AN0025 with Carboplatin, Paclitaxel, Durvalumab and Radiation for the Treatment of Patients with Stage III Non Small Cell Lung Cancer

Inclusion Criteria

• Have provided signed informed consent for the trial
• Aged ≥ 18 years at the time of informed consent
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Diagnosed with histologically confirmed locally advanced and nonresectable, or metastatic stage IIIA-C (American Joint Committee on Cancer [AJCC] 8th edition) non small cell lung cancer (NSCLC)
• Disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by the local site investigator and/or radiologist. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
• Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue
• Left ventricular ejection fraction (LVEF) greater than 50% on echocardiography or multiple gated acquisition (MUGA) scan
• Adequate staging with CT chest, PET/CT and, brain MRI within 8 weeks of therapy initiation
• Adequate lung function with forced expiratory volume in 1 second (FEV1) and diffusion capacity of the lung for carbon monoxide (DLCO) > 40%
• Lung V20 < 35%
• Absolute neutrophil count (ANC) ≥ 1.2 x 10^9/L. (Specimens must be collected within 7 days prior to the start of study treatment)
• Platelets ≥ 100 x 10^9/L. (Specimens must be collected within 7 days prior to the start of study treatment)
• Hemoglobin ≥ 90 g/L or ≥ 5.6 mmol/L. (Specimens must be collected within 7 days prior to the start of study treatment) * Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks
• Creatinine OR measured or calculated creatinine clearance (Crcl) (glomerular filtration rate [GFR] can also be used in place of creatinine or CrCl) ≤ 1.5 × upper limit of normal (ULN) OR ≥ 30 mL/min for participant with creatinine levels > 1.5 × institutional ULN. (Specimens must be collected within 7 days prior to the start of study treatment) * Creatinine clearance (CrCl) should be calculated per institutional standard
• Total bilirubin ≤ 1.5 × ULN OR direct bilirubin ≤ ULN for participants with total bilirubin levels > 1.5 × ULN (except patients with Gilbert Syndrome who must have a total bilirubin level of ≤ 3.0 x ULN). (Specimens must be collected within 7 days prior to the start of study treatment)
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/ alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 2.5 × ULN (≤ 5 × ULN for participants with liver metastases). (Specimens must be collected within 7 days prior to the start of study treatment)
• International normalized ratio (INR) OR prothrombin time (PT) activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants. (Specimens must be collected within 7 days prior to the start of study treatment)
• No active second cancers/malignancy
• Willing and able to comply with all aspects of the protocol
• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: * Not a woman of childbearing potential. Women are considered post-menopausal and not of child-bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks prior to screening. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered not of child-bearing potential. * Woman of childbearing potential who agrees to follow contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment. * Highly effective contraception is defined as either: ** Total abstinence: When this is in line with the preferred and usual lifestyle of the patient. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.) ** Female sterilization: When the female study patient has had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment ** Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). For female study patients, the vasectomized male partner should be the sole partner for that patient. ** Using a combination of any two of the following: *** Placement of an intrauterine device (IUD) or intrauterine system (IUS), and *** Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository. *** Hormonal contraception methods (e.g., oral, injected, implanted)
• A male participant must agree to use contraception during the treatment period and for at least 120 days after the last dose of study treatment

Exclusion Criteria

• Have been discontinued treatment due to a grade 3 or higher immune-related (irAE) from prior anti-PD-1or anti-PD-L1, or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137)
• Have received a live vaccine within 30 days prior to the first dose of study drug. 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 (e.g., FluMist®) are live attenuated vaccines and are not allowed
• Have had an allogenic tissue/solid organ transplant
• Have a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
• With a history of another primary malignancy within the past 2 years, with the exception of basal or squamous cell skin cancer, or carcinoma in situ of the cervix or breast that has undergone potentially curative therapy
• Have known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment
• Have known severe hypersensitivity to study treatment components
• Have an 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 (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed
• Participants with inflammatory bowel disease
• Have a history of (non-infectious) pneumonitis that required steroids or have current pneumonitis
• Have a history of interstitial lung disease
• Have an active infection requiring systemic therapy
• Participants with known human immunodeficiency virus (HIV) and/or history of hepatitis B or C infections, or known to be positive for Hepatitis B antigen (HBsAg)/ hepatitis B virus (HBV) deoxyribonucleic acid (DNA) or hepatitis C antibody (HCV) or ribonucleic acid (RNA). Active hepatitis C is defined by a known positive hepatitis C antibody (Ab) result and known quantitative HCV RNA results greater than the lower limits of detection of the assay
• Prolongation of corrected QT [QTcF (Fridericia's corrected QT interval)] interval to greater than 480 msec when electrolytes balance is normal
• Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, uncontrolled arterial hypertension, unstable angina, myocardial infarction, or stroke within 6 months of the first dose of study drug; or cardiac arrhythmia requiring medical treatment (including oral anticoagulation)
• Major surgery within 4 weeks before the first dose of study drug. Note: If a participant received major surgery, they must have recovered adequately from surgery and the toxicity and/or complications requiring the intervention prior to starting study treatment
• Inability to take oral medication, or malabsorption syndrome or any other uncontrolled gastrointestinal condition (eg., nausea, diarrhea, or vomiting) that might impair the bioavailability of AN0025
• Have a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
• Have a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study
• Is 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