non-small Cell Lung Carcinoma)

Intervention / Treatment
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* Drug: Ruxolitinib
* Drug: Placebo
* Drug: Pemetrexed
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ruxolitinib plus Pemetrexed/Cisplatin<br> | Drug: Ruxolitinib<br>* 5 mg tablets to be administered by mouth at dose selected from safety run-in phase (Ruxolitinib 15 mg twice daily (BID))<br>* Other names: Jakavi ®;Drug: Pemetrexed<br>* 500 mg/m^2 administered as an intravenous infusion over 10 minutes<br>* Other names: Alimta®;Drug: Cisplatin<br>* 75 mg/m^2 infused over 2 hours beginning 30 ± 5 minutes after the end of the pemetrexed infusion<br>|
| Active Comparator: Placebo plus Pemetrexed/Cisplatin<br> | Drug: Placebo<br>* 5 mg matching placebo tablets to be administered by mouth<br>Drug: Pemetrexed<br>* 500 mg/m^2 administered as an intravenous infusion over 10 minutes<br>* Other names: Alimta®;Drug: Cisplatin<br>* 75 mg/m^2 infused over 2 hours beginning 30 ± 5 minutes after the end of the pemetrexed infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Randomization until death due to any cause; up to 16 months or data cutoff 11FEB2016. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Randomization to disease progression, or death due to any cause if sooner; up to 16 months or to the data cutoff 11FEB2016. | 
| 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. | Baseline through end of study; up to 16 months or to the data cutoff 11FEB2016. | 
| 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. | From the start of response to the end of response; up to 16 months or to the data cutoff 11FEB2016. | 
| 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). | Baseline through approximately 30 days post treatment discontinuation; up to 16 months or to the data cutoff 11FEB2016. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non small cell lung cancer