KRAS-Targeted Vaccine With Nivolumab and Ipilimumab for Patients With NSCLC

Inclusion Criteria:

• Histologically- or cytologically-proven adenocarcinoma of the lung deemed to belocally advanced/unresectable or metastatic as per American Joint Committee onCancer (AJCC) version 8, who has not received prior therapy for this stage ofdisease.

• Prior therapy for early stage NSCLC allowed. Progressive disease after at least 6months of anti-programmed death (PD) ligand therapy (anti-PD-L1 therapy) (i.e.Durvalumab) for Stage III disease is allowed.

• Must have tumor lesions amenable to repeated biopsy, and patient's acceptance tohave a tumor biopsy of an accessible lesion at baseline and on treatment if thelesion can be biopsied with acceptable clinical risk (as judged by the PrincipalInvestigator).

• Measurable disease as defined by RECIST v1.1.

• Have one of the six KRAS mutations (KRAS G12C, KRAS G12V, KRAS G12D, KRAS G12A, KRASG13D or KRAS G12R) in vaccine expressed in tumor as defined by a Clinical LaboratoryImprovement Amendments (CLIA) certified tumor or plasma based genomic testingplatform performed either through a local laboratory or through the investigators'central laboratory.

• Age ≥18 years.

• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Appendix A).

• Patients must have adequate organ and marrow function as defined below:

Microliters (mcL) Microliter (uL)

• Leukocytes ≥ 3,000/mcL

• Lymphocytes > 500/mm3

• Absolute neutrophil count ≥ 1,000/mcL

• Platelets ≥ 75 × 103/uL

• Hemoglobin ≥ 8.0 g/dL

• Total bilirubin ≤ 1.5 x ULN (< 2.0 x ULN for subjects with documented Gilbert'ssyndrome)

• aspartate aminotransferase (AST) (SGOT) and alanine aminotransferase (ALT)(SGPT)≤ 2.5 × ULN (if liver metastases are present, ≤ 5 x ULN)

• Alkaline phosphatase ≤5.0 × ULN

• Creatinine ≤1.5 × ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using theCockcroft-Gault formula below):

Female CrCl = (140 - age in years) x weight in kg x 0.85 / 72 x serum creatinine in mg/dL

Male CrCl = (140 - age in years) x weight in kg x 1.00 / 72 x serum creatinine in mg/dL

• Women of childbearing potential (WOCBP) must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin (HCG). WOCBP is defined in Section 4.6. Note: If a patient has a positive orindeterminate serum or urine pregnancy test, then an ultrasound must be done to ruleout pregnancy to enroll on trial.

• WOCBP must agree to follow instructions for method(s) of contraception from the timeof enrollment for the duration of treatment with study drug(s) plus 5 half-lives ofstudy drug(s) plus 4 weeks (duration of ovulatory cycle) for a total of 5 monthspost treatment completion.

• Men who are sexually active with WOCBP must agree to follow instructions formethod(s) of contraception for the duration of treatment with study drug(s) plus 5half-lives of study drug(s) plus 90 days (duration of sperm turnover) for a total of 7 months post-treatment completion.

• At least one barrier method of contraception must be employed by all sexually activepatients (male and female), regardless of other methods, to prevent the transfer ofbody fluids.

• Ability to understand and willingness to sign a written informed consent document.

• Last dose of adjuvant chemotherapy or radiation therapy administered within 6 monthsof screening date

Exclusion Criteria:

• Patient is expected to require any other form of systemic or localizedantineoplastic therapy while on study.

• Any of the following procedures or medications:

• Within 2 weeks prior to initiation of study treatment:

• Systemic or topical corticosteroids at immunosuppressive doses (> 10 mg/day ofprednisone or equivalent). Inhaled or topical steroids, and adrenal replacementsteroid doses ≤ 10 mg daily prednisone equivalent, are permitted in the absenceof active autoimmune disease.

• Palliative or adjuvant radiation or gamma knife radiosurgery.

• Chemotherapy

• Within 4 weeks prior to initiation of study treatment:

• Any investigational cytotoxic drug. Exposure to any cytotoxic drug within 4weeks or 5 half-lives (whichever is shorter) is prohibited. If 5 half-lives areshorter than 4 weeks, agreement with Investigational New Drug (IND) Sponsor ismandatory.

• Any investigational device

• Non-oncology vaccines containing live virus. Examples include, but are notlimited to, the following: measles, mumps, rubella, chicken pox, yellow fever,rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Influenza,pneumonia vaccines (polysaccharide and conjugated forms) and Corona VirusDisease 2019 (COVID-19) vaccines will be allowed, however the investigatorsrecommend that subjects not receive any dose of vaccine within 7 days before orafter the subjects' scheduled KRAS peptide vaccination.

• Allergen hyposensitization therapy.

• Growth factors, e.g. granulocyte-colony stimulating factor (G-CSF), granulocytemacrophage-colony stimulating factor (GM-CSF), erythropoietin

• Major surgery (excludes celiac plexus block, biliary stent placement, and otherminor procedures such as dental work, skin biopsy, etc.).

• Patients with a history of prior treatment with immunotherapy agents (including, butnot limited to: Interleukin 2 (IL-2), interferon, anti-PD-L2, anti-cluster ofdifferentiation 137 (anti-CD137), anti-oxidation (OX) 40 (anti-OX-40), anti-clusterof differentiation 40 (anti-CD40), anti-cytotoxic T-lymphocyte-associated (CTLA)antigen 4 (anti-CTLA-4), or anti-lymphocyte activating gene (LAG) 3 (anti-LAG-3)antibodies).

• Prior anti-PD-(L)1 therapy for non-metastatic NSCLC (ie/Durvalumab) is allowedif patient had received at least 6 months of therapy prior to having diseaseprogression.

• History of severe hypersensitivity reaction to any monoclonal antibodies or relatedcompounds or to any of these agents' components (e.g., history of severehypersensitivity reactions to drugs formulated with polysorbate 80).

• This includes any prior immunotherapy agents; patients having toxicity withprior anti-PD-L1 therapy requiring cessation of treatment must be excluded.

• Untreated or symptomatic brain metastases.

• Treated brain metastases allowed on study if asymptomatic and therapy wascompleted at least 2 weeks prior to treatment start, and steroid dosing is as 3.2.2

• Has an active known or suspected autoimmune disease or which has required systemictherapy in the last 2 years. Subjects with type I diabetes mellitus, hypothyroidismonly requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, oralopecia) not requiring systemic treatment, or conditions not expected to recur inthe absence of an external trigger are permitted to enroll.

• Known history of interstitial lung disease or of (non-infectious) pneumonitis thatrequired steroids or current pneumonitis.

• Has a pulse oximetry < 90% on room air.

• Requires the use of home oxygen.

• Has a known history of Human Immunodeficiency Virus (HIV) (HIV1/2 antibodies),hepatitis B, or hepatitis C infection.

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina, cardiacarrhythmia, metastatic cancer, or psychiatric illness that would limit compliancewith study requirements.

• Patients who have been diagnosed with another cancer or myeloproliferative disorderin the past 5 years except for superficial bladder cancer, non-melanoma skincancers, or a low grade prostate cancer not requiring therapy.

• Has a diagnosis of immunodeficiency.

• Presence of any tissue or organ allograft, regardless of need for immunosuppression,including corneal allograft. Patients with a history of allogeneic hematopoieticstem cell transplant will be excluded.

• Any other sound medical or psychiatric reason as determined by the Investigator.

• Patient is, at the time of signing informed consent, a regular user (including "recreational use") of any illicit drugs or other substance abuse (includingalcohol) that could potentially interfere with adherence to study procedures orrequirements.

• Patient is unwilling or unable to follow the study schedule for any reason.

• Patient is pregnant or breastfeeding.