Personalized Therapeutic Anti-tumor Vaccine With Pembrolizumab and Standard of Care Chemotherapy in Squamous Non-Small Cell Lung Cancer and Extensive Stage Small Cell Lung Cancer
Personalized Therapeutic Anti-tumor Vaccine With Pembrolizumab and Standard of Care Chemotherapy in Squamous Non-Small Cell Lung Cancer and Extensive Stage Small Cell Lung Cancer
Both metastatic squamous non-small cell lung cancer (NSCLC) and extensive stage small cell
 lung cancer (SCLC) are incurable with current therapies, but due to mutations induced by
 cigarette smoke, typically express a large number of altered proteins that can be recognized
 as foreign by the immune system. This antigenicity is thought to explain the efficacy of
 pembrolizumab as either a first or second line treatment in this disease. For patients who
 receive chemotherapy plus immunotherapy as a first line therapy, there is sound rationale for
 combination treatment with immunotherapy and a therapeutic antitumor vaccine as a maintenance
 strategy. Regardless of PD-L1 expression in the tumor, monoclonal antibodies that block
 PD-1/PD-L1 interactions are effective second line therapies after chemotherapy in both NSCLC
 and SCLC. In addition, by targeting the immune system against tumor specific antigens using a
 peptide vaccine, the efficacy of pembrolizumab alone is expected to be enhanced, with an
 improved response rate and prolonged overall survival with no additional toxicity.

 This pilot study will provide a preliminary test of the feasibility of generating a
 personalized, tumor neoantigen-specific therapeutic vaccine and the safety of combining it
 with checkpoint blockade immunotherapy.
Please note that this study originally opened with ID# 201707041 but was withdrawn due to
 change in standard of care chemotherapy. This study was revised and submitted as an amendment
 to the same IND but our IRB required it to be submitted as a new study and it received a new
 ID#.
Inclusion Criteria:

 -  Cohort A: Histologically confirmed stage IV squamous NSCLC

 -  Cohort B: Histologically confirmed extensive stage SCLC

 -  Sufficient tumor tissue must be available for histologic assessment of PD-L1
 expression and for sequence and immunological analysis.

 -  Measurable disease by RECIST 1.1. Lesions situated in a previously irradiated area are
 considered measurable if progression has been demonstrated in such lesions.

 -  At least 18 years of age on the day of signing informed consent.

 -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

 -  Normal bone marrow and organ function as defined in the table below within 10 days of
 study entry:

 -  Absolute neutrophil count (ANC): ≥1500/µL

 -  Platelets: ≥100 000/µL

 -  Hemoglobin: ≥9.0 g/dL or ≥5.6 mmol/L (Criteria must be met without erythropoietin
 dependency and without packed red blood cell (pRBC) transfusion within last 2
 weeks)

 -  Creatinine: ≤1.5 × upper limit of normal (ULN) OR

 -  Measured or calculated2 creatinine clearance (GFR can also be used in place of
 creatinine or CrCl): ≥30 mL/min for patient with creatinine levels / >1.5 ×
 institutional ULN

 -  Total bilirubin: ≤1.5 ×ULN OR direct bilirubin ≤ULN for patients with total
 bilirubin levels >1.5 × ULN

 -  AST (SGOT) and ALT (SGPT): ≤2.5 × ULN (≤5 × ULN for patients with liver
 metastases)

 -  International normalized ratio (INR) OR prothrombin time (PT) activated partial
 thromboplastin time (aPTT): ≤1.5 × ULN unless patient is receiving anticoagulant
 therapy as long as PT or aPTT is within therapeutic range of intended use of
 anticoagulants

 -  Male Patients: A male patient must agree to use a contraception as detailed in this
 protocol during the treatment period and for at least 120 days, corresponding to time
 needed to eliminate any study treatment(s) after the last dose of study treatment and
 refrain from donating sperm during this period.

 -  Female Patients: A female patient is eligible to participate if she is not pregnant,
 not breastfeeding, and at least one of the following conditions applies: A woman of
 childbearing potential who agrees to follow the contraceptive guidance during the
 treatment period and for at least 120 days (corresponding to time needed to eliminate
 any study treatment(s). Should a woman become pregnant or suspect she is pregnant
 while participating in this study, she must inform her treating physician immediately.

 -  Ability to understand and willingness to sign an IRB approved written informed consent
 document (or that of legally authorized representative, if applicable).

 Exclusion Criteria:

 -  Cohort A: Received any prior systemic therapy for cancer treatment.

 -  Cohort B: May not have received more than one cycle of platinum doublet given with or
 without an anti-PD-1 or anti-PD-L1 immunotherapeutic.

 -  Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 14
 days prior to day 1 or who has not recovered (ie, ≤ Grade 1 or at baseline from
 adverse events due to previous therapies). Patients with ≤Grade 2 neuropathy may be
 eligible.

 Note: If patient received major surgery, they must have recovered adequately from the
 toxicity and/or complications from the intervention prior to starting study treatment.

 -  Received prior radiotherapy within 2 weeks of start of study treatment. Patients must
 have recovered from all radiation-related toxicities, not require corticosteroids, and
 not have had radiation pneumonitis. A 1-week washout is permitted for palliative
 radiation (≤2 weeks of radiotherapy) to non-CNS disease.

 -  Patients may not receive or have received any radiation therapy at the biopsy sites.

 -  Is currently participating in or has participated in a study of an investigational
 agent or has used an investigational device within 4 weeks prior to the first dose of
 study treatment.

 Note: Patients who have entered the follow-up phase of an investigational study may
 participate as long as it has been 4 weeks after the last dose of the previous
 investigational agent.

 -  Has had an allogeneic tissue/solid organ transplant.

 -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy > 10 mg
 prednisone daily or any other form of immunosuppressive therapy within 7 days prior to
 Day 1.

 -  Prior treatment with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

 -  Prior treatment with a cancer vaccine.

 -  Prior treatment with an agent directed to another stimulatory or co-inhibitory T-cell
 receptor (eg, CTLA-4, OX-40, CD137).

 -  Received a live vaccine within 30 days prior to Day 1. Examples of live vaccines
 include, but are not limited to, the following: measles, mumps, rubella,
 varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG),
 and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed
 virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®)
 are live attenuated vaccines and are not allowed.

 -  Known active 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 Day 1 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.

 -  Known additional malignancy that is progressing or has required active treatment
 within the past 3 years.

 Note: Patients with basal cell carcinoma of the skin, squamous cell carcinoma of the skin,
 or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone
 potentially curative therapy are not excluded.

 -Currently receiving any other investigational agents or has participated in a study of an
 investigational agent or using an investigational device within 4 weeks prior to Day 1.

 Note: Patients who have entered the follow-up phase of an investigational study may
 participate as long as it has been 4 weeks after the last dose of the previous
 investigational agent.

 -  A history of allergic reactions attributed to compounds of similar chemical or
 biologic composition to pembrolizumab or other agents used in the study.

 -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
 infection requiring systemic therapy, symptomatic congestive heart failure, unstable
 angina pectoris, cardiac arrhythmia, underlying pulmonary disease, or psychiatric
 illness/social situations that would limit compliance with study requirements.

 -  Active autoimmune disease requiring systemic treatment within the past 2 years (i.e.
 with use of disease modifying agents, corticosteroids (prednisone dose of 10 mg or
 less per day is allowed), or immunosuppressive drugs). Replacement therapy (e.g.,
 thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or
 pituitary insufficiency, etc.) is not considered a form of systemic treatment.

 -  Known history of, or any evidence of active, non-infectious pneumonitis.

 -  A woman of childbearing potential who has a positive urine pregnancy test within 72
 hours prior to treatment allocation. If the urine test is positive or cannot be
 confirmed as negative, a serum pregnancy test will be required.

 Note: In the event that 72 hours have elapsed between the screening pregnancy test and the
 first dose of study treatment, another pregnancy test (urine or serum) must be performed
 and must be negative in order for subject to start receiving study medication.

 -  Pregnant or breastfeeding or expecting to conceive or father children within the
 projected duration of the study, starting with the screening visit through 120 days
 after the last dose of study treatment.

 -  Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg]
 reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] is
 detected) infection.

 Note: No testing for hepatitis B and hepatitis C is required unless mandated by local
 health authority.

 -  Known history of active tuberculosis (TB).

 -  Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).

 -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
 that might confound the results of the study, interfere with the patient's
 participation for the full duration of the study, or is not in the best interest of
 the patient to participate, in the opinion of the treating investigator.

 -  Has a known psychiatric or substance abuse disorder that would interfere with the
 patient's ability to cooperate with the requirements of the study.