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Genetic Predictors of Benefit to Pembrolizumab

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ClinicalTrials.gov Identifier: NCT02710396
Recruitment Status : Active, not recruiting
First Posted : March 16, 2016
Last Update Posted : December 12, 2019
Sponsor:
Collaborators:
Merck Sharp & Dohme Corp.
Massachusetts General Hospital
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Naiyer Rizvi, Columbia University

Brief 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.

Condition or disease Intervention/treatment Phase
Carcinoma, Non-Small-Cell Lung Drug: Pembrolizumab Drug: Carboplatin Drug: Nab-paclitaxel Drug: Pemetrexed Phase 2

Detailed Description:

Somatic mutations leading to cancer are related to endogenous or exogenous DNA damaging processes. The resultant mutations can be separated into two categories - (i) mutations that provide selective advantage for clonal expansion and (ii) mutations that do not result in growth advantage. The latter have been termed passenger mutations, while the former are referred to as driver mutations. It is widely believed that the number of driver mutations in a cancer sample is limited to a handful, usually two or more but less than ten. In contrast, the genome of a cancer can harbor more than a million somatic mutations most of which are considered to be passengers.

Several studies have shown that the passenger mutations may not be oncogenic drivers but may be of importance in adaptive immune resistance of a tumor. In particular the relevant mutations are likely to be the nonsynonymous exonic mutations in tumors; these may give rise to novel proteins that differ from their wild type counterparts and are immunogenically more relevant. The study will explore if there is a relationship between the genetic mutations and the success of pembrolizumab.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 18 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Identifying Genetic Predictors of Durable Clinical Benefit to Pembrolizumab in Advanced Non-small Cell Lung Cancer (NSCLC) Alone and in Combination With Chemotherapy.
Actual Study Start Date : May 31, 2016
Estimated Primary Completion Date : March 2020
Estimated Study Completion Date : March 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Cohort 1
Subjects will receive single agent pembrolizumab 200 mg IV will be administered every 3 weeks for up to 2 years.
Drug: Pembrolizumab

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.

Other Names:
  • Keytruda
  • MK-3475
  • Lambrolizumab

Experimental: Cohort 2
Subjects will receive pembrolizumab 200 mg IV every 3 weeks for up to 2 years with 2 cycles of nab-paclitaxel and carboplatin administered with cycles 1 and 2.
Drug: Pembrolizumab

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.

Other Names:
  • Keytruda
  • MK-3475
  • Lambrolizumab

Drug: Carboplatin
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.
Other Name: Paraplatin

Drug: Nab-paclitaxel
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.
Other Name: Abraxane

Experimental: Cohort 3
Subject will receive pembrolizumab 200 mg IV every 3 weeks for up to 2 years with 2 cycles of pemetrexed and carboplatin administered with cycles 1 and 2.
Drug: Pembrolizumab

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.

Other Names:
  • Keytruda
  • MK-3475
  • Lambrolizumab

Drug: Carboplatin
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.
Other Name: Paraplatin

Drug: Pemetrexed
Pemetrexed 500 mg/m2 IV administered for 2 cycles concurrently with cycles 1 and 2 of pembrolizumab.
Other Name: Alimta




Primary Outcome Measures :
  1. Number of subjects with NSCLC who achieved DCB to study treatment. [ Time Frame: Up to 2 years ]
    Objective response to study treatment will be assessed by RECIST 1.1 by a study radiologist. Partial and complete responses will be confirmed by a repeat imaging occurring at least 4 weeks after the initial identification of response; unconfirmed responses will be considered stable or progressive disease dependent on results of the second CT scan. Durable clinical benefit (DCB) will be defined as stable disease or response (complete or partial) lasting longer than 6 months. No durable benefit (NDB) will be defined as progression of disease ≤ 6 months of beginning therapy.


Secondary Outcome Measures :
  1. Number of subjects with mutational smoking signature and achieved DCB to pembrolizumab. [ Time Frame: Up to 2 years ]

    Biomarker analysis will be performed to explore mutational load and mutational smoking signature.

    Durable clinical benefit (DCB) will be defined as stable disease or response (complete or partial) lasting longer than 6 months. No durable benefit (NDB) will be defined as progression of disease ≤ 6 months of beginning therapy.




Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02710396


Locations
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United States, New York
Laura & Isaac Perlmutter Cancer Center at NYU Langone
New York, New York, United States, 10016
Columbia University
New York, New York, United States, 10032
United States, Pennsylvania
Fox Chase Cancer Center
Philadelphia, Pennsylvania, United States, 19111
Sponsors and Collaborators
Naiyer Rizvi
Merck Sharp & Dohme Corp.
Massachusetts General Hospital
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Naiyer Rizvi, MD Columbia University
Publications:
Brahmer, J.R., et al., Clinical activity and safety of anti-PD1 (BMS-936558, MDX-1106) in patients with advanced non-small-cell lung cancer (NSCLC). J Clin Oncol, 2012(30): p. suppl; abstr 7509

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Responsible Party: Naiyer Rizvi, Professor of Medicine at the Columbia University Medical Center, Dept of Med Hematology & Onc, Columbia University
ClinicalTrials.gov Identifier: NCT02710396    
Other Study ID Numbers: AAAQ5450
1U54CA209997 ( U.S. NIH Grant/Contract )
First Posted: March 16, 2016    Key Record Dates
Last Update Posted: December 12, 2019
Last Verified: December 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Naiyer Rizvi, Columbia University:
Carcinoma, Non-Small-Cell Lung
Non-Small Cell Lung Cancer
Non-Small-Cell Lung Carcinoma
Nonsmall Cell Lung Cancer
NSCLC
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Non-Small-Cell Lung
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Paclitaxel
Carboplatin
Pembrolizumab
Pemetrexed
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological
Enzyme Inhibitors
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors