A Phase I/II Study of MEDI4736 (Anti-PD-L1 Antibody) in Combination
with Olaparib (PARP inhibitor) in Patients with Advanced Solid Tumors

Inclusion criteria are presented separately for each cohort of Modules 1 to 7
Small cell lung cancer cohort:
Patients must have histologically or cytologically confirmed progressive
metastatic or recurrent solid tumor (as defined below for each tumor
type). To be enrolled in the SCLC cohort, only the tumor types and
settings described below are allowed (see in the Protocol)
At least 1 measurable lesion that can be accurately assessed at baseline
by computed tomography (CT) (or magnetic resonance imaging [MRI]
where CT is contraindicated) and is suitable for repeated assessment as
per RECIST 1.1. The baseline scan must be obtained
within 28 days prior to the first dose of olaparib. Biomarker-only disease
is not considered evaluable.
Breast cancer cohort:
Patients must have histologically or cytologically confirmed progressive
metastatic or recurrent solid tumor (as defined below for each tumor
type). To be enrolled in the gBRCAm breast cancer cohort, only the
tumor types and settings described below are allowed (see in the
Protocol).
At least 1 measurable lesion that can be accurately assessed at baseline
by computed tomography (CT) (or magnetic resonance imaging [MRI]
where CT is contraindicated) and is suitable for repeated assessment as
per RECIST 1.1. The baseline scan must be obtained
within 28 days prior to the first dose of olaparib. Biomarker-only disease
is not considered evaluable.
gBRCAm human epidermal growth factor receptor 2 (HER2)-negative
breast cancer patients with metastatic or locally advanced disease,
which is unresectable (or the patient is not a candidate for resection),
may be first, second or third line but all patients must meet the following
specific criteria:
Must have confirmation of a germline mutation in BRCA1 or BRCA2 that
is predicted to be deleterious or suspected deleterious (known or
predicted to be detrimental/lead to loss of function).
Must have previously received treatment with an anthracycline (eg,
doxorubicin, epirubicin) unless contraindicated and/or a taxane (eg,
paclitaxel, docetaxel) in either a neo-adjuvant/adjuvant or metastatic
setting.
For all ovarian cancer (OC) cohorts:
Patients must have histologically confirmed recurrent ovarian cancer.
Patients must be naïve to prior PARP inhibitor treatment and
immunotherapy naïve
Patients must have had at least 1 prior line of platinum-based therapy
and be platinum sensitive (relapsed >= 24 weeks after administration of
last platinum treatment).
For 1st stage gBRCAm OC and 2nd stage expansion OC cohorts:
Patients must have a gBRCA mutation.
For 2nd stage doublet and triplet non-gBRCAm OC cohorts:
Patients must not have a gBRCA mutation.
Gastric cancer cohort:
Patients must have histologically or cytologically confirmed progressive
metastatic or recurrent solid tumor (as defined below for each tumor
type). To be enrolled in the gastric cancer cohort, only the tumor types
and settings described below are allowed (see in the
Protocol).
At least 1 measurable lesion that can be accurately assessed at baseline
by computed tomography (CT) (or magnetic resonance imaging [MRI]
where CT is contraindicated) and is suitable for repeated assessment as
per RECIST 1.1. The baseline scan must be obtained
within 28 days prior to the first dose of olaparib. Biomarker-only disease
is not considered evaluable.
Metastatic or recurrent gastric adenocarcinoma (including
gastroesophageal
junction adenocarcinoma) that has progressed following first-line
therapy, confirmed by imaging modalities:
The first-line regimen must have contained at least a doublet 5-
fluoropyrimidine and platinum based regimen.
Capecitabine is an acceptable 5-fluoropyrimidine-containing agent.
Relapse within 6 months of completion of adjuvant/neoadjuvant
chemotherapy containing doublet 5-fluoropyrimidine and platinum based
regimen is considered as first-line therapy.

Exclusion criteria are presented separately for each cohort in Modules 1 to 7
Small cell lung cancer cohort:
Prior chemotherapy or other systemic anticancer therapy (eg, targeted
biotherapy or hormonal agents) within 4 weeks prior to start of olaparib
treatment; 6 weeks for nitrosoureas or mitomycin. Exceptions and
treatments of particular importance are noted below (see Protocol)
Radiation therapy within 4 weeks prior to start of olaparib treatment
(includes radiation targeting bone metastases) or radionuclide
treatment within 6 weeks of treatment start.
Patients with mixed small cell and non-small cell lung cancer histology.
Breast cancer cohort:
Prior chemotherapy or other systemic anticancer therapy (eg, targeted
biotherapy or hormonal agents) within 4 weeks prior to start of olaparib
treatment; 6 weeks for nitrosoureas or mitomycin. Exceptions and
treatments of particular importance are noted below (see the Protocol).
Radiation therapy within 4 weeks prior to start of olaparib treatment
(includes radiation targeting bone metastases) or radionuclide
treatment within 6 weeks of treatment start.
Patients with HER2-positive disease (3+ by immunohistochemistry [IHC]
or in situ hybridization amplified >=2.0).
Patients cannot have received more than 2 prior lines of cytotoxic
chemotherapy for metastatic disease. Prior treatments with hormonal
therapy and non-hormonal targeted therapy are allowed and not counted
as a prior line of cytotoxic chemotherapy. For the purposes of this
protocol, the combination of an aromatase inhibitor and everolimus or
palbociclib, are not considered cytotoxic chemotherapy.
BRCA1 and/or BRCA2 variants that are considered to be non-detrimental
(eg, "Variants of uncertain clinical significance" or "Variant of unknown
significance" or "Variant, favor polymorphism" or "benign
polymorphism" etc).
1st stage OC cohort:
Prior chemotherapy or other systemic anticancer therapy within 4 weeks
prior to start of study treatment.
Radiation therapy within 4 weeks prior to start of olaparib treatment.
Other malignancy within 5 years.
2nd stage cohorts (expansion OC, doublet OC and triplet cohorts)
Same as 1st stage gBRCAm OC cohort
Patients who received more than 3 prior lines of chemotherapy.
Gastric cancer cohort:
Prior chemotherapy or other systemic anticancer therapy (eg, targeted
biotherapy or hormonal agents) within 4 weeks prior to start of olaparib
treatment; 6 weeks for nitrosoureas or mitomycin. Exceptions and
treatments of particular importance are noted below (see in the
Protocol).
Radiation therapy within 4 weeks prior to start of olaparib treatment
(includes radiation targeting bone metastases) or radionuclide
treatment within 6 weeks of treatment start
For HER2-negative patients: More than 1 prior chemotherapy regimen
(except for adjuvant/neoadjuvant chemotherapy with more than 6
months wash-out period) for the treatment of gastric cancer in the
metastatic or recurrent setting.
For HER2-positive patients: More than 2 prior chemotherapy regimens
(except for adjuvant/neoadjuvant with more than 6 months wash-out
period) for the treatment of gastric cancer in the metastatic or recurrent
setting.
Intestinal obstruction or CTCAE grade 3 or grade 4 upper
gastrointestinal bleeding within 4 weeks before the study entry