PRIMARY OBJECTIVES:
I. 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:
I. 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:
I. 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.
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], 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 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
