Safety and Efficacy Study of CC-486 With MK-3475 to Treat Locally Advanced or Metastatic Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine whether the combination therapy of CC-486 (oral azacitidine) and pembrolizumab provides improved patient outcomes compared to pembrolizumab alone in patients with previously treated locally advanced or metastatic non-small cell lung cancer.

Detailed Description
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This is a Phase 2, multicenter, international, randomized, placebo controlled, double-blind study to assess the safety and efficacy of CC-486 and pembrolizumab combination therapy versus pembrolizumab plus placebo in previously treated patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who had received one prior platinum-based chemotherapy regimen. Approximately 100 participants will be randomized 1:1 to receive CC-486 plus pembrolizumab or placebo plus pembrolizumab as follows: Arm A: CC-486 300 mg administered orally daily on days 1 to 14 plus pembrolizumab 200 mg administered as a 30-minute IV infusion on day 1 of a 21-day cycle Arm B: Placebo administered orally daily on days 1-14 plus pembrolizumab 200 mg administered as a 30-minute IV infusion on day 1 of a 21-day cycle Randomization will be stratified between treatment arms by histology (non-squamous versus squamous). The decision to discontinue a patient, which will not be delayed or refused by the Sponsor, remains the responsibility of the treating physician. However, prior to discontinuing a patient, the Investigator may contact the medical monitor and forward appropriate supporting documents for review and discussion. In the follow-up phase, anticancer treatment administered following the last dose of investigational product (IP) and survival will be followed every 8 weeks until death, withdrawal of consent, or lost-to follow-up, whichever occurs first, or the End of Trial. The study will be conducted in compliance with the International Council on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical Practice (GCP) and applicable regulatory requirements. Primary analysis will be conducted when 70 Progression Free Survival (PFS) events have occurred.

Official Title
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A Phase 2 Multicenter, Randomized, Placebo Controlled, Double Blind Study to Assess the Safety and Efficacy of CC-486 (Oral Azacitidine) in Combination With Pembrolizumab (MK-3475) Versus Pembrolizumab Plus Placebo in Subjects With Previously Treated Locally Advanced or Metastatic Non-small Cell Lung Cancer

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: CC-486
* Drug: Pembrolizumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant is ≥ 18 years of age at the time of signing the informed consent form. Participant has histologically or cytologically confirmed squamous or non-squamous non-small cell lung cancer (NSCLC). Participant has stage IIIB or IV NSCLC (American Joint Committee on Cancer [AJCC] Staging Manual, 7th edition [Edge, 2009]) and was pretreated with only 1 prior systemic platinum based chemotherapy. Participant has provided a formalin fixed tumor tissue sample from a biopsy of a tumor lesion either at the time of or after the diagnosis of metastatic disease has been made and from a site not previously irradiated to assess for a protein known as Programmed death-ligand 1( PD-L1) status. Fine needle aspirates, endobronchial ultrasound (EBUS) or cell blocks are not acceptable. Needle or excisional biopsies, or resected tissue is required. Archival tissue may be acceptable. Submission of formalin-fixed paraffin embedded tumor tissue sample blocks are preferred; if submitting unstained slides, the slides should be freshly cut and submitted to the testing laboratory within 14 days from site slide sectioning date otherwise a new specimen will be requested. Participant has radiographically-documented measurable disease, as per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1). Particiapant has an Eastern Cancer Oncology Group (ECOG) performance status of 0 to 1. Participant has adequate organ functions, evidenced by the following: Aspartate aminotransferase (AST), Serum glutamic oxaloacetic transaminase (SGOT), alanine aminotransferase (ALT), serum glutamic pyruvic transaminase (SGPT) ≤ 2.5 x upper limit of normal range (ULN), or ≤ 5 x ULN range if liver metastasis present Total bilirubin ≤ 1.5 x ULN Serum creatinine ≤ 1.5 x ULN Potassium within normal range, or correctable with supplements Participant has adequate bone marrow function, evidenced by the following: Absolute neutrophil count ≥ 1.5 x 10^9 cells/L Platelets ≥ 100 x 10^9 cells/L Hemoglobin ≥ 9 g/dL International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN unless participant is receiving anticoagulant therapy as long as prothrombin time (PT) or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants Female of childbearing potential (FCBP) (defined as a sexually mature woman who 1) has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or, 2) if ≥ 45 years old has not been naturally postmenopausal for at least 24 consecutive months (ie, has had menses at any time during the preceding 24 consecutive months) must: Have two negative pregnancy tests as verified by the Investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the participant practices true abstinence* from heterosexual contact. Either commit to true abstinence* from heterosexual contact (which must be reviewed on a monthly basis) or agree to use, and be able to comply with two effective methods of contraception without interruption, 28 days prior to starting IP, during the study therapy (including dose interruptions), and for 120 days after discontinuation (or longer if required by local requirements) of study therapy. The two methods of contraception can either be two barrier methods or a barrier method plus a hormonal method to prevent pregnancy. Male participants must practice true abstinence* (which must be reviewed on a monthly basis) or agree to the use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 3 months following investigational product discontinuation (or longer if required by local requirements), even if he has undergone a successful vasectomy. * True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the participant. Note: Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception. Participant is willing to adhere to the study visit schedule and other protocol requirements. Participant understands and voluntarily signs an informed consent document prior to any study related assessments or procedures are conducted. Exclusion Criteria: Participants with non-squamous histology has known or unknown sensitizing epidermal growth factor receptor (EGFR) and/or anaplastic lymphoma kinase positive (ALK) mutation. Note: Participants with squamous histology and unknown EGFR and ALK mutational status are eligible. Participant has received more than one line of therapy for stage IIIB or IV disease Participant has been previously treated with azacitidine (any formulation), decitabine, or any other hypomethylating agent. Particpant has received prior therapy with any other anti-PD-1, or PD-L1 or PD-L2 agent or an antibody targeting other immuno-regulatory receptors or mechanism, including participation in any other pembrolizumab trial and treatment with pembrolizumab. a. Examples of such antibodies include (but are not limited to) antibodies against indoleamine 2,3-dioxygenase (IDO), PD-L1, IL-2R, glucocorticoid-induced tumor necrosis factor receptor (GITR). Participant has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e. ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. Participant is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to administration of pembrolizumab and CC-486 Participant has previous severe hypersensitivity reaction to another monoclonal antibody (mAb). Participant has a known or suspected hypersensitivity to azacitidine, mannitol, or any other ingredient used in the manufacture of CC-486 (see the Azacitidine IB). Participant has had radiotherapy ≤ 4 weeks or limited field radiation for palliation Participant has received radiation therapy to the lung that is > 30 Gy within 6 months of the first dose of trial treatment Participant has received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted. Participant has not recovered from the acute toxic effects of prior anticancer therapy, radiation, or major surgery/significant trauma. Participant has an active infection requiring therapy. Participant has had an allogenetic tissue/solid organ ransplant. Participant has active autoimmune disease that has required systemic treatment within the past 2 years (eg, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Participant has known active Hepatitis B, Hepatitis C or tuberculosis. Active Hepatitis B is defined as a known positive HBsAg result. Active Hepatitis C is defined by a known positive Hepatitis C antibody result and known quantitative Hepatitis C virus (HCV) ribonucleic acid (RNA) results greater than the lower limits of detection of the assay. Participant has had any other malignancy within 5 years prior to randomization, with the exception of adequately treated in situ carcinoma of the cervix, uterus, or nonmelanomatous skin cancer (all treatment of which should have been completed 6 months prior to enrollment). Participant has a history of inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis), celiac disease (ie, sprue), prior gastrectomy or upper bowel removal, or any other gastrointestinal disorder or defect that would interfere with the absorption, distribution, metabolism, or excretion of the IP and/or predispose the participant to an increased risk of gastrointestinal toxicity. Participant has persistent diarrhea or clinically significant malabsorption syndrome or known sub-acute bowel obstruction ≥ Grade 2, despite medical management Participant has significant active cardiac disease within the previous 6 months including unstable angina or angina requiring surgical or medical intervention, significant cardiac arrhythmia, or New York Heart Association (NYHA) class 3 or 4 congestive heart failure. Participant has history of interstitial lung disease (ILD) OR a history of pneumonitis that has required oral or IV steroids. Participants whose pneumonitis was solely as a result of radiation therapy for their NSCLC would not be excluded from the study unless they received oral/IV steroids to manage the pneumonitis. Participant has a known history or current diagnosis of human immunodeficiency virus (HIV) infection, regardless of treatment status. Participant has any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator's judgment, contraindicate patient participation in the clinical study (eg, chronic pancreatitis, etc.). Participant with uncontrolled or symptomatic central nervous system (CNS) metastases and/or carcinomatous meningitis Participants with controlled and asymptomatic CNS metastases may participate in this trial. The patient must have completed any prior treatment for CNS metastases (must include radiotherapy and/or surgery) ≥ 28 days (≥ 14 days for stereotactic radiosurgery) and, if on corticosteroid therapy, should be receiving a stable dose of no greater than 4 mg/d dexamethasone (or equivalent anti-inflammatory potency of another corticosteroid) for at least 14 days before start of study treatment). Patients must not be receiving corticosteroids for brain metastases. Partcipant has not recovered from the acute toxic effects (Common Terminology Criteria for Adverse Events [CTCAE] grade ≤ 1) of prior anticancer therapy, radiation, or major surgery/significant trauma (except alopecia or other toxicities not considered a safety risk for the particiapants at the Investigator's discretion). Participant has an impaired ability to swallow oral medication. Participant is pregnant or breast feeding. Participant has any condition that confounds the ability to interpret data from the study. Participant is or has an immediate family member (spouse or children) who is investigational site or sponsor staff directly involved with this trial, unless prospective Institutional Review Board (IRB) approval (by chair or designee) is given allowing exception to this criterion for a specific participant.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CC-486 plus Pembrolizumab<br>In the experimental arm, participants will receive a combination of two investigational drugs, CC-486 and pembrolizumab every 21-days. | Drug: CC-486<br>* CC-486 will be administered orally at a dose of 300 mg daily on days 1-14 of each 21-day cycle.<br>* Other names: Oral Azacitidine;Drug: Pembrolizumab<br>* Pembrolizumab will be administered as a 30-minute IV infusion on day 1 of each 21-day cycle.<br>* Other names: MK-3475;|
| Experimental: Pembrolizumab plus Placebo<br>In this control arm, participants will receive pembrolizumab as a 30 minute IV infusion on day 1 of each 21-day cycle and placebo will be administered by mouth daily on days 1 to 14 of each 21 day cycle. Placebo will also be administered in order to allow blinding of the study. | Drug: Pembrolizumab<br>* Pembrolizumab will be administered as a 30-minute IV infusion on day 1 of each 21-day cycle.<br>* Other names: MK-3475;Drug: Placebo<br>* Placebo will be administered orally daily on days 1-14 of each 21-day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kaplan Meier Estimate of Progression-Free Survival (PFS) Based on Food and Drug Administration (FDA) Methodology | PFS was defined according to the FDA Methodology as the time in months from the date of randomization to the date of disease progression according to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 (documented by computed tomography scan, not including symptomatic deterioration) or death for (any cause) on or prior to the clinical cutoff date, whichever occurred earlier. Those who did not have disease progression or had not died as of the data cutoff date were censored at the time of the last radiologic assessment where the participant was documented to be progression-free prior to the data cutoff date. Progressive disease includes at least a 20% increase in the sum of diameters of target lesions from nadir or appearance of a new lesion. | From Day 1 of study drug treatment to the date of disease progression; up to the clinical cut-off date of 12 April 2017; overall maximum treatment duration was 61 weeks for the CC-486 + PBZ arm and 60 weeks for the PBZ + Placebo arm | 
| Kaplan Meier Estimate of Progression-Free Survival (PFS) Based on European Medicines Agency Methodology | Progression-free survival was defined according to EMA methodology as the time from the date of randomization to the date of disease progression according to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 (documented by computed tomography scan result, not including symptomatic deterioration) or death for (any cause) on or prior to the data cutoff date, whichever occurred earlier. Participants who did not have disease progression or had not died were censored at the last known time that the participant was progression free. However, occasional missing observations or initiation of subsequent new anticancer therapy would not result in censoring for this analysis. Progressive disease is at least a 20% increase in the sum of diameters of target lesions from nadir or appearance of a new lesion. | From Day 1 of study drug treatment to the date of disease progression; up to the clinical cut-off date of 12 April 2017; overall maximum treatment duration was 61 weeks for the CC-486 + PBZ arm and 60 weeks for the PBZ + Placebo arm | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved a Complete Response (CR), Partial Response (PR) or Stable Disease (SD) for a Minimum Duration of 18 Weeks Compared to Baseline | Disease control rate was defined as the percentage of participants who had confirmed stable disease, complete or partial response during the course of study, according to RECIST v1.1, as evaluated by the investigator. RECIST v 1.1 is defined as: Complete response: disappearance of all target lesions Partial response: at least a 30% decrease in the sum of diameters of target lesions from baseline Stable disease: neither sufficient shrinkage to qualify for PR nor sufficient increase of lesions to qualify for progressive disease Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions from nadir or appearance of a new lesion. When stable disease was believed to be the best response, it must have met the minimum duration of 10 weeks from randomization. | Response was assessed every 6 weeks for the first 24 weeks, then every 9 weeks until DP, new anticancer initiation, or withdrawal of consent; maximum treatment exposure for CC-486 + PBZ was 61 weeks and 60 weeks for PBO +PBZ | 
| Kaplan Meier Estimate of Overall Survival | Overall survival (OS) was defined as the time in months between day 1 of treatment and death from any cause. Participants who were still alive as of the clinical cut-off date had their OS censored at the date of last contact or clinical cut-off, whichever was earlier. Participants who were lost to follow-up prior to the end of the study or who were withdrawn from the study were censored at the time of last contact. | From Day 1 of treatment up to the clinical cut-off date of 12 April 2017, whichever occurred earlier; median follow-up time for OS was 11.3 months in the CC-486 + PBZ arm and 12.2 months in the PBZ + Placebo arm | 
| Percentage of Participants Who Achieved a Best Overall Response of Complete Response or Partial Response | The best overall response is defined as the percentage of participants who achieved an objective confirmed complete response or partial response according to RECIST v1.1, compared with baseline where baseline was the last computed tomography (CT) scan obtained prior to or on day 1 of study treatment. RECIST v1.1 is defined as: Complete response: disappearance of all target lesions Partial response: at least a 30% decrease in the sum of diameters of target lesions from baseline Stable disease: neither sufficient shrinkage to qualify for PR nor sufficient increase of lesions to qualify for progressive disease Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions from nadir or appearance of a new lesion. | Response was assessed every 6 weeks for the first 24 weeks, then every 9 weeks until DP, new anticancer initiation, or withdrawal of consent; maximum treatment exposure for CC-486 + PBZ was 61 weeks and 60 weeks for PBZ + PBO | 
| Number of Participants With Treatment Emergent Adverse Events | Treatment-emergent adverse events (TEAEs) were defined as any adverse event (AE) or serious adverse event (SAE) that occurred or worsened on or after the day of the first dose of the investigational product (IP) through 28 days after the last dose of IP. In addition, any SAE with an onset date more than 28 day after the last dose of IP that was assessed by the investigator as related to IP was considered a TEAE. The severity of AEs was graded based on National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 and based on the following scale: Grade 1 = Mild; Grade 2 = Moderate Grade 3 = Severe Grade 4 = Life threatening Grade 5 = Death. | From date of first dose of study treatment until 30 days after the last dose of IP; overall maximum treatment duration was 61 weeks for the CC-486 + PBZ arm and 60 weeks for the PBZ + Placebo arm | 
| Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC∞) of CC-486 | Area under the plasma concentration-time curve from Time 0 extrapolated to infinity, calculated as [AUCt + Ct/ λz]. Ct is the last quantifiable concentration. No AUC extrapolation was performed with unreliable λz. If AUC % extrap is ≥25%, AUCi inf was not reported. | Pharmacokinetic (PK) blood samples collected at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6 and 8 hours after CC-486 administration on Cycle 1 Day 1 and Cycle 2 Day 1 | 
| Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUCt) of CC-486 | Area under the plasma concentration-time curve from Time 0 to the time of the last quantifiable concentration, calculated by linear trapezoidal method when concentrations are increasing and the logarithmic trapezoidal method when concentrations are decreasing. | PK blood samples collected at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6 and 8 hours after CC-486 administration on Cycle 1 Day 1 and Cycle 2 Day 1 | 
| Maximum Observed Plasma Concentration (Cmax) of CC-486 | Maximum observed plasma concentration, obtained directly from the observed concentration versus time data. | PK blood samples collected at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6 and 8 hours after CC-486 administration on Cycle 1 Day 1 and Cycle 2 Day 1 | 
| Time to Maximum Plasma Concentration (Tmax) of CC-486 | Time to maximum observed plasma concentration obtained directly from the observed concentration versus time data. | PK blood samples collected at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6 and 8 hours after CC-486 administration on Cycle 1 Day 1 and Cycle 2 Day 1 | 
| Terminal Phase of Half-life (T1/2) of CC-486 | Terminal phase half-life in plasma, calculated as [(ln 2)/λz]. t1/2 was only be calculated when a reliable estimate for λz could be obtained. | PK blood samples collected at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6 and 8 hours after CC-486 administration on Cycle 1 Day 1 and Cycle 2 Day 1 | 
| Apparent Total Plasma Clearance (CL/F) of CC-486 | Apparent total plasma clearance (CL/F) of CC-486 was calculated as Dose/AUC∞ | PK blood samples collected at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6 and 8 hours after CC-486 administration on Cycle 1 Day 1 and Cycle 2 Day 1 | 
| Apparent Volume of Distribution (Vd/F) of CC-486 | Apparent volume of distribution, was calculated according to the equation: Vd/F = (CL/F)/λz | PK blood samples collected at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6 and 8 hours after CC-486 administration on Cycle 1 Day 1 and Cycle 2 Day 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NSCLC, CC-486, Azacitidine, Oral azacitidine, Methyltransferase inhibitor, Hypomethylation, Hypomethylating agent, Epigenetic, MK-3475, Pembrolizumab, Keytruda, PD-1, PD-L1, ImmunotherapyAdvanced non-small cell lung cancer, Metastatic non-small cell lung cancer, Non-small cell lung cancer, Merck Pembrolizumab (Keynote-117)