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

• Sponsor: Celgene (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02546986
• Collaborator: (none)
• Enrollment: 100
• Locations: 33
• Arms: 2
• Anticipated Duration (Months): 89.8
• Patients Per Site: 3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Non-Small-Cell Lung	Drug: CC-486; Drug: Pembrolizumab; Drug: Placebo	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Oct 9, 2015
• Actual Primary Completion Date: Apr 13, 2017
• Anticipated Study Completion Date: Apr 2, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CC-486 plus Pembrolizumab In the experimental arm, participants will receive a combination of two investigational drugs, CC-486 and pembrolizumab every 21-days.	Drug: CC-486; CC-486 will be administered orally at a dose of 300 mg daily on days 1-14 of each 21-day cycle.; Other Names: Oral Azacitidine ; Drug: Pembrolizumab; Pembrolizumab will be administered as a 30-minute IV infusion on day 1 of each 21-day cycle.; Other Names: MK-3475
Experimental: Pembrolizumab plus Placebo 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; Pembrolizumab will be administered as a 30-minute IV infusion on day 1 of each 21-day cycle.; Other Names: MK-3475 ; Drug: Placebo; Placebo will be administered orally daily on days 1-14 of each 21-day cycle.

Outcome Measures

Primary Outcome Measures

1. Kaplan Meier Estimate of Progression-Free Survival (PFS) Based on Food and Drug Administration (FDA) Methodology [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]

   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.

2. Kaplan Meier Estimate of Progression-Free Survival (PFS) Based on European Medicines Agency Methodology [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]

   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.

Secondary Outcome Measures

1. 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 [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]

   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.

2. Kaplan Meier Estimate of Overall Survival [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]

   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.

3. Percentage of Participants Who Achieved a Best Overall Response of Complete Response or Partial Response [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]

   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.

4. Number of Participants With Treatment Emergent Adverse Events [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]

   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.

5. Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC∞) of CC-486 [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 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.

6. Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUCt) of CC-486 [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 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.

7. Maximum Observed Plasma Concentration (Cmax) of CC-486 [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, obtained directly from the observed concentration versus time data.

8. Time to Maximum Plasma Concentration (Tmax) of CC-486 [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 observed plasma concentration obtained directly from the observed concentration versus time data.

9. Terminal Phase of Half-life (T1/2) of CC-486 [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 half-life in plasma, calculated as [(ln 2)/λz]. t1/2 was only be calculated when a reliable estimate for λz could be obtained.

10. Apparent Total Plasma Clearance (CL/F) of CC-486 [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 was calculated as Dose/AUC∞

11. Apparent Volume of Distribution (Vd/F) of CC-486 [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, was calculated according to the equation: Vd/F = (CL/F)/λz

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Participant is ≥ 18 years of age at the time of signing the informed consent form.

2. Participant has histologically or cytologically confirmed squamous or non-squamous non-small cell lung cancer (NSCLC).

3. 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.

4. 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.

5. Participant has radiographically-documented measurable disease, as per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1).

6. Particiapant has an Eastern Cancer Oncology Group (ECOG) performance status of 0 to 1.

7. Participant has adequate organ functions, evidenced by the following:

8. 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

9. Total bilirubin ≤ 1.5 x ULN

10. Serum creatinine ≤ 1.5 x ULN

11. Potassium within normal range, or correctable with supplements

12. Participant has adequate bone marrow function, evidenced by the following:

13. Absolute neutrophil count ≥ 1.5 x 10^9 cells/L

14. Platelets ≥ 100 x 10^9 cells/L

15. Hemoglobin ≥ 9 g/dL

16. 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

17. 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

18. 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:

19. 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.

20. 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.

21. 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.

1. Participant is willing to adhere to the study visit schedule and other protocol requirements.

2. Participant understands and voluntarily signs an informed consent document prior to any study related assessments or procedures are conducted.

Exclusion Criteria:

1. 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.

2. Participant has received more than one line of therapy for stage IIIB or IV disease

3. Participant has been previously treated with azacitidine (any formulation), decitabine, or any other hypomethylating agent.

4. 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.

1. 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).

1. 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.

2. 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

3. Participant has previous severe hypersensitivity reaction to another monoclonal antibody (mAb).

4. 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).

5. Participant has had radiotherapy ≤ 4 weeks or limited field radiation for palliation

6. Participant has received radiation therapy to the lung that is > 30 Gy within 6 months of the first dose of trial treatment

7. 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.

8. Participant has not recovered from the acute toxic effects of prior anticancer therapy, radiation, or major surgery/significant trauma.

9. Participant has an active infection requiring therapy.

10. Participant has had an allogenetic tissue/solid organ ransplant.

11. 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.

12. 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.

13. 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).

14. 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.

15. Participant has persistent diarrhea or clinically significant malabsorption syndrome or known sub-acute bowel obstruction ≥ Grade 2, despite medical management

16. 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.

17. 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.

18. Participant has a known history or current diagnosis of human immunodeficiency virus (HIV) infection, regardless of treatment status.

19. 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.).

20. 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.

21. 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).

22. Participant has an impaired ability to swallow oral medication.

23. Participant is pregnant or breast feeding.

24. Participant has any condition that confounds the ability to interpret data from the study.

25. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Palo Verde Hematology Oncology	Glendale	Arizona	United States	85304
2	UCLA Hematology Oncology	Los Angeles	California	United States	90095
3	Georgetown University Medical Center	Washington	District of Columbia	United States	20057
4	University Cancer and Blood Center, LLC	Athens	Georgia	United States	30607
5	Research Medical Center	Kansas City	Missouri	United States	64132
6	Washington Univ School of Medicine	Saint Louis	Missouri	United States	63110
7	North Shore Hematology Oncology Associates	East Setauket	New York	United States	11733-3456
8	Beth Israel Comprehensive Cancer Center	New York	New York	United States	10011
9	NYU Langone Medical Center	New York	New York	United States	10016
10	Vanderbilt Univ Medical Center	Nashville	Tennessee	United States	37232-6307
11	Centre Leon Berard	Lyon		France	69008
12	CHU Amiens Picardie- Hôpital Nord	Marseille		France	13915
13	Centre Hospitalier Universitaire de Toulouse	Toulouse		France	31059
14	Institut Gustave Roussy IGR Centre de Lutte Contre le Canc	Villejuif		France	94805
15	Evangelische Lungenklinik Berlin	Berlin		Germany	13125
16	Klinikum Esslingen GmbH	Esslingen Am Neckar		Germany	73730
17	Universitatsklinikum Koln	Koeln		Germany	50937
18	Klinik Lowenstein gGmbH	Löwenstein		Germany	74245
19	IASO General	Athens		Greece	15562
20	Centro Di Riferimento Oncologico	Aviano		Italy	33081
21	Azienda Ospedaliero Universitaria Policlinico Vittorio Emanuele	Catania		Italy	95122
22	Ospedale San Raffaele S.r.l.	Milano		Italy	20132
23	Istituto Nazionale Dei Tumori	Milano		Italy	20133
24	Istituto Nazionale Per Lo Studio E La Cura Dei Tumori Fondazione Giovanni Pascale	Napoli, Campania		Italy	80131
25	A.O.U. Maggiore della Carità	Novara		Italy	28100
26	Policlinico Universitario Campus Biomedico Di Roma	Roma		Italy	128
27	Hospital De Cruces	Baracaldo		Spain	48903
28	Hospital Universitario Vall D hebron	Barcelona		Spain	08035
29	Hospital Universitario Ramon y Cajal	Madrid		Spain	28034
30	Fundacion Jimenez Daaz	Madrid		Spain	28040
31	Hospital Clinico San Carlos	Madrid		Spain	28040
32	Hospital Universitario 12 de Octubre	Madrid		Spain	28041
33	Hospital General Universitario de Valencia	Valencia		Spain	46014

Sponsors and Collaborators

• Celgene

Investigators

• Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Study Documents (Full-Text)

• Study Protocol: CC-486-NSCL-001_original protocol_Redacted.15May2015 - May 15, 2015
• Study Protocol: CC-486-NSCL-001.ProtocolAM1.14December 2015 - Dec 14, 2015
• Statistical Analysis Plan - Jun 28, 2017

More Information

Publications

None provided.

• Responsible Party: Celgene
• ClinicalTrials.gov Identifier: NCT02546986
• Other Study ID Numbers: CC-486-NSCL-001
• First Posted: Sep 11, 2015
• Last Update Posted: Jan 28, 2022
• Last Verified: Jan 1, 2022

• Keywords provided by Celgene: 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; NSCLC; Merck Pembrolizumab (Keynote-117)
• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Pembrolizumab; Azacitidine; Cc-486

Study Results

Participant Flow

Recruitment Details	This study was a multicenter study with 25 sites from the United States, France. Germany, Italy, and Spain.
Pre-assignment Detail	Qualified participants were randomized in a 1:1 ratio to one of the two treatment groups. Randomization was stratified by cancer histology (non-squamous versus squamous).

Arm/Group Title	CC-486 and Pembrolizumab (CC-486 + PBZ)	Placebo and Pembrolizumab (PBO + PBZ)
Arm/Group Description	Participants received CC-486 300 mg tablets by mouth (PO) on Days 1-14 of each 21-day treatment cycle and pembrolizumab (PBZ) 200 mg administered as a 30-minute intravenous (IV) infusion on Day 1 of each 21-day cycle until radiologic disease progression (DP), unacceptable toxicity, initiation of a new anticancer therapy, withdrawal of consent, subject refusal, physician decision, or death.	Participant received placebo tablets (identically matching in appearance to CC-486) administered orally daily on Days 1-14 plus pembrolizumab 200 mg administered as a 30-minute IV infusion on Day 1 of each 21-day cycle until radiologic disease progression, unacceptable toxicity, initiation of a new anticancer therapy, withdrawal of consent, subject refusal, physician decision, or death.
Period Title: Treatment Period
STARTED	51	49
COMPLETED	0	0
NOT COMPLETED	51	49
Period Title: Treatment Period
STARTED	36	35
COMPLETED	0	0
NOT COMPLETED	36	35

Baseline Characteristics

Arm/Group Title	CC-486 and Pembrolizumab (CC-486 + PBZ)	Placebo and Pembrolizumab (PBO + PBZ)	Total
Arm/Group Description	Participants received CC-486 300 mg tablets by mouth (PO) on Days 1-14 of each 21-day treatment cycle and pembrolizumab (PBZ) 200 mg administered as a 30-minute intravenous (IV) infusion on Day 1 of each 21-day cycle until radiologic disease progression (DP), unacceptable toxicity, initiation of a new anticancer therapy, withdrawal of consent, subject refusal, physician decision, or death.	Participant received placebo tablets (identically matching in appearance to CC-486) administered orally daily on Days 1-14 plus pembrolizumab 200 mg administered as a 30-minute IV infusion on Day 1 of each 21-day cycle until radiologic disease progression, unacceptable toxicity, initiation of a new anticancer therapy, withdrawal of consent, subject refusal, physician decision, or death.	Total of all reporting groups
Overall Participants	51	49	100
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	62.8 (10.03)	64.9 (9.89)	63.9 (9.96)
Sex: Female, Male (Count of Participants)
Female	25 49%	18 36.7%	43 43%
Male	26 51%	31 63.3%	57 57%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	1 2%	1 1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	3 5.9%	2 4.1%	5 5%
White	42 82.4%	45 91.8%	87 87%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	6 11.8%	1 2%	7 7%
Eastern Cooperative Oncology Group (ECOG) Performance Status (Count of Participants)
0 = Fully Active	15 29.4%	17 34.7%	32 32%
1 = Restrictive but ambulatory	36 70.6%	32 65.3%	68 68%
2 = ambulatory but unable to work	0 0%	0 0%	0 0%
3 = limited self-care	0 0%	0 0%	0 0%
Stage at Primary Diagnosis (Count of Participants)
Stage I	3 5.9%	2 4.1%	5 5%
Stage II	0 0%	4 8.2%	4 4%
Stage IIIA	2 3.9%	4 8.2%	6 6%
Stage IIIB	8 15.7%	7 14.3%	15 15%
Stage IV	38 74.5%	32 65.3%	70 70%
Histology (Count of Participants)
Squamous cell carcinoma	10 19.6%	8 16.3%	18 18%
Adenocarcinoma	38 74.5%	36 73.5%	74 74%
Other	3 5.9%	5 10.2%	8 8%
Number of Metastatic Sites (Metastatic sites) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Metastatic sites]	3.1 (1.33)	2.8 (1.25)	3.0 (1.29)
Number of Participants Randomized by Strata (Count of Participants)
Squamous Cell Carcinoma	9 17.6%	9 18.4%	18 18%
Non-Squamous Cell Carcinoma	42 82.4%	40 81.6%	82 82%

Outcome Measures

1. Primary Outcome

Title	Kaplan Meier Estimate of Progression-Free Survival (PFS) Based on Food and Drug Administration (FDA) Methodology
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

The Intent-to-Treat population includes all participants who were randomized, regardless of whether they received assigned treatment or not.

Arm/Group Title	CC-486 and Pembrolizumab (CC-486 + PBZ)	Placebo and Pembrolizumab (PBO + PBZ)
Arm/Group Description	Participants received CC-486 300 mg tablets by mouth (PO) on Days 1-14 of each 21-day treatment cycle and pembrolizumab (PBZ) 200 mg administered as a 30-minute intravenous (IV) infusion on Day 1 of each 21-day cycle until radiologic disease progression (DP), unacceptable toxicity, initiation of a new anticancer therapy, withdrawal of consent, subject refusal, physician decision, or death.	Participant received placebo tablets (identically matching in appearance to CC-486) administered orally daily on Days 1-14 plus pembrolizumab 200 mg administered as a 30-minute IV infusion on Day 1 of each 21-day cycle until radiologic disease progression, unacceptable toxicity, initiation of a new anticancer therapy, withdrawal of consent, subject refusal, physician decision, or death.
Measure Participants	51	49
Median (90% Confidence Interval) [months]	2.9	4.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CC-486 and Pembrolizumab (CC-486 + PBZ), Placebo and Pembrolizumab (PBO + PBZ)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1789
	Comments
	Method	Stratified Log-Rank Test
	Comments	Stratified by squamous cell carcinoma versus non-squamous cell carcinoma
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.374
	Confidence Interval	(2-Sided) 90%; 0.926 to 2.038
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio and associated 2-sided 90% CIs were estimated using a Cox proportional hazard model

2. Secondary Outcome

Title	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
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

The Intent-to-Treat population includes all participants who were randomized, regardless of whether they received assigned treatment or not.

Arm/Group Title	CC-486 and Pembrolizumab (CC-486 + PBZ)	Placebo and Pembrolizumab (PBO + PBZ)
Arm/Group Description	Participants received CC-486 300 mg tablets by mouth (PO) on Days 1-14 of each 21-day treatment cycle and pembrolizumab (PBZ) 200 mg administered as a 30-minute intravenous (IV) infusion on Day 1 of each 21-day cycle until radiologic disease progression (DP), unacceptable toxicity, initiation of a new anticancer therapy, withdrawal of consent, subject refusal, physician decision, or death.	Participant received placebo tablets (identically matching in appearance to CC-486) administered orally daily on Days 1-14 plus pembrolizumab 200 mg administered as a 30-minute IV infusion on Day 1 of each 21-day cycle until radiologic disease progression, unacceptable toxicity, initiation of a new anticancer therapy, withdrawal of consent, subject refusal, physician decision, or death.
Measure Participants	51	49
Number (90% Confidence Interval) [Percentage of Participants]	25.5 50%	38.8 79.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CC-486 and Pembrolizumab (CC-486 + PBZ), Placebo and Pembrolizumab (PBO + PBZ)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1572
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Stratified by squamous cell carcinoma vs non-squamous cell carcinoma
Method of Estimation	Estimation Parameter	Disease Control Rate Difference
	Estimated Value	-13.3
	Confidence Interval	(2-Sided) 90%; -29.0 to 3.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Kaplan Meier Estimate of Overall Survival
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

The Intent-to-Treat population includes all participants who were randomized.

Arm/Group Title	CC-486 and Pembrolizumab (CC-486 + PBZ)	Placebo and Pembrolizumab (PBO + PBZ)
Arm/Group Description	Participants received CC-486 300 mg tablets by mouth (PO) on Days 1-14 of each 21-day treatment cycle and pembrolizumab (PBZ) 200 mg administered as a 30-minute intravenous (IV) infusion on Day 1 of each 21-day cycle until radiologic disease progression (DP), unacceptable toxicity, initiation of a new anticancer therapy, withdrawal of consent, subject refusal, physician decision, or death.	Participant received placebo tablets (identically matching in appearance to CC-486) administered orally daily on Days 1-14 plus pembrolizumab 200 mg administered as a 30-minute IV infusion on Day 1 of each 21-day cycle until radiologic disease progression, unacceptable toxicity, initiation of a new anticancer therapy, withdrawal of consent, subject refusal, physician decision, or death.
Measure Participants	51	49
Median (90% Confidence Interval) [months]	11.9	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CC-486 and Pembrolizumab (CC-486 + PBZ), Placebo and Pembrolizumab (PBO + PBZ)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2968
	Comments
	Method	Stratified Log Rank
	Comments	Stratified by squamous cell carcinoma vs non-squamous cell carcinoma).
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.375
	Confidence Interval	(2-Sided) 90%; 0.830 to 2.276
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio and associated 2-sided 90% CIs were estimated using Cox proportional hazard model.

4. Secondary Outcome

Title	Percentage of Participants Who Achieved a Best Overall Response of Complete Response or Partial Response
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

The Intent-to-Treat population includes all participants who were randomized.

Arm/Group Title	CC-486 and Pembrolizumab (CC-486 + PBZ)	Placebo and Pembrolizumab (PBO + PBZ)
Arm/Group Description	Participants received CC-486 300 mg tablets by mouth (PO) on Days 1-14 of each 21-day treatment cycle and pembrolizumab (PBZ) 200 mg administered as a 30-minute intravenous (IV) infusion on Day 1 of each 21-day cycle until radiologic disease progression (DP), unacceptable toxicity, initiation of a new anticancer therapy, withdrawal of consent, subject refusal, physician decision, or death.	Participant received placebo tablets (identically matching in appearance to CC-486) administered orally daily on Days 1-14 plus pembrolizumab 200 mg administered as a 30-minute IV infusion on Day 1 of each 21-day cycle until radiologic disease progression, unacceptable toxicity, initiation of a new anticancer therapy, withdrawal of consent, subject refusal, physician decision, or death.
Measure Participants	51	49
Number (90% Confidence Interval) [Percentage of Participants]	19.6 38.4%	14.3 29.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CC-486 and Pembrolizumab (CC-486 + PBZ), Placebo and Pembrolizumab (PBO + PBZ)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Overall Response Rate (ORR) Difference
	Estimated Value	5.3
	Confidence Interval	(2-Sided) 90%; -11.5 to 21.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	The 90% exact unconditional confidence interval was used for ORR difference.

5. Secondary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

The safety population includes all participants who were randomized and received at least one dose of study drug.

Arm/Group Title	CC-486 and Pembrolizumab (CC-486 + PBZ)	Placebo and Pembrolizumab (PBO + PBZ)
Arm/Group Description	Participants received CC-486 300 mg tablets by mouth (PO) on Days 1-14 of each 21-day treatment cycle and pembrolizumab (PBZ) 200 mg administered as a 30-minute intravenous (IV) infusion on Day 1 of each 21-day cycle until radiologic disease progression (DP), unacceptable toxicity, initiation of a new anticancer therapy, withdrawal of consent, subject refusal, physician decision, or death.	Participant received placebo tablets (identically matching in appearance to CC-486) administered orally daily on Days 1-14 plus pembrolizumab 200 mg administered as a 30-minute IV infusion on Day 1 of each 21-day cycle until radiologic disease progression, unacceptable toxicity, initiation of a new anticancer therapy, withdrawal of consent, subject refusal, physician decision, or death.
Measure Participants	51	49
Any TEAE	51 100%	49 100%
Any TEAE Related to Study Drug	47 92.2%	37 75.5%
Any Serious TEAE	31 60.8%	27 55.1%
Any Serious TEAE Related to Study Drug	12 23.5%	6 12.2%
Any CTC Grade 3/4 TEAE	40 78.4%	27 55.1%
Any CTC Grade 3/4 TEAE Related to Study Drug	25 49%	10 20.4%
Any TEAE Leading to Death	6 11.8%	9 18.4%
Any TEAE Leading to Dose Reduction	10 19.6%	1 2%
Any TEAE Leading to Dose Interruption	32 62.7%	20 40.8%
Any TEAE Leading to Drug Discontinuation	20 39.2%	8 16.3%

6. Primary Outcome

Title	Kaplan Meier Estimate of Progression-Free Survival (PFS) Based on European Medicines Agency Methodology
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

The Intent-to-Treat population includes all participants who were randomized, regardless of whether they received assigned treatment or not.

Arm/Group Title	CC-486 and Pembrolizumab (CC-486 + PBZ)	Placebo and Pembrolizumab (PBO + PBZ)
Arm/Group Description	Participants received CC-486 300 mg tablets by mouth (PO) on Days 1-14 of each 21-day treatment cycle and pembrolizumab (PBZ) 200 mg administered as a 30-minute intravenous (IV) infusion on Day 1 of each 21-day cycle until radiologic disease progression (DP), unacceptable toxicity, initiation of a new anticancer therapy, withdrawal of consent, subject refusal, physician decision, or death.	Participant received placebo tablets (identically matching in appearance to CC-486) administered orally daily on Days 1-14 plus pembrolizumab 200 mg administered as a 30-minute IV infusion on Day 1 of each 21-day cycle until radiologic disease progression, unacceptable toxicity, initiation of a new anticancer therapy, withdrawal of consent, subject refusal, physician decision, or death.
Measure Participants	51	49
Median (90% Confidence Interval) [months]	2.9	4.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CC-486 and Pembrolizumab (CC-486 + PBZ), Placebo and Pembrolizumab (PBO + PBZ)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1990
	Comments
	Method	Stratified Log-Rank Test
	Comments	Stratified by squamous cell carcinoma versus non-squamous cell carcinoma
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.352
	Confidence Interval	(2-Sided) 90%; 0.914 to 2.000
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio and associated 2-sided 90% CIs were estimated using a Cox proportional hazard model

7. Secondary Outcome

Title	Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC∞) of CC-486
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

The PK population includes participants with evaluable CC-486 plasma PK profile.

Arm/Group Title	CC-486 and Pembrolizumab (CC-486 + PBZ)
Arm/Group Description	Participants received CC-486 300 mg tablets by mouth (PO) on Days 1-14 of each 21-day treatment cycle and pembrolizumab (PBZ) 200 mg administered as a 30-minute intravenous (IV) infusion on Day 1 of each 21-day cycle until radiologic disease progression (DP), unacceptable toxicity, initiation of a new anticancer therapy, withdrawal of consent, subject refusal, physician decision, or death.
Measure Participants	15
Cycle 1 Day 1	156.0 (82.64)
Cycle 2 Day 1	212.7 (78.06)

8. Secondary Outcome

Title	Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUCt) of CC-486
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

The PK population includes participants with evaluable CC-486 plasma PK profile.

Arm/Group Title	CC-486 and Pembrolizumab (CC-486 + PBZ)
Arm/Group Description	Participants received CC-486 300 mg tablets by mouth (PO) on Days 1-14 of each 21-day treatment cycle and pembrolizumab (PBZ) 200 mg administered as a 30-minute intravenous (IV) infusion on Day 1 of each 21-day cycle until radiologic disease progression (DP), unacceptable toxicity, initiation of a new anticancer therapy, withdrawal of consent, subject refusal, physician decision, or death.
Measure Participants	15
Cycle 1 Day 1	152.3 (85.67)
Cycle 2 Day 1	196.6 (88.63)

9. Secondary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) of CC-486
Description	Maximum observed plasma concentration, obtained directly from the observed concentration versus time data.
Time Frame	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

Outcome Measure Data

Analysis Population Description

The PK population includes participants with evaluable CC-486 plasma PK profile.

Arm/Group Title	CC-486 and Pembrolizumab (CC-486 + PBZ)
Arm/Group Description	Participants received CC-486 300 mg tablets by mouth (PO) on Days 1-14 of each 21-day treatment cycle and pembrolizumab (PBZ) 200 mg administered as a 30-minute intravenous (IV) infusion on Day 1 of each 21-day cycle until radiologic disease progression (DP), unacceptable toxicity, initiation of a new anticancer therapy, withdrawal of consent, subject refusal, physician decision, or death.
Measure Participants	15
Cycle 1 Day 1	94.7 (69.49)
Cycle 2 Day 1	110.0 (73.46)

10. Secondary Outcome

Title	Time to Maximum Plasma Concentration (Tmax) of CC-486
Description	Time to maximum observed plasma concentration obtained directly from the observed concentration versus time data.
Time Frame	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

Outcome Measure Data

Analysis Population Description

The PK population includes participants with evaluable CC-486 plasma PK profile.

Arm/Group Title	CC-486 and Pembrolizumab (CC-486 + PBZ)
Arm/Group Description	Participants received CC-486 300 mg tablets by mouth (PO) on Days 1-14 of each 21-day treatment cycle and pembrolizumab (PBZ) 200 mg administered as a 30-minute intravenous (IV) infusion on Day 1 of each 21-day cycle until radiologic disease progression (DP), unacceptable toxicity, initiation of a new anticancer therapy, withdrawal of consent, subject refusal, physician decision, or death.
Measure Participants	15
Cycle 1 Day 1	1.5
Cycle 2 Day 1	1.5

11. Secondary Outcome

Title	Terminal Phase of Half-life (T1/2) of CC-486
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

The PK population includes participants with evaluable CC-486 plasma PK profile.

Arm/Group Title	CC-486 and Pembrolizumab (CC-486 + PBZ)
Arm/Group Description	Participants received CC-486 300 mg tablets by mouth (PO) on Days 1-14 of each 21-day treatment cycle and pembrolizumab (PBZ) 200 mg administered as a 30-minute intravenous (IV) infusion on Day 1 of each 21-day cycle until radiologic disease progression (DP), unacceptable toxicity, initiation of a new anticancer therapy, withdrawal of consent, subject refusal, physician decision, or death.
Measure Participants	15
Cycle 1 Day 1	0.7 (30.22)
Cycle 2 Day 1	0.9 (91.72)

12. Secondary Outcome

Title	Apparent Total Plasma Clearance (CL/F) of CC-486
Description	Apparent total plasma clearance (CL/F) of CC-486 was calculated as Dose/AUC∞
Time Frame	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

Outcome Measure Data

Analysis Population Description

The PK population includes participants with evaluable CC-486 plasma PK profile.

Arm/Group Title	CC-486 and Pembrolizumab (CC-486 + PBZ)
Arm/Group Description	Participants received CC-486 300 mg tablets by mouth (PO) on Days 1-14 of each 21-day treatment cycle and pembrolizumab (PBZ) 200 mg administered as a 30-minute intravenous (IV) infusion on Day 1 of each 21-day cycle until radiologic disease progression (DP), unacceptable toxicity, initiation of a new anticancer therapy, withdrawal of consent, subject refusal, physician decision, or death.
Measure Participants	15
Cycle 1 Day 1	1922.7 (82.64)
Cycle 2 Day 1	1410.4 (78.06)

13. Secondary Outcome

Title	Apparent Volume of Distribution (Vd/F) of CC-486
Description	Apparent volume of distribution, was calculated according to the equation: Vd/F = (CL/F)/λz
Time Frame	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

Outcome Measure Data

Analysis Population Description

The PK population includes participants with evaluable CC-486 plasma PK profile.

Arm/Group Title	CC-486 and Pembrolizumab (CC-486 + PBZ)
Arm/Group Description	Participants received CC-486 300 mg tablets by mouth (PO) on Days 1-14 of each 21-day treatment cycle and pembrolizumab (PBZ) 200 mg administered as a 30-minute intravenous (IV) infusion on Day 1 of each 21-day cycle until radiologic disease progression (DP), unacceptable toxicity, initiation of a new anticancer therapy, withdrawal of consent, subject refusal, physician decision, or death.
Measure Participants	15
Cycle 1 Day 1	1836.2 (100.80)
Cycle 2 Day 1	1777.1 (163.62)

Adverse Events

Time Frame	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 for the PBZ + PBO arm.
Adverse Event Reporting Description	All-cause mortality timeframe includes deaths from day 1 of study treatment to final data cut-off date of 12 April 2017
Arm/Group Title	CC-486+Pembrolizumab		Pembrolizumab+Placebo
Arm/Group Description	Participants received CC-486 300 mg tablets by mouth (PO) on Days 1-14 of each 21-day treatment cycle and pembrolizumab (PBZ) 200 mg administered as a 30-minute intravenous (IV) infusion on Day 1 of each 21-day cycle until radiologic disease progression (DP), unacceptable toxicity, initiation of a new anticancer therapy, withdrawal of consent, subject refusal, physician decision, or death.		Participants received placebo tablets orally on days 1-14 plus pembrolizumab 200 mg administered as a 30-minute IV infusion on day 1 of a 21-day cycle until radiologic disease progression, unacceptable toxicity, initiation of a new anticancer therapy, withdrawal of consent, subject refusal, physician decision, or death.
All Cause Mortality
	CC-486+Pembrolizumab		Pembrolizumab+Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/51 (45.1%)		20/49 (40.8%)
Serious Adverse Events
	CC-486+Pembrolizumab		Pembrolizumab+Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	31/51 (60.8%)		27/49 (55.1%)
Blood and lymphatic system disorders
Febrile neutropenia	2/51 (3.9%)		0/49 (0%)
Cardiac disorders
Pericardial effusion	1/51 (2%)		0/49 (0%)
Eye disorders
Diplopia	0/51 (0%)		1/49 (2%)
Gastrointestinal disorders
Abdominal pain	0/51 (0%)		1/49 (2%)
Colitis	2/51 (3.9%)		0/49 (0%)
Diarrhoea	3/51 (5.9%)		0/49 (0%)
Intestinal perforation	0/51 (0%)		1/49 (2%)
Nausea	4/51 (7.8%)		0/49 (0%)
Vomiting	4/51 (7.8%)		0/49 (0%)
General disorders
Asthenia	1/51 (2%)		0/49 (0%)
Death	0/51 (0%)		1/49 (2%)
Fatigue	1/51 (2%)		0/49 (0%)
General physical health deterioration	3/51 (5.9%)		1/49 (2%)
Non-cardiac chest pain	1/51 (2%)		0/49 (0%)
Pyrexia	1/51 (2%)		3/49 (6.1%)
Hepatobiliary disorders
Autoimmune hepatitis	1/51 (2%)		0/49 (0%)
Cholelithiasis	0/51 (0%)		1/49 (2%)
Hepatic failure	2/51 (3.9%)		1/49 (2%)
Hepatitis toxic	1/51 (2%)		0/49 (0%)
Hypertransaminasaemia	1/51 (2%)		0/49 (0%)
Infections and infestations
Bronchitis	1/51 (2%)		1/49 (2%)
Device related infection	1/51 (2%)		0/49 (0%)
Intervertebral discitis	1/51 (2%)		0/49 (0%)
Lower respiratory tract infection bacterial	1/51 (2%)		0/49 (0%)
Osteomyelitis	1/51 (2%)		0/49 (0%)
Pneumonia	2/51 (3.9%)		4/49 (8.2%)
Respiratory tract infection	1/51 (2%)		0/49 (0%)
Subcutaneous abscess	1/51 (2%)		0/49 (0%)
Injury, poisoning and procedural complications
Drug administration error	1/51 (2%)		0/49 (0%)
Toxicity to various agents	0/51 (0%)		1/49 (2%)
Investigations
Alanine aminotransferase increased	1/51 (2%)		0/49 (0%)
Aspartate aminotransferase increased	1/51 (2%)		0/49 (0%)
Metabolism and nutrition disorders
Diabetes mellitus	0/51 (0%)		1/49 (2%)
Electrolyte imbalance	0/51 (0%)		1/49 (2%)
Musculoskeletal and connective tissue disorders
Back pain	1/51 (2%)		0/49 (0%)
Bone pain	1/51 (2%)		0/49 (0%)
Flank pain	1/51 (2%)		0/49 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lymphangiosis carcinomatosa	0/51 (0%)		1/49 (2%)
Malignant pleural effusion	1/51 (2%)		0/49 (0%)
Metastases to central nervous system	1/51 (2%)		0/49 (0%)
Non-small cell lung cancer metastatic	0/51 (0%)		1/49 (2%)
Nervous system disorders
Ataxia	0/51 (0%)		1/49 (2%)
Dysarthria	0/51 (0%)		1/49 (2%)
Epilepsy	1/51 (2%)		0/49 (0%)
Ischaemic stroke	1/51 (2%)		0/49 (0%)
Somnolence	0/51 (0%)		1/49 (2%)
Psychiatric disorders
Irritability	0/51 (0%)		1/49 (2%)
Mental status changes	1/51 (2%)		0/49 (0%)
Renal and urinary disorders
Acute kidney injury	0/51 (0%)		1/49 (2%)
Nephritis	0/51 (0%)		1/49 (2%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	4/51 (7.8%)		3/49 (6.1%)
Haemoptysis	0/51 (0%)		3/49 (6.1%)
Hypoxia	0/51 (0%)		1/49 (2%)
Lung infiltration	0/51 (0%)		1/49 (2%)
Pleural effusion	0/51 (0%)		1/49 (2%)
Pleuritic pain	0/51 (0%)		1/49 (2%)
Pneumonia aspiration	1/51 (2%)		0/49 (0%)
Pneumonitis	0/51 (0%)		1/49 (2%)
Pneumothorax	0/51 (0%)		1/49 (2%)
Pulmonary embolism	0/51 (0%)		1/49 (2%)
Respiratory arrest	1/51 (2%)		0/49 (0%)
Respiratory failure	3/51 (5.9%)		3/49 (6.1%)
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysaesthesia syndrome	0/51 (0%)		1/49 (2%)
Other (Not Including Serious) Adverse Events
	CC-486+Pembrolizumab		Pembrolizumab+Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	51/51 (100%)		48/49 (98%)
Blood and lymphatic system disorders
Anaemia	12/51 (23.5%)		8/49 (16.3%)
Leukopenia	3/51 (5.9%)		1/49 (2%)
Neutropenia	8/51 (15.7%)		1/49 (2%)
Cardiac disorders
Tachycardia	3/51 (5.9%)		0/49 (0%)
Endocrine disorders
Hyperthyroidism	2/51 (3.9%)		3/49 (6.1%)
Hypothyroidism	3/51 (5.9%)		3/49 (6.1%)
Gastrointestinal disorders
Abdominal pain	8/51 (15.7%)		4/49 (8.2%)
Abdominal pain upper	5/51 (9.8%)		2/49 (4.1%)
Constipation	18/51 (35.3%)		9/49 (18.4%)
Diarrhoea	20/51 (39.2%)		12/49 (24.5%)
Dyspepsia	4/51 (7.8%)		2/49 (4.1%)
Gastrooesophageal reflux disease	3/51 (5.9%)		1/49 (2%)
Nausea	37/51 (72.5%)		13/49 (26.5%)
Stomatitis	4/51 (7.8%)		1/49 (2%)
Vomiting	32/51 (62.7%)		9/49 (18.4%)
General disorders
Asthenia	22/51 (43.1%)		17/49 (34.7%)
Fatigue	10/51 (19.6%)		3/49 (6.1%)
General physical health deterioration	3/51 (5.9%)		1/49 (2%)
Non-cardiac chest pain	4/51 (7.8%)		0/49 (0%)
Oedema peripheral	5/51 (9.8%)		8/49 (16.3%)
Pyrexia	18/51 (35.3%)		13/49 (26.5%)
Hepatobiliary disorders
Hypertransaminasaemia	3/51 (5.9%)		0/49 (0%)
Infections and infestations
Bronchitis	0/51 (0%)		5/49 (10.2%)
Oral candidiasis	3/51 (5.9%)		0/49 (0%)
Upper respiratory tract infection	5/51 (9.8%)		2/49 (4.1%)
Investigations
Alanine aminotransferase increased	4/51 (7.8%)		2/49 (4.1%)
Aspartate aminotransferase increased	4/51 (7.8%)		3/49 (6.1%)
Blood alkaline phosphatase increased	4/51 (7.8%)		0/49 (0%)
Weight decreased	11/51 (21.6%)		3/49 (6.1%)
Metabolism and nutrition disorders
Decreased appetite	19/51 (37.3%)		20/49 (40.8%)
Hyperglycaemia	0/51 (0%)		3/49 (6.1%)
Hypoalbuminaemia	3/51 (5.9%)		2/49 (4.1%)
Hypokalaemia	6/51 (11.8%)		1/49 (2%)
Hypomagnesaemia	6/51 (11.8%)		0/49 (0%)
Hyponatraemia	4/51 (7.8%)		1/49 (2%)
Hypophosphataemia	3/51 (5.9%)		0/49 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	4/51 (7.8%)		3/49 (6.1%)
Back pain	9/51 (17.6%)		3/49 (6.1%)
Bone pain	0/51 (0%)		4/49 (8.2%)
Musculoskeletal chest pain	3/51 (5.9%)		4/49 (8.2%)
Musculoskeletal pain	4/51 (7.8%)		5/49 (10.2%)
Myalgia	0/51 (0%)		5/49 (10.2%)
Neck pain	1/51 (2%)		3/49 (6.1%)
Pain in extremity	3/51 (5.9%)		5/49 (10.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	4/51 (7.8%)		8/49 (16.3%)
Nervous system disorders
Dizziness	5/51 (9.8%)		4/49 (8.2%)
Headache	5/51 (9.8%)		4/49 (8.2%)
Paraesthesia	3/51 (5.9%)		4/49 (8.2%)
Somnolence	2/51 (3.9%)		3/49 (6.1%)
Psychiatric disorders
Anxiety	4/51 (7.8%)		2/49 (4.1%)
Insomnia	3/51 (5.9%)		2/49 (4.1%)
Respiratory, thoracic and mediastinal disorders
Cough	12/51 (23.5%)		17/49 (34.7%)
Dyspnoea	10/51 (19.6%)		11/49 (22.4%)
Haemoptysis	3/51 (5.9%)		2/49 (4.1%)
Productive cough	2/51 (3.9%)		3/49 (6.1%)
Skin and subcutaneous tissue disorders
Alopecia	3/51 (5.9%)		1/49 (2%)
Pruritus	4/51 (7.8%)		4/49 (8.2%)
Rash pruritic	4/51 (7.8%)		2/49 (4.1%)
Vascular disorders
Hypertension	6/51 (11.8%)		1/49 (2%)
Hypotension	4/51 (7.8%)		1/49 (2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Results from a center cannot be submitted for publication before results of multicenter study are published unless it is more than 1 year from study completion. Investigator can publish if manuscript is submitted to Celgene 60 days prior to submission. If Celgene decides publication would hinder drug development, Investigator must delay submission for up to 90 additional days. Investigator must delete confidential information before submission or defer publication to permit patent applications.