Phase I/II Study of the Anti-Programmed Death Ligand-1 Antibody MEDI4736 in Combination With Olaparib and/or Cediranib for Advanced Solid Tumors and Advanced or Recurrent Ovarian, Triple Negative Breast, Lung, Prostate and Colorectal Cancers

Background:

- Disruption of the immune checkpoint PD-1/PD-L1 pathway yielded clinical activity in
subsets of advanced solid tumors, such as melanoma and lung cancer.

- Olaparib (O), a PARP inhibitor (PARPi), has demonstrated single agent activity in
recurrent ovarian cancer (OvCa), and subsets of prostate, triple negative breast or lung
cancers.

- Our recent randomized phase 2 study showed that O and cediranib (C), a VEGFR1-3
inhibitor was clinically superior to O alone in platinum-sensitive recurrent OvCa.

- We hypothesize that increased DNA damage by PARP inhibition and/or reduced angiogenesis
by VEGFR inhibition will complement the anti-tumor activity of an immune checkpoint
nhibitor, MEDI4736, in recurrent OvCa and other solid tumors.

Objectives:

- Phase I: To determine the recommended phase II dose (RP2D) and the safety of doublet
herapies (MEDI4736/olaparib [MEDI+O] and MEDI4736/cediranib [MEDI+C]) and triplet
therapy (MEDI+O+C) in patients with advanced solid tumors.

- Phase II Cohort 1 OvCa; MEDI+O, MEDI+C and MEDI+O+C arms: To determine clinical efficacy
as measured by overall response rate (ORR)

- Phase II Cohort 2 non-small cell lung cancer (NSCLC); MEDI+O and MEDI+C arms: To
determine clinical efficacy as measured by progression-free survival (PFS)

- Phase II Cohort 3 small cell lung cancer (SCLC); MEDI+O arm: To determine clinical
efficacy as measured by ORR

- Phase II Cohort 4 metastatic castrate-resistant prostate cancer (mCRPC); MEDI+O arm: To
determine clinical efficacy as measured by PFS

- Phase II Cohort 5 triple negative breast cancer (TNBC); MEDI+O arm: To determine
clinical efficacy as measured by ORR

- Phase II Cohort 6 colorectal cancer (CRC): C+MEDI arm: To determine clinical efficacy as
measured by PFS

Eligibility:

- Phase I: Advanced or recurrent solid tumors with evaluable disease.

- Phase II Cohort 1 MEDI+O, MEDI+C and MEDI+O+C arms: Advanced or recurrent OvCa

- Phase II Cohort 2 MEDI+O and MEDI+C arms: Advanced or recurrent NSCLC

- Phase II Cohort 3 MEDI+O arm: Advanced or recurrent SCLC

- Phase II Cohort 4 MEDI+O arm: mCRPC

- Phase II Cohort 5 MEDI+O arm: Advanced or recurrent TNBC

- Phase II Cohort 6 C+MEDI arm: Advanced or recurrent CRC

- Patients must be off prior chemotherapy, radiation therapy or biologic therapy for at
least 3 weeks. mCPRC patients (Cohort 4) may be on hormonal therapy with GnRH
agonists/antagonists.

- Adults with ECOG performance status 0-2, and adequate organ and marrow function.

Design:

- Phase I: MEDI+O, MEDI+C and MEDI+O+C will dose escalate simultaneously. MEDI4736 will be
administered once every 2 weeks or once every 4 weeks until disease progression. O
tablets and C will be given orally on a continuous or intermittent dosing schedule. The
DLT period will be one cycle, 28 days. Patients on the 2-week schedule greater than one
year will be changed to the 4-week schedule until progression.

- MEDI+O: MEDI4736 (3 mg/kg or 10 mg/kg IV every 2 weeks, or a fixed dose of 1500 mg
every 4 weeks) and O tablets (150 mg or 200 mg or 300 mg BID)

- MEDI+C: MEDI4736 (3 mg/kg or 10 mg/kg IV every 2 weeks, or a fixed dose of 1500 mg
every 4 weeks) and C (15 mg or 20 mg or 30 mg daily or 5 days/week)

- MEDI+O+C: MEDI4736 (a fixed dose of 1500mg every 4 weeks) with O tablets (200 mg or
300 mg BID) and C (15 mg or 20 mg 5 days/week)

- Phase II Cohort 1 OvCa MEDI+O arm: Patients will be treated with MEDI+O at RP2D (O 300mg
tablets bid daily and MEDI4736 at 1500 mg IV every 4 weeks).

- Phase II Cohort 1 OvCa MEDI+C arm: Patients will be treated with MEDI+C at RP2D (C 20mg
once a day [5 days on/2 days off] and MEDI4736 at 1500 mg every 4 weeks).

- Phase II Cohort 1 OvCa MEDI+O+C arm: Patients with OvCa (Cohort 1) will be treated with
RP2D (O tablets 300mg BID, C 20mg once a day [5 days on/2 days off] and MEDI4736 at 1500
mg every 4 weeks).

- Phase II Cohort 2 NSCLC; MEDI+O arm: Patients will be treated with MEDI+O at RP2D (O
300mg tablets bid daily and MEDI4736 at 1500 mg IV every 4 weeks).

- Phase II Cohort 2 NSCLC; MEDI+C arm: Patients will be treated with MEDI+C at RP2D (C
20mg once a day [5 days on/2 days off] and MEDI4736 at 1500 mg every 4 weeks).

- Phase II Cohort 3 SCLC; MEDI+O arm: Patients will be treated with MEDI+O at RP2D (O
300mg tablets bid daily and MEDI4736 at 1500 mg IV every 4 weeks).

- Phase II Cohort 4 mCRPC; MEDI+O arm: Patients will be treated with MEDI+O at RP2D (O
300mg tablets bid daily and MEDI4736 at 1500 mg IV every 4 weeks).

- Phase II Cohort 5 TNBC; MEDI+O arm: Patients will be treated with MEDI+O at RP2D (O
300mg tablets bid daily and MEDI4736 at 1500 mg IV every 4 weeks).

- Phase II Cohort 6 CRC; C+MEDI arm: Patients in the Cohort 6 will be treated with C 20mg
daily alone for 14 days followed by the combination at RP2D (C 20mg once a day [5 days
on/2 days off] and MEDI4736 at 1500 mg every 4 weeks).

- Phase II Correlative studies: Research samples including whole blood, CTCs, cell free
DNA and plasma will be obtained at pretreatment, prior to cycle 1 day 15, prior to cycle
3 day 1 and at progression. Mandatory baseline core biopsy and two optional biopsies
will be obtained.

- Patients will be evaluated for toxicity every 4 weeks by CTCAEv4.0, and for response
every two cycles (8 weeks) by RECIST 1.1. Patients with mCRPC (MEDI+O Cohort 4) will be
evaluated for response initially at 8 weeks then every 12 weeks using RECIST v1.1
criteria as per the Prostate Cancer Clinical Trials Working Group 2 (PCWG2).

- INCLUSION CRITERIA GENERAL:

- Patients must be at least 18 years of age.

- Patients must have adequately controlled blood pressure on a maximum of three
antihypertensive medications.

- Patients who have the following clinical conditions are considered to be at increased
risk for cardiac toxicities. Patients with any cardiac history of the following
conditions within 1 year prior to study enrollment are excluded from the study:

- Prior events including myocardial infarction, pericardial effusion, and
myocarditis.

- Prior cardiac arrhythmia including atrial fibrillation and atrial flutter, or
requiring concurrent use of drugs or biologics with pro-arrhythmic potential.

- NYHA Class II or greater heart failure.

- If cardiac function assessment is clinically indicated or performed, an LVEF less
than normal per institutional guidelines, or <55%, if threshold for normal is not
otherwise specified by institutional guidelines.

- QTc prolongation >470 msec or other significant ECG abnormality noted within 14
days of treatment.

- Hypertensive crisis or hypertensive encephalopathy.

- Clinically significant peripheral vascular disease or vascular disease, including
rapidly growing aortic aneurysm or abdominal aortic aneurysm >5 cm or aortic
dissection.

- Unstable angina.

- Eligibility for patients with asymptomatic and a previous diagnosis of immune or
inflammatory colitis, or patients with chronic diarrhea > 1 month without immune or
inflammatory colitis is a PI decision on an individual patient basis.

- Patients with a history of cerebrovascular accident or transient ischemic attack
within 1 year prior to study enrollment are not eligible.

- Patients with a history of previous clinical diagnosis of tuberculosis are not
eligible.

- Patients with a history of auto-immune disease requiring steroid maintenance, or
history of primary immunodeficiency are not eligible.

- HIV-positive patients on antiretroviral therapy are ineligible because of potential
pharmacokinetic interactions with study drugs.

- HBV-or HCV-positive patients are ineligible because of potential reactivation of
hepatitis virus following steroids.

- Patients with a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to MEDI4736, olaparib, cediranib, or to other
humanized monoclonal antibodies, or a history of anaphylaxis, angioedema, laryngeal
edema, serum sickness, or uncontrolled asthma, are not eligible.

- Patients who have had prior immune checkpoint inhibitors, such as MEDI4736 or other
PD1 or PD-L1 inhibitors or an anti-CTLA4 therapy are not eligible.

- Pregnant and breastfeeding women are excluded from this study.

- Patients with any other concomitant or prior invasive malignancies are ineligible.

PHASE I STUDY ELIGIBILITY CRITERIA

- Patients must have histologically or cytologically confirmed advanced solid tumor that
is refractory to standard treatment or for which no standard treatment exists, with
evaluable disease.

- Patients are allowed to have received prior PARP inhibitors (PARPi), and/or
anti-angiogenesis therapy. However, patients who were treated with both olaparib and
cediranib, either in combination or sequentially are not eligible. For this study,
BSI-201 (iniparib) is not considered as PARPi.

PHASE II MEDI4736 PLUS OLAPARIB OR CEDIRANIB STUDY ELIGIBILITY CRITERIA - OVARIAN CANCER

- Patients must have histologically or cytologically confirmed persistent or recurrent
ovarian, fallopian tube, or primary peritoneal cancer and have received at least two
prior platinum-containing regimens or who are platinum resistant or refractory during
or after a first platinum containing regimen.

- Patients must have at least one lesion deemed safe to biopsy and be willing to undergo
a mandatory baseline biopsy.

- Patients are allowed to have received prior PARPi, and/or anti-angiogenesis therapy
including but not limited to thalidomide, bevacizumab, sunitinib, sorafenib, or other
anti-angiogenics. However, patients who were treated with both olaparib and cediranib,
either in combination or sequentially are not eligible. For this study, BSI-201
(iniparib) is not considered as PARPi.

PHASE II STUDY MEDI4736 PLUS OLAPARIB ELIGIBILITY CRITERIA TRIPLE NEGATIVE BREAST CANCER

- Patients must have histologically confirmed persistent or recurrent triple-negative
breast cancer (TNBC)

- ER/PR/HER2 status needs to be documented either by an outside source or at NCI.

- Documentation of germline BRCA1 and BRCA2 mutation (gBRCAm) status will be required
for eligibility.

- Patients must have measurable disease as defined by RECIST v1.1.

- Patients must have at least one lesion deemed safe to biopsy and be willing to undergo
a mandatory baseline biopsy.

- Patients who have received more than three lines of prior therapy in the metastatic or
recurrent settings are not eligible.

- Patients who have received prior PARPi or immune checkpoint inhibitors are ineligible.

PHASE II MEDI4736 PLUS OLAPARIB OR CEDIRANIB STUDY ELIGIBILITY CRITERIA - NON-SMALL CELL
LUNG CANCER

- Histologically or cytologically confirmed advanced NSCLC with at least one prior line
of platinum-based chemotherapy (or treatment with EGFR, ALK, or BRAF-targeted tyrosine
kinase inhibitors if tumors harbor an EGFR-sensitizing mutation, ALK translocation, or
BRAF V600E mutation, respectively).

- Patients must have measurable disease as defined by RECIST v1.1.

- Patients must have at least one lesion deemed safe to biopsy and be willing to undergo
a mandatory baseline biopsy.

- Patients who have received anti-angiogenesis therapy are eligible. However, patients
who were treated with cediranib, either in combination or monotherapy are not
eligible.

- Patients who have had prior PARPi are not eligible.

- Patients who have received more than three lines of prior therapy in the metastatic or
recurrent settings are not eligible.

- Patients with prior history of pneumonitis and/or interstitial lung disease will be
excluded.

PHASE II MEDI4736 PLUS OLAPARIB STUDY ELIGIBILITY CRITERIA - SMALL CELL LUNG CANCER

- Histologically or cytologically confirmed SCLC with at least one prior line of
platinum-based chemotherapy are eligible. Patients with both platinum-sensitive and
platinum-refractory disease will be eligible.

- Patients must have measurable disease as defined by RECIST v1.1.

- Patients must have at least one lesion deemed safe to biopsy and be willing to undergo
a mandatory baseline biopsy.

- Patients who have received anti-angiogenesis therapy are eligible. However, patients
who were treated with cediranib, either in combination or monotherapy are not
eligible.

- Patients who have had prior PARPi are not eligible.

- Patients who have received more than three lines of prior therapy in the metastatic or
recurrent settings are not eligible.

- Patients with any other concomitant or prior invasive malignancies are ineligible.
Patients with prior history of pneumonitis and/or interstitial lung disease will be
excluded.

PHASE II MEDI4736 PLUS OLAPARIB STUDY ELIGIBILITY CRITERIA - METASTATIC CASTRATE-RESISTANT
PROSTATE CANCER

- Patients must have metastatic, progressive, castrate resistant prostate cancer
(mCRPC).

- All patients must have at least one lesion deemed safe to biopsy and be willing to
undergo a mandatory baseline biopsy.

- Patients must have received prior treatment with enzalutamide and/or abiraterone.

- Patients must have undergone bilateral surgical castration or must agree to continue
on GnRH agonists/antagonists for the duration of the study.

- Patients who have had treatment with docetaxel for the treatment of metastatic
castrate-sensitive prostate cancer within 6 months before the first dose of study
treatment are not eligible.

- Patients who have had progression of prostate cancer on prior docetaxel treatment for
castrate sensitive disease are ineligible.

- Patients who have had prior treatment with PARPi are not eligible.

- Patients who have received radionuclide treatment within 6 weeks prior to the first
dose of the study treatment are not eligible.

- Patients with any other concomitant or prior invasive malignancies are ineligible.

PHASE II MEDI4736 PLUS CEDIRANIB ELIGIBILITY CRITERIA - COLORECTAL CANCER

- Histologically or cytologically confirmed advanced colorectal cancer. Patients must
have progressed on, been intolerant of or refused prior oxaliplatin- and
irinotecan-containing chemotherapeutic regimen, and have disease that is not amenable
to potentially curative resection. Patients who have a known KRAS wild type tumor must
have progressed, been intolerant of or refused cetuximab or panitumumab-based
chemotherapy.

- Patients are allowed to have received prior anti-angiogenesis therapy with the
exception of prior cediranib. However, patients must not have received other
anti-angiogenesis therap(ies) within 6 months prior to study enrollment.

- Patients must be MSI-stable (or low).

- Patients must have at least one focus of metastatic disease that is amenable to
pre-and on-treatment biopsy.

- Patients who were previously treated with cediranib are ineligible.

- Patients with any other concomitant or prior invasive malignancies are ineligible.

- Patients with prior history of pneumonitis and/or interstitial lung disease will be
excluded.

Additional eligibility criteria may apply as defined per protocol.