Genetic Predictors of Benefit to Pembrolizumab

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Identifying Genetic Predictors of Durable Clinical Benefit to Pembrolizumab in Advanced Non-small Cell Lung Cancer (NSCLC) Alone and in Combination With Chemotherapy.

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: Pembrolizumab
* Drug: Carboplatin
* Drug: Nab-paclitaxel
* Drug: Pemetrexed


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Subjects will receive single agent pembrolizumab 200 mg IV will be administered every 3 weeks for up to 2 years. | Drug: Pembrolizumab<br>* 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.<br>* Other names: Lambrolizumab;|
| Experimental: Cohort 2<br>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<br>* 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.<br>* Other names: Lambrolizumab;Drug: Carboplatin<br>* 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.<br>* Other names: Paraplatin;Drug: Nab-paclitaxel<br>* 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.<br>* Other names: Abraxane;|
| Experimental: Cohort 3<br>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<br>* 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.<br>* Other names: Lambrolizumab;Drug: Carboplatin<br>* 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.<br>* Other names: Paraplatin;Drug: Pemetrexed<br>* Pemetrexed 500 mg/m2 IV administered for 2 cycles concurrently with cycles 1 and 2 of pembrolizumab.<br>* Other names: Alimta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With NSCLC Who Achieved DCB | 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 (Neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study), OR complete response (disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.), OR partial response (At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters) lasting longer than 6 months. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR is defined as participants with a partial (At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters) or complete response (Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm) as assessed by RECIST 1.1 criteria. | Up to 2 years | 
| Progression Free Survival (PFS) | The length of time from treatment initiation to progression of disease (at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression) as assessed by RECIST 1.1. | Up to 2 years | 
| Overall Survival (OS) | The length of time from the start of treatment to death. | Up to 28 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NSCLC, Carcinoma, Non-Small-Cell Lung, Non-Small Cell Lung Cancer, Non-Small-Cell Lung Carcinoma, Nonsmall Cell Lung Cancer