Testing the Addition of an Anti-Cancer Drug, TRC102, to the Usual Chemotherapy Treatment (Pemetrexed, Cisplatin or Carboplatin) During Radiation Therapy for Stage III Non-Squamous Non-Small Cell Lung Cancer

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed adenocarcinoma or largecell carcinoma of the lung with confirmation by immunohistochemistry (histologictissue diagnosis is preferred, but cytology is acceptable).

• Patients must have newly staged IIIA, IIIB or IIIC disease according to the 8thtumor, node, metastasis (TNM) staging classification and to be consideredappropriate candidates for aggressive chemoradiotherapy.

• Patients must have measurable disease, defined as at least one lesion that can beaccurately measured in at least one dimension (longest diameter to be recorded fornon-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chestx-ray or as >= 10 mm (>= 1 cm) with CT scan, MRI, or calipers by clinical exam.

• Patients must have diagnosed NSCLC, with no prior overlapping radiation therapydelivered for locally advanced NSCLC. Prior stereotactic radiation therapy for stageI lung cancer without overlapping is allowed. Prior systemic antineoplastic therapyis allowed, as deemed appropriate by the treating physician. Prior surgery isallowed. History of previous stage I NSCLC with new mediastinal nodal recurrence (new stage III are eligible).

• Age >= 18 years. Because no dosing or adverse event data are currently available onthe use of TRC102 in combination with pemetrexed, cisplatin, and durvalumab inpatients < 18 years of age, children are excluded from this study.

• Body weight > 30 kg with acceptable nutritional status based on evaluation bytreating physician.

• Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%).

• Leukocytes >= 3,000/mcL.

• Hemoglobin >= 9.0 g/dL.

• Absolute neutrophil count >= 1,500/mcL.

• Platelets >= 150,000/mcL.

• Serum bilirubin within normal institutional limits (0 - 1.2 mg/ dl). (This will notapply to patients with confirmed Gilbert's syndrome [persistent or recurrenthyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis orhepatic pathology], who will be allowed only in consultation with their physician.).

• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT]) =< 2.5 x institutional upper limit of normal (=< 39 U/L).

• Alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 2.5x institutional upper limit of normal (=< 52 U/L).

• Creatinine =< 1.3 mg/dL.

• Measured creatinine clearance >= 60 mL/min OR glomerular filtration rate (GFR) >= 50mL/min/1.73 m^2.

• Acceptable pulmonary function as assessed by treating physician.

• Evidence of post-menopausal status or negative urinary or serum pregnancy test forfemale pre-menopausal patients. Women will be considered post-menopausal if theyhave been amenorrheic for 12 months without an alternative medical cause. Thefollowing age-specific requirements apply:

• Women < 60 years of age would be considered post-menopausal if they have beenamenorrheic for 12 months or more following cessation of exogenous hormonaltreatments and if they have luteinizing hormone and follicle-stimulatinghormone levels in the post-menopausal range for the institution or underwentsurgical sterilization (bilateral oophorectomy or hysterectomy).

• Women >= 60 years of age will be considered post-menopausal.

• Life expectancy >= 12 months.

• Patients who are human immunodeficiency virus (HIV) positive may participate IF theymeet the following eligibility requirements:

• They must be stable on their anti-retroviral regimen with evidence of at leasttwo undetectable viral loads within the past 6 months on the same regimen; themost recent undetectable viral load must be within the past 12 weeks.

• They must have a CD4 count of greater than 250 cells/mcL over the past 6 monthson this same anti-retroviral regimen and must not have had a CD4 count < 200cells/mcL over the past 2 years, unless it was deemed related to the cancerand/or chemotherapy induced bone marrow suppression.

• For patients who have received chemotherapy in the past 6 months, a CD4count < 250 cells/mcL during chemotherapy is permitted as long as viralloads were undetectable during this same chemotherapy.

• They must have an undetectable viral load and a CD4 count >= 250 cells/mcLwithin 7 days of enrollment.

• They must not be currently receiving prophylactic therapy for an opportunisticinfection and must not have had an opportunistic infection within the past 6months.

• HIV-infected patients should be monitored every 12 weeks for viral load and CD4counts.

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated.

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load.

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association functional classification. To beeligible for this trial, patients should be class 2B or better.

• The effects of TRC102 on the developing human fetus are unknown. For this reason andbecause biochemical inhibitors of the BER pathway agents as well as othertherapeutic agents used in this trial are known to be teratogenic, women ofchild-bearing potential and men must agree to use adequate contraception (hormonalor barrier method of birth control; abstinence) prior to study entry, for theduration of study participation, and for 6 months after completion of durvalumabmonotherapy. Should a woman become pregnant or suspect she is pregnant while she orher partner is participating in this study, she should inform her treating physicianimmediately. Men treated or enrolled on this protocol must also agree to useadequate contraception prior to the study, for the duration of study participation,and 6 months after completion of durvalumab administration, if having sex with womenof childbearing potential.

• Ability to understand and the willingness to sign a written informed consentdocument. Participants with impaired decision-making capacity who have alegally-authorized representative (LAR) and/or family member available will also beeligible.

• Patients with prior stage I/II non-small cell lung cancer treated with surgery areeligible. Patients with prior stage I NSCLC treated with stereotactic bodyradiotherapy (SBRT) without overlapping radiation fields would also be eligible.Patients with prior chemotherapy are eligible, at physician's discretion.

Exclusion Criteria:

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia.

• Patients who are receiving any other investigational agents.

• Patients with treated brain metastases are not eligible as the study is for stageIII disease only.

• Patients with new or progressive brain metastases (active brain metastases) orleptomeningeal disease are not eligible as the study includes only stage IIIdisease.

• Patients with EGFR or ALK mutations are ineligible.

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to TRC102 or other agents used in study.

• Patients with uncontrolled intercurrent illness, including but not limited to,ongoing or active infection, symptomatic congestive heart failure, uncontrolledhypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lungdisease, serious chronic gastrointestinal conditions associated with diarrhea, orpsychiatric illness/social situations that would limit compliance with studyrequirement, substantially increase risk of incurring adverse events (AEs) orcompromise the ability of the patient to give written informed consent.

• Patients with psychiatric illness/social situations that would limit compliance withstudy requirements.

• Pregnant women are excluded from this study because TRC102 is a biochemicalinhibitor of the BER pathway and durvalumab is an anti-PDL1 antibody, agents withthe potential for teratogenic or abortifacient effects. Because there is an unknownbut potential risk for adverse events in nursing infants secondary to treatment ofthe mother with TRC102 or durvalumab, breastfeeding should be discontinued if themother is treated with TRC102 or durvalumab. These potential risks may also apply toother agents used in this study.

• Women of child-bearing potential and men must agree to use adequatecontraception (hormonal or barrier method of birth control; abstinence) priorto study entry, for the duration of study participation, and for 6 months afterdurvalumab monotherapy. Should a woman become pregnant or suspect she ispregnant while she or her partner is participating in this study, she shouldinform her treating physician immediately. Men treated or enrolled on thisprotocol must also agree to use adequate contraception prior to the study, forthe duration of study participation, and 6 months after completion ofdurvalumab.

• Patients with active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease],diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus,sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves'disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following areexceptions to this criterion:

• Patients with vitiligo or alopecia.

• Patients with hypothyroidism (e.g. following Hashimoto thyroiditis) stable onhormone replacement.

• Any chronic skin condition that does not require systemic therapy.

• Patients without active disease in the last 5 years may be included but onlyafter consultation with the study physician.

• Patients with celiac disease controlled by diet alone.

• Active infection including tuberculosis (clinical evaluation that includes clinicalhistory, physical examination and radiographic findings, and tuberculosis [TB]testing in line with local practice), hepatitis B (known positive HBV surfaceantigen [HBsAg] result), or hepatitis C. Patients with a past or resolved HBVinfection (defined as the presence of hepatitis B core antibody [anti-HBc] andabsence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody areeligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA).

• History of allogenic organ transplantation.

• History of another primary malignancy except for:

• Malignancy treated with curative intent and with no active disease before thefirst dose of investigational product (IP) and of low potential risk forrecurrence.

• Adequately treated non-melanoma skin cancer or lentigo maligna without evidenceof disease.

• Adequately treated any carcinoma in situ without evidence of disease.

• Prostate cancer with stable disease with active or prior treatment that willnot interfere with current lung cancer treatment will be eligible.