Pilot Study of Abequolixron (RGX-104) and Durvalumab in Lung Cancer

A Pilot Window of Opportunity Study Evaluating Durvalumab (MEDI4736) in Combination With Platinum Doublet Chemotherapy Followed by Evaluation of Durvalumab (MEDI4736) in Combination With Platinum Doublet Chemotherapy and Abequolixron (RGX-104) in Non-small Cell Lung Cancer

Non-Small Cell Lung Cancer (NSCLC) is one of the deadliest types of cancer. In lung cancer patients with a tumor that can be removed by surgery, adjuvant chemotherapy increases survival. Neoadjuvant therapy may have advantages such as, it may be more tolerable prior to surgery, earlier treatment may be more efficacious, and it can provide an indication of treatment response. Neoadjuvant treatment can provide pre- and post-treatment specimens for correlative analysis to better understand mechanisms of action and resistance. This pilot study will investigate the effects of neoadjuvant durvalumab plus platinum doublet chemotherapy and neoadjuvant durvalumab plus platinum doublet chemotherapy in combination with abequolixron (RGX-104), an LXR/ApoE agonist, in subjects with NSCLC who are scheduled to undergo surgical resection as part of their standard of care. The purpose of this study is to study how well using a combination of durvalumab, platinum doublet chemotherapy (carboplatin/abraxane or carboplatin/pemetrexed), and abequolixron treats non-small cell lung cancer before surgery. Durvalumab (a type of immunotherapy) and platinum doublet chemotherapy are drugs that are individually approved for use during the treatment of cancer. FDA (Food and Drug Administration) has not approved the combined use of these drugs in treating non-small cell lung cancer. Abequolixron is not FDA approved for the treatment of cancer.

Subjects with operable Non-Small Cell Lung Cancer received neoadjuvant durvalumab plus platinum doublet chemotherapy and neoadjuvant durvalumab plus platinum doublet chemotherapy in combination with abequolixron (RGX-104), an LXR/ApoE agonist.

100 or 120 mg Abequolixron will be administered by mouth twice a day for 5 days followed by 2 days off throughout your treatment (5 days a week for up to 9 weeks).

Feasibility will be evaluated as the delay time between the completion of neoadjuvant therapy and surgery. A failure of feasibility will be defined as a delay in the planned surgery of more than 42 days (surgical delay of 35 days, plus 7 days for scheduling).

Toxicities related to study treatment therapy will be classified and graded according to The NCI Common Terminology Criteria for Adverse Events (NCI-CTCAE v5.0). NCI-CTCAE v5.0 is a descriptive terminology that can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE.

Major pathologic complete response rate after neoadjuvant chemotherapy will be assessed via surgical pathology report in subjects with non-small cell lung carcinoma - squamous histology. Major pathologic response is defined as equal to or less than 10% residual tumor following neoadjuvant therapy.

Major pathologic complete response rate after neoadjuvant chemotherapy will be assessed via surgical pathology report in subjects with non-small cell lung carcinoma - nonsquamous histology. Major pathologic response is defined as equal to or less than 10% residual tumor following neoadjuvant therapy.

Pathologic complete response rate (PCR) -durvalumab in combination with platinum doublet chemotherapy

PCR -durvalumab in combination with platinum doublet chemotherapy will be histologically evaluated at the time of surgery, in subjects receiving neoadjuvant treatment with durvalumab in combination with platinum doublet chemotherapy. Pathologic complete response (pCR) is the disappearance of all signs of cancer in tissue samples removed during surgery or biopsy (pT0). Also called pathologic complete remission. Pathologic Partial Response (pPR), is the presence of only non-invasive cancer in tissue samples (<pT2)

Pathologic complete response rate (PCR) - durvalumab in combination with platinum doublet chemotherapy plus abequolixron

Pathologic complete response rate (PCR) - durvalumab in combination with platinum doublet chemotherapy plus abequolixron will be histologically evaluated at the time of surgery, in subjects receiving neoadjuvant treatment with durvalumab in combination with platinum doublet chemotherapy plus abequolixron. Pathologic complete response (pCR) is the disappearance of all signs of cancer in tissue samples removed during surgery or biopsy (pT0). Also called pathologic complete remission. Pathologic Partial Response (pPR), is the presence of only non-invasive cancer in tissue samples (<pT2)

CRR is defined as the clinical response rate is the combination of complete response (CR) + partial response (PR) defined by The overall response rate will be assessed per Response Evaluation Criteria Solid Tumors (RECIST) 1.1 in subjects receiving durvalumab in combination with platinum doublet chemotherapy. Based on RECIST v1.1, Complete Response (CR) is the Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; and Overall Response Rate (ORR) = CR + PR/total number of subjects.

Clinical response rate (CRR) - durvalumab in combination with platinum doublet chemotherapy plus abequolixron

CRR is defined as the clinical response rate is the combination of complete response (CR) + partial response (PR) defined by The overall response rate will be assessed per Response Evaluation Criteria Solid Tumors (RECIST) 1.1 in subjects receiving durvalumab in combination with platinum doublet chemotherapy plus abequolixron. Based on RECIST v1.1, Complete Response (CR) is the Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; and Overall Response Rate (ORR) = CR + PR/total number of subjects.

RFS - durvalumab in combination with platinum doublet chemotherapy will be defined as the time from the time after surgery to disease recurrence or death (whichever occurs first) and will be defined by RECIST 1.1. in subjects receiving neoadjuvant therapy with durvalumab in combination with platinum doublet chemotherapy. Based on RECIST v1.1 Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), no response or less response than Partial or Progressive; or Progressive Disease (PD), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Recurrence-free survival (RFS)- durvalumab in combination with platinum doublet chemotherapy plus abequolixron

RFS - durvalumab in combination with platinum doublet chemotherapy will be defined as the time from the time after surgery to disease recurrence or death (whichever occurs first) and will be defined by RECIST 1.1. in subjects receiving neoadjuvant therapy with durvalumab in combination with platinum doublet chemotherapy plus abequolixron Based on RECIST v1.1 Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), no response or less response than Partial or Progressive; or Progressive Disease (PD), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

OS - durvalumab is defined as the time from the first day of study therapy to the date of death for any cause, in subjects receiving neoadjuvant therapy with durvalumab in combination with platinum doublet chemotherapy.

Overall Survival (OS) - durvalumab in combination with platinum doublet chemotherapy plus abequolixron

OS - durvalumab in combination with platinum doublet chemotherapy plus abequolixron is defined as the time from the first day of study therapy to date of death for any cause, in subjects receiving neoadjuvant therapy with durvalumab in combination with platinum doublet chemotherapy plus abequolixron.

Inclusion Criteria: Willing and able to provide written informed consent obtained to participate in the study and HIPAA authorization for the release of personal health information. Age ≥ 18 years at the time of consent. Histologically or cytologically confirmed non-small cell lung cancer for which surgical resection would be standard of care. ECOG Performance Status of 0-1 Body weight of > 40 kg Is able to swallow and retain oral medication. Exclusion Criteria: Participation in another clinical study with an investigational product during the last 3 weeks Concurrent enrollment in another clinical study unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment with the exception of those mentioned in this protocol. Concurrent use of hormonal therapy for noncancer- related conditions (e.g., hormone replacement therapy) is acceptable. Lack of full recovery from a major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. History of allogenic organ transplantation.