Durvalumab and Tremelimumab in Treating Patients With Recurrent Stage IV Lung Cancer

PRIMARY OBJECTIVES:

I. To evaluate the objective response rate (confirmed and unconfirmed, complete and partial)
by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 among patients treated with
durvalumab (MEDI4736) plus tremelimumab.

SECONDARY OBJECTIVES:

I. To estimate the duration of response (DoR) among patients who achieve a complete response
(CR) or partial response (PR) (confirmed and unconfirmed) by RECIST 1.1.

II. To estimate the duration of response (DoR) per immune-related response criteria among
patients who achieve a complete response (CR) or partial response (PR) (confirmed and
unconfirmed) by RECIST 1.1.

III. To evaluate overall survival (OS) among patients treated with durvalumab (MEDI4736) plus
tremelimumab.

IV. To evaluate investigator-assessed progression-free survival (IA-PFS) among patients
treated with durvalumab (MEDI4736) plus tremelimumab.

V. To evaluate IA-PFS assessed by immune-related response criteria (irRC-IA-PFS) among
patients treated with durvalumab (MEDI4736) plus tremelimumab.

VI. To evaluate the frequency and severity of toxicities associated with durvalumab
(MEDI4736) plus tremelimumab.

TERTIARY OBJECTIVES:

I. To explore the association of potential predictive markers identified in S1400A, with
response and progression-free survival (PFS).

II. To explore the association of PD-L1 expression status with response and PFS.

III. To contribute to an ongoing serum and tumor bank in S1400.

OUTLINE:

Patients receive tremelimumab intravenously (IV) over 60 minutes on day 1 for courses 1-4 and
durvalumab IV over 60 minutes on day 1. Courses repeat every 28 days in the absence of
disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for 2 years, and
then at the end of year 3.

Inclusion Criteria:

- Patients must have been assigned to S1400F

- Patients must have progressed during or after prior platinum-based chemotherapy;
patients whose only prior platinum-based chemotherapy regimen was for stage I-III
disease (i.e. patient has not received any platinum-based chemotherapy for stage IV or
recurrent disease), disease progression on platinum-based chemotherapy must have
occurred within one year from the last date that patient received that therapy;
patients must have experienced disease progression during or after prior anti-PD-1 or
anti-PD-L1 antibody monotherapy as their most recent line of treatment; prior
PD-1/PD-L1 combination therapy is not permitted

- Prior exposure to CTLA-4 inhibitors (ipilimumab and tremelimumab) is not permitted;
prior exposure to the following is allowed: attenuated vaccines, anti-EGFR agents, and
granulocyte-macrophage colony-stimulating factor (GM-CSF)

- Patients must not have received nitrosoureas or mitomycin-C within 42 days prior to
sub-study registration

- Patients must not have any prior documented autoimmune or inflammatory disease
(including inflammatory bowel disease, diverticulitis with the exception of
diverticulosis, celiac disease, irritable bowel disease; Wegner syndrome; Hashimoto
syndrome) within 3 years prior to sub-study registration; patients with vitiligo,
immune-mediated alopecia, Grave?s disease, or psoriasis requiring systemic treatment
within the past 2 years are not eligible; patients with hypothyroidism (e.g. post
Hashimoto syndrome) who are stable on hormone replacement therapy are eligible

- Patients must not have any history of primary immunodeficiency

- Patients must not have received any immunosuppressive medication within 28 days prior
to sub-study registration and must not be planning to receive these medications while
on protocol therapy; systemic corticosteroids must be stopped at least 24 hours prior
to sub-study registration; however, intranasal and inhaled corticosteroids are allowed
at any time before and during protocol therapy

- Patients must not have experienced a grade 3 or worse immune-related adverse event
(irAE) (except asymptomatic nonbullous/nonexfoliative rash) or any unresolved irAE
grade 2, nor have experienced a toxicity that led to permanent discontinuation of
prior anti-PD-1/PD-L1 immunotherapy

- Patients must not have any history of organ transplant that requires use of
immunosuppressives

- Patients must not have any known allergy or reaction to any component of the
durvalumab (MEDI4736) and/or tremelimumab formulation

- Patients must not have clinical signs or symptoms of active tuberculosis infection

- Patients must not have received a live attenuated vaccination within 28 days prior to
sub-study registration

- Patients must not have known human immunodeficiency virus (HIV), or a known positive
test for hepatitis B virus surface antigen (HBV sAg), or hepatitis C virus ribonucleic
acid (HCV antibody) indicating current acute or chronic infection; patients with a
positive hepatitis C antibody with a negative viral load are allowed

- Patients must have a thyroid-stimulating hormone (TSH) with reflex free T3/free T4 (if
TSH is out of normal range) and electrocardiogram (EKG) obtained within 7 days prior
to sub-study registration

- Patients must also be offered participation in banking and in the correlative studies
for collection and future use of specimens