Patient case: 61-year-old male with Ampullary carcinoma. Genetic variant: KRAS. Other conditions: None.

Clinical trial: Genetic Predictors of Benefit to Pembrolizumab

Summary: The primary objectives are to determine if tumor genetics (non-synonymous mutation burden > 200 mutations and mutational smoking signature [transversion high]) can predict durable clinical benefit (DCB) to pembrolizumab. The secondary objective is to determine if a combined genetic and immune (PD-L1, immune signature) analysis can predict durable clinic benefit better than either test alone. The exploratory objectives are to identify and validate candidate neoantigens in vitro; and explore mechanisms of resistance to pembrolizumab.

Detailed description: This will be a single-arm, multi-center, open-label, biomarker trial of pembrolizumab in patients with advanced solid tumor restricted to tumor types with known relationship to smoking carcinogen exposure (NSCLC, SCLC, HPV negative head and neck cancer, esophageal cancer and bladder cancer). Pembrolizumab will be administered as experimental treatment and a total of 5 core biopsies will be collected.
  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 [12]. 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 [13]. In contrast, the genome of a cancer can harbour more than a million somatic mutations [14] 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 (reviewed in [10]). The study will explore if there is a relationship between the genetic mutations and the success of pembrolizumab.

Eligibility: Inclusion Criteria:
  -  Be willing and able to provide written informed consent/assent for the trial.
  -  Advanced or recurrent non-small cell lung cancer, HPV negative head and neck cancer, transitional cell bladder cancer or squamous esophageal cancer.
  -  NSCLC patients may be chemotherapy naïve or pre-treated. For NSCLC patients with lung adenocarcinoma, tumors must be epidermal growth factor receptor (EGFR) and Alkaline phosphatase (ALK) wild-type; if a Kirsten rat sarcoma (KRAS) mutation is detected, EGFR and ALK testing is not required.
  -  HPV negative head and neck cancer, transitional cell bladder cancer and squamous esophageal cancer patients must have received at least one prior line of therapy for their disease; treatment may include surgery, radiation, chemotherapy and/or a biologic agent.
  -  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.
  -  Be willing to undergo tumor biopsies pre-treatment and at Cycle 2 Day 8 (C2D8) (+/- 7 days). For patients who progress after DCB, also repeat biopsy at progression.
  -  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 (Section 8.4.4). 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 / 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., HCV RNA [qualitative] is detected).
  -  Has a known history of active TB (Bacillus Tuberculosis)
  -  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.

Relevance to patient case: not relevant