Clinical Trials /

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

NCT02546986

Description:

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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Safety and Efficacy Study of <span class="go-doc-concept go-doc-intervention">CC-486</span> With <span class="go-doc-concept go-doc-intervention">MK-3475</span> to Treat Locally Advanced or Metastatic Non-small Cell <span class="go-doc-concept go-doc-disease">Lung Cancer</span>

Title

  • Brief Title: Safety and Efficacy Study of CC-486 With MK-3475 to Treat Locally Advanced or Metastatic Non-small Cell Lung Cancer
  • 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
  • Clinical Trial IDs

    NCT ID: NCT02546986

    ORG ID: CC-486-NSCL-001

    Trial Conditions

    Carcinoma, Non-Small-Cell Lung

    Trial Interventions

    Drug Synonyms Arms
    CC-486 Oral Azacitidine CC-486 plus Pembrolizumab
    Pembrolizumab MK-3475 CC-486 plus Pembrolizumab, Pembrolizumab plus Placebo
    Placebo Pembrolizumab plus Placebo

    Trial Purpose

    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 subjects with previously treated locally advanced or metastatic non-small cell lung
    cancer.

    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 subjects with locally advanced or
    metastatic Non-small cell lung cancer (NSCLC) who have received one prior platinum-based
    chemotherapy regimen.

    Approximately 90 subjects 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 1-14 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 Safety will be
    evaluated by an independent data monitoring committee (DMC). A safety analysis will be
    performed in the first 10 subjects in each arm after the last enrolled subject has
    completed 1 cycle of treatment.

    Randomization will be stratified between treatment arms by:

    - Histology (non-squamous versus squamous) The decision to discontinue a subject, which will
    not be delayed or refused by the Sponsor, remains the responsibility of the treating
    physician. However, prior to discontinuing a subject, the Investigator may contact the
    medical monitor and forward appropriate supporting documents for review and discussion.

    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 PFS events have occurred.

    Trial Arms

    Name Type Description Interventions
    CC-486 plus Pembrolizumab Experimental In this experimental arm, subjects will receive a combination of two investigational drugs, CC-486 and pembrolizumab. CC-486, Pembrolizumab
    Pembrolizumab plus Placebo Experimental In this control arm, subjects will receive an active comparator, the investigational drug pembrolizumab. Placebo will also be administered in order to allow blinding of the study. Pembrolizumab, Placebo

    Eligibility Criteria

    Inclusion Criteria:

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

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

    3. Subject has stage IIIB or IV NSCLC (American Joint Committee on Cancer [AJCC] Staging
    Manual, 7th edition) and was pretreated with 1 prior systemic platinum based
    chemotherapy.

    4. Subject 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 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. Subject has radiographically-documented measurable disease, as per Response
    Evaluation Criteria in Solid Tumors (RECIST) 1.1.

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

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

    - Aspartame aminotransferase (AST) or serum glutamic oxaloacetic transaminase
    (SGOT), alanine aminotransferase (ALT) or 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

    8. Subject has adequate bone marrow function, evidenced by the following:

    - Absolute neutrophil count 1.5 x 109 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
    subject is receiving anticoagulant therapy as long as 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 subject is
    receiving anticoagulant therapy as long as PT or PTT is within therapeutic range
    of intended use of anticoagulants

    9. 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 (i.e., 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 subject 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 investigational product, 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.

    10. Male subjects 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 subject. Note: Periodic abstinence (eg, calendar, ovulation,
    symptothermal, postovulation methods) and withdrawal are not acceptable methods of
    contraception.

    11. Subject is willing to adhere to the study visit schedule and other protocol
    requirements.

    12. Subject understands and voluntarily signs an informed consent document prior to any
    study related assessments/procedures are conducted.

    Exclusion Criteria:

    1. Subject has known sensitizing endothelial growth factor receptor (EGFR) and/or
    positive anaplastic lymphoma kinase (ALK) mutation.

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

    3. Subject has received prior therapy with any other anti-programmed death-1
    (anti-PD-1), or programmed death-ligand 1 (PD-L1) or programmed death-ligand 2
    (PD-L2) agent or an antibody targeting other immuno-regulatory receptors or
    mechanism, including participation in any other pembrolizumab trial and treatment
    with pembrolizumab.

    - Examples of such antibodies include (but are not limited to) antibodies against
    indoleamine 2,3-dioxygenase (IDO), PD-L1, interleukin-2 receptor (IL-2R),
    glucocorticoid-induced tumor necrosis factor receptor (GITR).

    4. Subject 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.

    5. Subject 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

    6. Subject has previous severe hypersensitivity reaction to another monoclonal antibody
    (mAb).

    7. Subject has a known or suspected hypersensitivity to azacitidine, mannitol, or any
    other ingredient used in the manufacture of CC-486.

    8. Subject has had radiotherapy 4 weeks or limited field radiation for palliation 2
    weeks prior to starting IP, and/or from whom 30% of the bone marrow was irradiated.

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

    10. Subject has received a live-virus vaccination within 30 days of planned treatment
    start. Seasonal flu vaccines that do not contain live virus are permitted.

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

    12. Subject has an active infection requiring therapy.

    13. Subject has had an allogenetic tissue/solid organ transplant.

    14. Subject 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.

    15. Subject 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 Hep C antibody (Ab) result and known quantitative Hepatitis C virus (HCV)
    ribonucleic acid (RNA) results greater than the lower limits of detection of the
    assay.

    16. Subject 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).

    17. Subject 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
    subject to an increased risk of gastrointestinal toxicity.

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

    19. Subject 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.

    20. Subject has history of interstitial lung disease (ILD) OR a history of pneumonitis
    that has required oral or IV steroids. Subjects 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.

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

    22. Subject has any other concurrent severe and/or uncontrolled medical condition that
    would, in the Investigator's judgment, contraindicate subject participation in the
    clinical study (eg, chronic pancreatitis, etc.).

    23. Subject with uncontrolled or symptomatic central nervous system (CNS) metastases
    and/or carcinomatous meningitis - Subjects with controlled and asymptomatic CNS
    metastases may participate in this trial. The subject 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

    24. Subject 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 subject at the Investigator's discretion).

    25. Subject has an impaired ability to swallow oral medication.

    26. Subject is pregnant or breast feeding.

    27. Subject has any condition that confounds the ability to interpret data from the
    study.

    28. Subject 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 subject.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Progression-Free Survival (PFS)

    Secondary Outcome Measures

    Number of subjects with Stable Disease (SD) for 18 weeks measured via CT scan or MRI

    Number of subjects with Complete Response (CR) measured via CT scan or MRI

    Number of subjects with Partial Response (PR) measured via CT scan or MRI

    Number of subjects with Disease Control Rate (DCR)

    Number of subjects with Overall Survival (OS)

    Number of subjects who achieved Overall Response Rate (ORR)

    Pharmacokinetics Maximum Observed Concentration (Cmax) for CC-486

    Pharmacokinetics - Area Under the Curve (AUC) for CC-486

    Pharmacokinetics Time to Maximum Concentration (Tmax) for CC-486

    Pharmacokinetics Terminal Half-Life (t1/2) for CC-486

    Pharmacokinetics Apparent Total Body Clearance (CL/F) for CC-486

    Pharmacokinetics (Apparent Volume of Distribution (Vz/F) for CC-486

    Adverse Events (AEs)

    Trial Keywords

    CC-486

    Azacitidine

    Oral azacitidine

    Methyltransferase inhibitor

    Hypomethylation

    Hypomethylating agent

    Epigenetic

    MK-3476

    Penbrolizumab

    Keytruda

    PD-1

    PD-L1

    Immunotherapy

    Advanced non-small cell lung cancer

    Metastatic non-small cell lung cancer

    Non-small cell lung cancer

    NSCLC