Sirolimus and Durvalumab for the Treatment of Stage I-IIIA Non-small Cell Lung Cancer

Summary

Objectives

PRIMARY OBJECTIVES:
I. To evaluate the safety and tolerability of sirolimus followed by durvalumab as neoadjuvant treatment by incidence of adverse events, with severity per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0.
II. To evaluate the efficacy of sirolimus followed by durvalumab as neoadjuvant treatment for stage I, II, and IIIA non-small cell lung cancer (NSCLC) by complete pathologic response at surgical resection scored by a pathologist.

SECONDARY OBJECTIVES:
I. To evaluate the efficacy of sirolimus in combination with durvalumab as neoadjuvant treatment for stage I, II, and IIIA NSCLC by investigator-assessed response rate per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, disease free survival and overall survival.
II. To evaluate response to sirolimus in combination with durvalumab in patients with PD-L1-positive versus (vs.) PD-L1-negative tumors by complete pathologic response rate.
III. To evaluate the association between blood mutation burden and response to sirolimus and durvalumab by overall response rate in PD-L1-positive and PD-L1-negative groups based on mutational burden.
IV. To evaluate impact of neoadjuvant durvalumab and sirolimus on post-surgical recovery by length of hospital stay after surgery.

EXPLORATORY OBJECTIVES:
I. To evaluate the immune-mediated effects of combination sirolimus and durvalumab by assessment of immune responses by flow cytometry, cytokine analysis, and genetic assessments in serial blood and tissue samples and correlate with clinical outcome.
II. To investigate tumor and immune microenvironment changes in tissue samples by pathological analyses (which may include immunohistochemistry immunofluorescence) of tissue samples pre- and post- neoadjuvant therapy.

OUTLINE:
Patients receive sirolimus orally (PO) once daily (QD) on days 1-21 in the absence of disease progression or unacceptable toxicity. Starting on day 22, patients receive durvalumab intravenously (IV) over 1 hour. Treatment with durvalumab repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Within a 2-3 week period after the second dose of durvalumab, but not earlier than two weeks after the administration of durvalumab, patients undergo standard of care surgery.

After completion of study treatment, patients are followed up every 3 months for 2 years.