Tremelimumab and Durvalumab With or Without Radiation Therapy in Patients With Relapsed Small Cell Lung Cancer

PRIMARY OBJECTIVE:

I. To assess the efficacy (progression free survival [PFS] and objective response rate [ORR])
of combined immune checkpoint inhibitor therapy as treatment for relapsed small-cell lung
cancer (SCLC).

SECONDARY OBJECTIVES:

I. To assess the impact of antigen priming using radiation therapy (XRT) on the efficacy of
immune checkpoint inhibitors.

II. To determine immune related objective response rate.

III. To estimate overall survival measured as time from randomization to death from any
cause.

TERTIARY OBJECTIVES:

I. To characterize tumor infiltrating lymphocytes (TILs) and programmed cell death 1 ligand 1
(PD-L1)/programmed cell death 1 (PD1) expression in paired tumor biopsies at baseline, end of
cycle 2 and at the time of progression.

II. To determine dynamic changes in cell free deoxyribonucleic acid (DNA) (cfDNA) and the
immunophenotype of peripheral blood repertoire of circulating lymphocytes using
multiparameter flow cytometry.

III. To determine changes in circulating cytokine mediators of inflammation and immunity
using Luminex assay.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive tremelimumab intravenously (IV) over 1 hour on day 1. Treatment
repeats every 4 weeks for up to 4 courses in the absence of disease progression or
unacceptable toxicity. Patients also receive durvalumab IV over 1 hour on day 1. Treatment
repeats every 4 weeks for up to 1 year in the absence of disease progression or unacceptable
toxicity. Patients achieving disease control may restart treatment upon evidence of
progressive disease, with or without confirmation.

ARM II: Patients undergo radiation therapy daily for 5 days over 1 week or for 3 fractions
every other day for 1 week and then receive the same treatment as in Arm I.

After completion of study treatment, patients are followed up periodically.

Inclusion Criteria:

- Written informed consent and any locally-required authorization (e.g.,) obtained from
the subject prior to performing any protocol-related procedures, including screening
evaluations

- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

- Hemoglobin ≥ 9.0 g/dL

- Absolute neutrophil count (ANC) ≥ 1.5 x 10⁹/L (≥ 1500 per mm³)

- Platelet count ≥ 100 x 10⁹/L (≥ 100,000 per mm³)

- Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN); this will not apply
to subjects with confirmed Gilbert's syndrome (persistent or recurrent
hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or
hepatic pathology), who will be allowed only in consultation with their physician

- 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

- Serum creatinine clearance (CL) > 40 mL/min by the Cockcroft-Gault formula or by
24-hour urine collection for determination of creatinine clearance

- Female subjects must either be of non-reproductive potential (i.e., post-menopausal by
history: ≥ 60 years old and no menses for ≥ 1 year without an alternative medical
cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history
of bilateral oophorectomy) or must have a negative serum pregnancy upon study entry

- Subject 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 have baseline evaluations performed prior to the first dose of study
drug and must meet all inclusion and exclusion criteria

- Patients must have histologically or cytologically confirmed small cell lung cancer

- Patients must have measurable disease, defined as at least one lesion (excluding the
lesion for XRT) that can be accurately measured in at least one dimension (longest
diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >
20 mm with conventional techniques or as > 10 mm with spiral computed tomography (CT)
scan

- Patient must have failed or found to be intolerant of standard frontline
platinum-based regimens and must not have received > 2 prior lines of therapy (nota
bene [NB]: retreatment with a platinum-based doublet for sensitive relapse counts as
another line therapy; however substitution of cisplatin with carboplatin or vice versa
due to toxicity does not count as a separate regimen)

- Negative serum pregnancy test within 48 hours before starting study treatment in women
with childbearing potential

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at the study site)

- Previous enrollment or randomization in the present study

- Treatment with an investigational product during the last 2 weeks

- Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an
anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4), including tremelimumab

- Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy,
endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal
antibodies, other investigational agent) ≤ 14 days prior to the first dose of study
drug (≤ 7 days or four half-lives, whichever is longer, prior to the first dose of
study drug for subjects who have received prior tyrosine kinase inhibitors [TKIs]
[e.g., erlotinib, gefitinib and crizotinib] and within 6 weeks for nitrosourea or
mitomycin C)

- Mean QT interval corrected for heart rate (QTc) ≥ 470 ms calculated from 3
electrocardiograms (ECGs) using Fredericia's Correction

- Current or prior use of immunosuppressive medication within 28 days before the first
dose of durvalumab or tremelimumab, with the exceptions of intranasal and inhaled
corticosteroids or systemic corticosteroids at physiological doses, which are not to
exceed 10 mg/day of prednisone, or an equivalent corticosteroid

- Any unresolved toxicity (> Common Terminology Criteria for Adverse Events [CTCAE]
grade 2) from previous anti-cancer therapy; subjects with irreversible toxicity that
is not reasonably expected to be exacerbated by the investigational product may be
included (e.g., hearing loss, peripherally neuropathy)

- Any prior grade ≥ 3 immune-related adverse event (irAE) while receiving any previous
immunotherapy agent, or any unresolved irAE > grade 1

- Active or prior documented autoimmune disease within the past 2 years; NOTE: subjects
with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within
the past 2 years) are not excluded

- Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
ulcerative colitis)

- History of primary immunodeficiency

- History of allogeneic organ transplant

- History of hypersensitivity to durvalumab or any excipient

- History of hypersensitivity to the combination or comparator agent

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active
bleeding diatheses including any subject known to have evidence of acute or chronic
hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric
illness/social situations that would limit compliance with study requirements or
compromise the ability of the subject to give written informed consent

- Known history of previous clinical diagnosis of tuberculosis

- History of leptomeningeal carcinomatosis

- Receipt of live attenuated vaccination within 30 days prior to study entry or within
30 days of receiving durvalumab or tremelimumab

- Female subjects who are pregnant, breast-feeding or male or female patients of
reproductive potential who are not employing an effective method of birth control

- Any condition that, in the opinion of the investigator, would interfere with
evaluation of study treatment or interpretation of patient safety or study results

- Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive
of but not limited to surgery, radiation and/or corticosteroids

- Subjects with uncontrolled seizures

- 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 180 days after the last dose of durvalumab + tremelimumab combination
therapy or 90 days after the last dose of durvalumab monotherapy, whichever is the
longer time period

- Patients receiving any other investigational agents for any reason or
non-investigational agents administered for the purpose of controlling cancer growth
(use of conventional external beam radiation therapy will be allowed during protocol
therapy solely for palliation of localized painful lesions or bone lesions at risk of
fracture provided the radiation field does not encompass any selected target lesions
required for assessment)