E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Nonsquamous NSCLC that is Stage IIIB, Stage IV, or recurrent |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029522 |
E.1.2 | Term | Non-small cell lung cancer stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029521 |
E.1.2 | Term | Non-small cell lung cancer stage IIIB |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10059515 |
E.1.2 | Term | Non-small cell lung cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061873 |
E.1.2 | Term | Non-small cell lung cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029515 |
E.1.2 | Term | Non-small cell lung cancer recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
•Part 1: To evaluate the safety and tolerability of ruxolitinib in combination with pemetrexed/cisplatin and select a dose for further evaluation
•Part 2: To evaluate and compare the OS of subjects with nonsquamous NSCLC that is Stage IIIB, Stage IV, or recurrent when treated with ruxolitinib or placebo in combination with pemetrexed/cisplatin and subsequently pemetrexed maintenance
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E.2.2 | Secondary objectives of the trial |
•To evaluate and compare the efficacy of the 2 treatment arms with respect to PFS
•To evaluate and compare the efficacy of the 2 treatment arms with respect to overall tumor response and duration of response
•To evaluate and compare the safety and tolerability of ruxolitinib in combination with pemetrexed/cisplatin versus pemetrexed/cisplatin alone
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Men or women aged 18 or older.
•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).
Subjects who have recurrent NSCLC after prior surgery or radiation therapy are allowed to enter. At least 4 weeks must have elapsed between prior radiation therapy and Cycle1 Day1, and all radiation therapy–related toxicities must have resolved.
Subjects who have received radiation to the spine, pelvis, ribs, or femur should be discussed with the sponsor, as extensive radiation to marrow-forming region may compromise a subject's ability to tolerate myelosuppressive chemotherapy.
Subjects must not have received prior chemotherapy for advanced or metastatic disease.
•An mGPS of 1 or 2 as defined below:
Criteria Score
C-reactive protein > 10 mg/L AND albumin ≥ 35 g/L 1
C-reactive protein > 10 mg/L AND albumin < 35 g/L 2
•Radiographically measurable or evaluable disease.
•Life expectancy of at least 12 weeks.
•Tumor without activating driver mutations for which there is an available therapy (eg, tumor without mutations in epidermal growth factor receptor or anaplastic lymphoma kinase).
•ECOG performance status of 0 to 1.
•Adequate renal, hepatic, and bone marrow function demonstrated by protocol-specified laboratory parameters at the screening visit:
Absolute neutrophil count ≥ 1.5 × 109/L.
Platelet count ≥ 100 × 109/L.
Hemoglobin ≥ 85 g/L (transfusion supported is acceptable).
Alanine aminotransferase and aspartate aminotransferase ≤ 2.5 × upper limit of laboratory normal (ULN) or ≤ 5 × ULN in the presence of liver metastases.
Total bilirubin ≤ 1.5 × ULN; if total bilirubin is > 1.5 × ULN, then direct bilirubin must be ≤ 1.5 × ULN.
Creatinine clearance ≥ 50 mL/min measured or calculated by Cockroft-Gault equation, or glomerular filtration rate ≥ 50 mL/min/1.73 m2 as calculated using the Modification of Diet in Renal Disease formula.
•Female subjects of childbearing potential must have a negative serum pregnancy test at screening. All female subjects of childbearing potential must agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening to follow-up.
•Male subjects must agree to take appropriate precautions to avoid fathering children (with at least 99% certainty) from screening through follow-up. Permitted methods that are at least 99% effective in preventing pregnancy should be communicated to the subject and their understanding confirmed. |
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E.4 | Principal exclusion criteria |
•Squamous or mixed histology (eg, adenosquamous) NSCLC
•Previous systemic therapy for advanced or metastatic disease. (Subjects who completed a platinum-containing regimen as adjuvant, neoadjuvant, or part of a course of chemoradiation therapy within the 6 months before screening are also excluded.)
•Known active (untreated) central nervous system (CNS) metastases. Subjects with CNS metastases who have completed a course of therapy would be eligible for the study provided they are clinically stable for at least 4 weeks before study entry, defined as:
•No evidence of new or enlarging CNS metastasis or new neurological symptoms attributable to CNS metastases.
•Asymptomatic and receiving either no or stable doses of anticonvulsants and/or corticosteroids for the 4 weeks prior to study entry.
•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.
•Known hypersensitivity to any of the active substances or any of their excipients, including ruxolitinib, cisplatin, or pemetrexed.
•Inability to take brief courses of dexamethasone each month.
•Unwillingness or inability to take vitamin B12 and folic acid supplements.
•Chronic or current active infectious disease requiring systemic antibiotics, antifungals, or antivirals.
•Known HIV-positive status.
•Hepatitis B virus (HBV) or hepatitis C virus (HCV) viremia or at risk for HBV reactivation. HBV DNA and testing for HCV RNA must be undetectable. At risk for HBV reactivation is defined as hepatitis B surface antigen positive or anti-hepatitis B core antibody positive.
•Pregnant or breastfeeding women.
•Unwillingness to be transfused with blood components
•Prior treatment with any JAK inhibitor.
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E.5 End points |
E.5.1 | Primary end point(s) |
•Part 1: Determination of the dose of ruxolitinib that is safe and tolerable in combination with pemetrexed/cisplatin.
•Part 2: Overall survival as determined from the date of randomization until death due to any cause.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint is OS, defined as number of days from randomization to death. This analysis will be based on the intent-to-treat population, according to treatment assignment. Survival data will be analyzed by the Kaplan-Meier method stratified by mGPS score, treating subjects with no observed death as censored at their last date known to be alive. The Arm1/Arm2 HR and its 80% CI will be estimated using Cox regression model with mGPS score as covariate.
The OS will also be analyzed based on per-protocol population as sensitivity analysis.
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E.5.2 | Secondary end point(s) |
•Progression-free survival as determined from the randomization date until the earliest date of disease progression, as measured by investigator assessment of objective radiographic disease assessments per RECIST (v1.1), or death due to any cause if earlier.
•Objective response rate and duration of response determined by radiographic disease assessments per RECIST (v1.1).
•Safety and tolerability of the treatment regimens assessed by monitoring the frequency, duration, and severity of AEs; performing physical examinations; and evaluating change in vital signs and laboratory results.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Progression-free survival will be determined from the randomization date until the earliest date of disease progression, as measured by investigator assessment of objective radiographic disease assessments per RECIST (v1.1), or death due to any cause if earlier.
The rates of responders will be compared with Cochran–Mantel–Haenszel test stratified by mGPS score. The duration of response is defined as the difference of the end of response and the start of response for subjects who have at least one response measurement. The start of a response will be the first visit where the subject achieves PR or better based on RECIST v1.1 criteria. The end of response will be the first visit after PD based on RECIST v1.1 criteria. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 35 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
European Union |
Hong Kong |
Korea, Republic of |
Singapore |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The study will be considered completed when the required number of subjects have died to assess the primary endpoint, and no subjects are receiving study treatment. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 2 |