Sirolimus and Durvalumab for the Treatment of Stage I-IIIA Non-small Cell Lung Cancer
18 Years and older, Male and Female
Winship4867-19 (primary)
NCI-2019-07427
19-20015
Summary
This trial studies the side effects of sirolimus and durvalumab and to see how well they work in treating patients with stage I-IIIA non-small cell lung cancer. Sirolimus is an oral medication that blocks the mTOR cellular pathway which may help the immune system work better. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving sirolimus before durvalumab may help the immune system get rid of cancer.
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.
Eligibility
- Patients with pathologically documented NSCLC who are deemed to be candidates for definitive surgery: Stage will be categorized based on 8th edition of American Joint Committee on Cancer (AJCC) Non-small cell Lung Cancer Staging system
- Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (e.g., Health Insurance Portability and Accountability Act in the United States [US]) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations
- Age >= 18 years at time of study entry
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Life expectancy of >= 26 weeks
- Body weight > 30 kg
- Hemoglobin >= 9.0 g/dL
- Absolute neutrophil count (ANC) 1.5 x 10^9/L (>= 1500 per mm^3)
- Platelet count >= 100 x 10^9/L (>= 100,000 per mm^3)
- Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be =< 5 x ULN
- Measured creatinine clearance (CL) > 40 mL/min or calculated creatinine CL > 40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance
- 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 < 50 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 >= 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)
- Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
- Patients must consent to pre-treatment research biopsy and study peripheral blood collection
- Patients must have measurable disease, defined by RECIST v 1.1
- Patient is able to take oral medications
- Patient consents to heavy water (D2O) self-administration if on optional heavy water labelling study
Treatment Sites in Georgia
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