Have you or your loved ones been diagnosed with carcinoma, non-small-cell lung?
You may be eligible to participate in a carcinoma, non-small-cell lung clinical trial.
Have you or your loved ones been diagnosed with carcinoma, non-small-cell lung? You may be eligible to participate in a carcinoma, non-small-cell lung clinical trial.
What is a clinical trial? Is participating in a clinical trial right for you? Learn more
Carcinoma, Non-Small-Cell Lung Clinical Trial in Philadelphia PA
Have you or your loved ones been diagnosed with carcinoma, non-small-cell lung?
You may be eligible to participate in a carcinoma, non-small-cell lung clinical trial.
Have you or your loved ones been diagnosed with carcinoma, non-small-cell lung? You may be eligible to participate in a carcinoma, non-small-cell lung clinical trial.
Active not recruiting
Male & Female
18 Years +
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.
Details for the study
Brief Title
Genetic Predictors of Benefit to Pembrolizumab
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.
Brief Summary
The primary objective is to determine if mutation load underlies sensitivity to pembrolizumab<br /> alone and in combination with chemotherapy. This will be a 3-arm, multi-center, open-label,<br /> non-randomized biomarker trial in patients with advanced, treatment-naive NSCLC. Patients<br /> will receive 1 of 3 possible cohorts as per investigator's discretion. Patients with<br /> non-squamous histology may receive any of the 3 cohorts; patients with squamous histology may<br /> receive either cohorts 1 and 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.
Treatments and/or Procedures
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.
Pemetrexed
Pemetrexed 500 mg/m2 IV administered for 2 cycles concurrently with cycles 1 and 2 of pembrolizumab.
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.
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.
Outcome Measures
Outcome measures are the tests that investigators perform to prove whether or not a treatment being tested in a clinical trial is having any effect.
Primary
Number of subjects with NSCLC who achieved DCB to study treatment.
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
Number of subjects with mutational smoking signature and achieved DCB to pembrolizumab.
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.
Study 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.