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

Sponsor

Emory University (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT04348292

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Arm

47.1

Anticipated Duration (Months)

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Lung Non-Small Cell Carcinoma Stage I Lung Cancer AJCC v8 Stage IA1 Lung Cancer AJCC v8 Stage IA2 Lung Cancer AJCC v8 Stage IA3 Lung Cancer AJCC v8 Stage IB Lung Cancer AJCC v8 Stage II Lung Cancer AJCC v8 Stage IIA Lung Cancer AJCC v8 Stage IIB Lung Cancer AJCC v8 Stage IIIA Lung Cancer AJCC v8	Drug: Durvalumab Drug: Sirolimus	Phase 1

Detailed Description

PRIMARY OBJECTIVES:

To evaluate the safety and tolerability of sirolimus followed by durvalumab as neoadjuvant treatment 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)

SECONDARY OBJECTIVES:

To evaluate the efficacy of sirolimus in combination with durvalumab as neoadjuvant treatment for stage I, II, and IIIA NSCLC II. To evaluate response to sirolimus in combination with durvalumab in patients with PD-L1-positive versus (vs.) PD-L1-negative tumors III. To evaluate the association between blood mutation burden and response to sirolimus and durvalumab

EXPLORATORY OBJECTIVES:

To evaluate the immune-mediated effects of combination sirolimus and durvalumab II. To investigate tumor and immune microenvironment changes in tissue samples

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

3 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1b Neoadjuvant Trial of Sirolimus Followed by Durvalumab (MEDI4736) in Resectable Non-small Cell Lung Cancer

Actual Study Start Date :

Jan 22, 2021

Anticipated Primary Completion Date :

Dec 25, 2023

Anticipated Study Completion Date :

Dec 25, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (sirolimus, durvalumab) Patients receive sirolimus PO QD on days 1-21 in the absence of disease progression or unacceptable toxicity. Starting on day 22, patients receive durvalumab 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.	Drug: Durvalumab Given IV Other Names: Imfinzi Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer MEDI-4736 MEDI4736 Drug: Sirolimus Given PO Other Names: AY 22989 RAPA Rapamune Rapamycin SILA 9268A WY-090217

Arm

Intervention/Treatment

Experimental: Treatment (sirolimus, durvalumab)

Patients receive sirolimus PO QD on days 1-21 in the absence of disease progression or unacceptable toxicity. Starting on day 22, patients receive durvalumab 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.

Drug: Durvalumab

Given IV

Other Names:

Imfinzi

Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer

MEDI-4736

MEDI4736

Drug: Sirolimus

Given PO

Other Names:

AY 22989

RAPA

Rapamune

Rapamycin

SILA 9268A

WY-090217

Outcome Measures

Primary Outcome Measures

Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 [2 years]
Other adverse events will be listed and summarized by severity, seriousness, and by system organ class. The number and percentage of subjects who experience AEs will be presented in tabular and/or graphical format and summarized descriptively, where appropriate. The frequency of overall toxicity, categorized by toxicity grades 1 through 5, will be described.
The effectiveness of sirolimus followed by durvalumab will be assessed by complete pathologic response rate in the efficacy population [2 years]
If the null hypothesis is rejected then this is evidence that the response rate exceeds 10% when sirolimus followed by durvalumab is given before resection. The one-sided 95% confidence interval (CI) for complete pathologic response will be reported. Exact binomial test will be used to compare the estimated complete pathologic response rate to the historical reference.

Secondary Outcome Measures

Complete pathologic response rates for PDL-1 negative and PDL-1 positive patients [2 years]
A comparison of both the complete pathologic response and investigator assessed response rates per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 rates between the PD-L1 positive and PD-L1 negative groups will be performed by calculating the lower bound of a one-sided 80% CI for the difference, complete pathologic response for PDL-1 positive patients - complete pathologic response for PDL-1 negative patients. Chi-square test or Fisher's exact test will be used to compare the efficacy in term of response rate between the different groups stratified by other factors, respectively. Logistics regression model will be further employed to test the adjusted effect of each other factor on the response rate after adjusting for other clinical factors and demographic factors, respectively. Correlation of response will be performed for tumor mutation burden using spearman correlation coefficient and tested with Wald's test.

Other Outcome Measures

Dose limiting toxicity (DLT) [2 years]
DLTs will be summarized and tabulated by type and grade. DLT rate by dose level will be calculated as proportion (Patients with DLT/Total patients) along with 95% confidence intervals using the Clopper-Pearson method. Chi-square test or Fisher's exact test will be used to compare the probability of DLT between the different other factors, such as PD-L1 status.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients with pathologically documented NSCLC: Stage I, II, IIIa NSCLC 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 (eg, 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
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

Exclusion Criteria:

Patients who have had prior therapy for lung cancer including chemotherapy, hormonal therapy, or radiotherapy
Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study
Prior treatment with anti-PD-1, anti-PDL-1, other PD-1/PDL-1 pathway targeting agents, or mTOR inhibition
History of allogenic organ transplantation
Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], 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 syndrome) 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
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 adverse events (AEs) or compromise the ability of the patient to give written informed consent
History of another primary malignancy except for
Malignancy treated with curative intent and with no known active disease >= 5 years before the first dose of investigational product (IP) and of low potential risk for recurrence
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
Adequately treated carcinoma in situ without evidence of disease
QT interval corrected for heart rate using Fridericia's formula (QTcF) >= 470 ms. Patient safety and the cardiac SKG should be consulted as needed
History of active primary immunodeficiency
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 hepatitis B virus [HBV] surface antigen [HBsAg] result), 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 virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA)
Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:
Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
Steroids as premedication for hypersensitivity reactions (e.g., computed tomography [CT] scan premedication)
Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP
Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy
Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
Prior randomization or treatment in a previous durvalumab clinical study regardless of treatment arm assignment
Patients with a history of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
Inability to stop prohibited concomitant medications
Judgment by the investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements