Genetic Predictors of Benefit to Pembrolizumab
Condition: Carcinoma, Non-Small-Cell Lung
MeSH terms: Carcinoma; Carcinoma, Non-Small-Cell Lung
Intervention: Pembrolizumab; Carboplatin; Nab-paclitaxel; Pemetrexed
Intervention description: Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the immunoglobulin G4 (IgG4)/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2 (programmed cell death (PD) proteins).
Pembrolizumab 200 mg will be administered IV every 3 weeks.; Carboplatin AUC (area under curve (AUC)) = 5 IV on day 1 every 3 weeks administered for 2 cycles concurrently with cycles 1 and 2 of pembrolizumab.; Nab-paclitaxel 100 mg/m2 IV on days 1, 8 and 15 every 3 weeks administered for 2 cycles concurrently with cycles 1 and 2 of pembrolizumab.; Pemetrexed 500 mg/m2 IV administered for 2 cycles concurrently with cycles 1 and 2 of pembrolizumab.
Intervention MeSH terms: Paclitaxel; Carboplatin; Pembrolizumab; Pemetrexed
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 19.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Carcinoma, Non-Small-Cell Lung; Non-Small Cell Lung Cancer; Non-Small-Cell Lung Carcinoma; Nonsmall Cell Lung Cancer; NSCLC

Summary:

      The primary objective is to determine if mutation load underlies sensitivity to pembrolizumab
      alone and in combination with chemotherapy. This will be a 3-arm, multi-center, open-label,
      non-randomized biomarker trial in patients with advanced, treatment-naive NSCLC. Patients
      will receive 1 of 3 possible cohorts as per investigator's discretion. Patients with
      non-squamous histology may receive any of the 3 cohorts; patients with squamous histology may
      receive either cohorts 1 and 2.
    

Eligibility criteria:

        Inclusion Criteria:

          -  NSCLC patients of all histologies may enroll to Cohorts 1 and 2. Only patients of
             non-squamous histologies may enroll to Cohort 3. If enrollment to a cohort is
             completed, enrollment may continue to other open cohorts.

          -  Be willing and able to provide written informed consent/assent for the trial.

          -  Chemotherapy naïve NSCLC patients.For NSCLC patients with lung adenocarcinoma, tumors
             must be Epidermal Growth Factor Receptor (EGFR) and Anaplastic Lymphoma Kinase (ALK)
             wild-type; if a Kirsten Ras (KRAS) mutation is detected, EGFR and ALK testing is not
             required.

          -  Diagnosis must be documented by histology or cytology from brushings, washings, or
             needle aspiration of a defined lesion but not from sputum cytology.

          -  Be ≥ 18 years of age on day of signing informed consent.

          -  Have measurable disease based on RECIST 1.1.

          -  Sufficient archived tumor material available (equivalent to 2 core biopsies or
             greater); if insufficient archived tumor material available new tumor biopsy is
             mandatory.

          -  Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
             Performance Scale.

          -  Female subject of childbearing potential should have a negative urine or serum
             pregnancy within 72 hours prior to receiving the first dose of study medication. If
             the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
             will be required.

          -  Female subjects of childbearing potential should be willing to use 2 methods of birth
             control or be surgically sterile, or abstain from heterosexual activity for the course
             of the study through 120 days after the last dose of study medication. Subjects of
             childbearing potential are those who have not been surgically sterilized or have not
             been free from menses for > 1 year.

          -  Male subjects should agree to use an adequate method of contraception starting with
             the first dose of study therapy through 120 days after the last dose of study therapy.

          -  Demonstrate adequate organ function as defined below, all screening labs should be
             performed within 10 days of treatment initiation.

             -- Hematological

          -  Absolute neutrophil count (ANC): ≥1,500 /mcL

          -  Platelets: ≥100,000 / microliter (mcL)

          -  Hemoglobin: ≥9 g/dL or ≥5.6 mmol/L

             -- Renal

          -  Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be used
             in place of creatinine or CrCl): ≤1.5 X upper limit of normal (ULN) OR ≥60 mL/min for
             subject with creatinine levels > 1.5 X institutional ULN

             -- Hepatic

          -  Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total
             bilirubin levels > 1.5 ULN

          -  Aspartate aminotransferase (AST) (SGOT) and alanine aminotransferase (ALT) (SGPT) ≤
             2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases

             -- Coagulation

          -  International Normalized Ratio (INR) or Prothrombin Time (PT): ≤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

          -  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

        Exclusion Criteria:

          -  Is currently participating in or has participated in a study of an investigational
             agent or using an investigational device within 4 weeks of the first dose of
             treatment.

          -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
             other form of immunosuppressive therapy within 7 days prior to the first dose of trial
             treatment.

          -  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.

          -  Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
             within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at
             baseline) from adverse events due to a previously administered agent. Note: Subjects
             with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the
             study. Note: If subject received major surgery, they must have recovered adequately
             from the toxicity and/or complications from the intervention prior to starting
             therapy.

          -  Has a known additional malignancy that is progressing or requires active treatment.
             Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
             skin, or in situ cervical cancer that has undergone potentially curative therapy.

          -  Has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis. Subjects with previously treated brain metastases may participate provided
             they are stable (without evidence of progression by imaging for at least four weeks
             prior to the first dose of trial treatment and any neurologic symptoms have returned
             to baseline), have no evidence of new or enlarging brain metastases, and are not using
             steroids for at least 7 days prior to trial treatment.

          -  Has active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e. 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.

          -  Has evidence of interstitial lung disease or active, non-infectious pneumonitis.Has an
             active infection requiring systemic therapy.

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the subject's
             participation for the full duration of the trial, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator.

          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the pre-screening or screening visit
             through 120 days after the last dose of trial treatment.

          -  Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or
             anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including
             ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation
             or checkpoint pathways).

          -  Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

          -  Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., Hepatitis C
             (HCV) RNA [qualitative] is detected).

          -  Has a known history of active tuberculosis (TB)

          -  Has received a live vaccine within 30 days prior to the first dose of trial treatment.

          -  History of allergy or hypersensitivity to any component of the treatment.