CTEP #10512: A Phase 2 Randomized Study of the BER Inhibitor TRC102 in Combination with Standard Pemetrexed-Platinum-Radiation in Stage III Non-Squamous Non-Small Cell Lung Cancer

Inclusion Criteria

- Patients must have histologically or cytologically confirmed adenocarcinoma or large

cell carcinoma of the lung with confirmation by immunohistochemistry (histologic

tissue diagnosis is preferred, but cytology is acceptable).

- Patients must have stage IIIA, IIIB or IIIC disease according to the 8th tumor, node,

metastasis (TNM) staging classification and to be considered appropriate candidates

for aggressive chemoradiotherapy.

- Patients must have measurable disease, defined as at least one lesion that can be

accurately measured in at least one dimension (longest diameter to be recorded for

non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chest

x-ray or as >= 10 mm (>= 1 cm) with computed tomography (CT) scan, magnetic resonance

imaging (MRI), or calipers by clinical exam.

- Patients must have newly diagnosed non small cell lung cancer (NSCLC), with no prior

overlapping radiation therapy delivered for locally advanced NSCLC. Prior stereotactic

radiation therapy for stage I lung cancer without overlapping is allowed. Prior

systemic antineoplastic therapy is allowed, as deemed appropriate by the treating

physician. Prior surgery is allowed.

- Age >= 18 years. Because no dosing or adverse event data are currently available on

the use of TRC102 in combination with pemetrexed, cisplatin, and durvalumab in

patients < 18 years of age, children are excluded from this study.

- Body weight > 30 kg with acceptable nutritional status based on evaluation by treating

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 not

apply to patients with confirmed Gilbert's syndrome [persistent or recurrent

hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or

hepatic 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]) =< 2.5 x

institutional upper limit of normal (=< 52 U/L).

- Creatinine =< 1.3 mg/dL.

- Measured creatinine clearance >= 60 mL/min OR glomerular filtration rate (GFR) >= 50

mL/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 for

female pre-menopausal patients. Women will be considered post-menopausal if they have

been amenorrheic for 12 months without an alternative medical cause. The following

age-specific requirements apply:

- Women < 60 years of age would be considered post-menopausal if they have been

amenorrheic for 12 months or more following cessation of exogenous hormonal

treatments and if they have luteinizing hormone and follicle-stimulating hormone

levels in the post-menopausal range for the institution or underwent surgical

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 they

meet the following eligibility requirements:

- They must be stable on their anti-retroviral regimen with evidence of at least

two undetectable viral loads within the past 6 months on the same regimen; the

most 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 months

on this same anti-retroviral regimen and must not have had a CD4 count < 200

cells/mcL over the past 2 years, unless it was deemed related to the cancer

and/or chemotherapy induced bone marrow suppression.

- For patients who have received chemotherapy in the past 6 months, a CD4

count < 250 cells/mcL during chemotherapy is permitted as long as viral

loads were undetectable during this same chemotherapy.

- They must have an undetectable viral load and a CD4 count >= 250 cells/mcL within

7 days of enrollment.

- They must not be currently receiving prophylactic therapy for an opportunistic

infection and must not have had an opportunistic infection within the past 6

months.

- HIV-infected patients should be monitored every 12 weeks for viral load and CD4

counts.

- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral

load must be undetectable on suppressive therapy, if indicated.

- Patients with a history of hepatitis C virus (HCV) infection must have been treated

and cured. For patients with HCV infection who are currently on treatment, they are

eligible if they have an undetectable HCV viral load.

- Patients with known history or current symptoms of cardiac disease, or history of

treatment with cardio toxic agents, should have a clinical risk assessment of cardiac

function using the New York Heart Association functional classification. To be

eligible for this trial, patients should be class 2B or better.

- The effects of TRC102 on the developing human fetus are unknown. For this reason and

because biochemical inhibitors of the BER pathway agents as well as other therapeutic

agents used in this trial are known to be teratogenic, women of child-bearing

potential and men must agree to use adequate contraception (hormonal or barrier method

of birth control; abstinence) prior to study entry, for the duration of study

participation, and for 6 months after completion of durvalumab monotherapy. Should a

woman become pregnant or suspect she is pregnant while she or her partner is

participating in this study, she should inform her treating physician immediately. Men

treated or enrolled on this protocol must also agree to use adequate contraception

prior to the study, for the duration of study participation, and 6 months after

completion of durvalumab administration, if having sex with women of childbearing

potential.

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

Participants with impaired decision-making capacity who have a legally-authorized

representative (LAR) and/or family member available will also be eligible.

- Patients with actionable mutations are eligible. Treatment with durvalumab during

consolidative phase will be at physician discretion.

- Patients with prior stage I/II non-small cell lung cancer treated with surgery are

eligible. Patients with prior stage I NSCLC treated with stereotactic body

radiotherapy (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 stage III

disease only.

- Patients with new or progressive brain metastases (active brain metastases) or

leptomeningeal disease are not eligible as the study includes only stage III disease.

- History of allergic reactions attributed to compounds of similar chemical or biologic

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, uncontrolled hypertension,

unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious

chronic gastrointestinal conditions associated with diarrhea, or psychiatric

illness/social situations that would limit compliance with study requirement,

substantially increase risk of incurring AEs or compromise the ability of the patient

to give written informed consent.

- Patients with psychiatric illness/social situations that would limit compliance with

study requirements.

- Pregnant women are excluded from this study because TRC102 is a biochemical inhibitor

of the BER pathway and durvalumab is an anti-PDL1 antibody, agents with the potential

for teratogenic or abortifacient effects. Because there is an unknown but potential

risk for adverse events in nursing infants secondary to treatment of the mother with

TRC102 or durvalumab, breastfeeding should be discontinued if the mother is treated

with TRC102 or durvalumab. These potential risks may also apply to other agents used

in this study.

- Women of child-bearing potential and men must agree to use adequate contraception

(hormonal or barrier method of birth control; abstinence) prior to study entry,

for the duration of study participation, and for 6 months after durvalumab

monotherapy. Should a woman become pregnant or suspect she is pregnant while she

or her partner is participating in this study, she should inform her treating

physician immediately. Men treated or enrolled on this protocol must also agree

to use adequate contraception prior to the study, for the duration of study

participation, and 6 months after completion of durvalumab.

- 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 are

exceptions to this criterion:

- Patients with vitiligo or alopecia.

- Patients with hypothyroidism (e.g. following Hashimoto thyroiditis) stable on

hormone replacement.

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

- Patients without active disease in the last 5 years may be included but only

after consultation with the study physician.

- Patients with celiac disease controlled by diet alone.

- Active infection including tuberculosis (clinical evaluation that includes clinical

history, physical examination and radiographic findings, and tuberculosis [TB] testing

in line with local practice), hepatitis B (known positive HBV surface antigen [HBsAg]

result), or hepatitis C. Patients with a past or resolved HBV infection (defined as

the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are

eligible. Patients positive for hepatitis C (HCV) antibody are eligible 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 the

first dose of IP and of low potential risk for recurrence.

- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence

of disease.

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

- Prostate cancer with stable disease with active or prior treatment that will not

interfere with current lung cancer treatment will be eligible.