Olaparib and Ramucirumab in Treating Patients With Metastatic or Locally Recurrent Gastric or Gastroesophageal Junction Cancer That Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

I. To determine the safe dose of olaparib with ramucirumab, but not to exceed olaparib dose
of 300 mg twice daily (tablet formulation). (Phase I) II. To determine the efficacy of
olaparib plus ramucirumab as measured by the objective response rates (ORR) stratified by
BROCA-HR biomarker status. (Phase II).

SECONDARY OBJECTIVES:

I. To estimate median progression-free survival (PFS) stratified by BROCA-HR biomarker
status.

II. To estimate median overall survival (OS) stratified by BROCA-HR biomarker status.

III. To measure the prevalence of the BROCA-HR biomarker in our study population.

IV. To determine toxicity of olaparib and ramucirumab combination.

TERTIARY OBJECTIVES:

I. To assess the correlation between the signature 3 status, and mutations in BROCA-HR panel.

II. To evaluate the association between findings from BROCA-HR panel with response to
therapy.

III. To evaluate the association between findings from BROCA-HR panel and signature 3 results
with response to therapy.

IV. To determine results of immunoassay for poly-ADP-ribosylated (PAR) substrates in tumor
tissue.

V. To create a PDX model to study deoxyribonucleic acid (DNA) repair in gastric tumors
treated with PARP inhibitors (PARPi) from both pre-treatment biopsy and repeat biopsy after
16 weeks of treatment.

VI. Development of a novel genomic assay for BRCAness VII. Defining T cell receptor diversity
of gastric cancer patients +/- BRCAness VIII. Biobank additional tumor tissue for future
genomic analysis. IX. Biobank peripheral blood for future genomic analysis and assessment of
circulating tumor DNA.

OUTLINE: This is a phase I, dose-escalation study of olaparib followed by a phase II study.

Patients receive olaparib orally (PO) twice daily (BID) on days 1-14 and ramucirumab
intravenously (IV) over 60 minutes on day 1. Courses repeat every 14 days in the absence of
disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 4 weeks and then every 3-6
weeks thereafter.

Inclusion Criteria:

- The patient must have histologically confirmed, gastric carcinoma, including
gastroesophageal junction (GEJ) adenocarcinoma (patients with adenocarcinoma of the
distal esophagus are eligible if the primary tumor involves the GEJ)

- The patient has metastatic disease or locally recurrent, unresectable disease

- The patient must have measurable disease by Response Evaluation Criteria in Solid
Tumors (RECIST) version (v)1.1

- The patient must have experienced disease progression during or within 4 months after
the last dose of chemotherapy for metastatic disease, during or within 6 months after
the last dose of adjuvant chemotherapy, or have been intolerant of previous
chemotherapy

- The patient must have experienced disease progression or intolerance as outlined above
after treatment with 1 or more prior chemotherapies

- All previous treatments are acceptable as long as they did not contain bevacizumab,
ramucirumab or PARP inhibitors

- Elevation in tumor markers without radiographic evidence of disease progression is not
satisfactory for progression on previous treatment

- The patient has a life expectancy of >= 16 weeks

- Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1 (Karnofsky
>= 60%)

- Hemoglobin ≥ 10 g/dL with no blood transfusions (packed red blood cells and platelet
transfusions) in the past 28 days, within 28 days prior to administration of study
treatment

- White blood cells (WBC) > 3 x 10^9/L, within 28 days prior to administration of study
treatment

- Absolute neutrophil count (ANC) >= 1.5 10^9/L, within 28 days prior to administration
of study treatment

- Platelet count >= 100 X 10^9/L, within 28 days prior to administration of study
treatment

- No features suggestive of MDS/AML on peripheral blood smear or bone marrow biopsy, if
clinically indicated, within 28 days prior to administration of study treatment

- Total bilirubin =< 1.5 x the institutional upper limit of normal (ULN), within 28 days
prior to administration of study treatment

- Aspartate aminotransferases (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional ULN unless liver metastases are present in which case they must
be =< 5 x ULN, within 28 days prior to administration of study treatment

- Calculated serum creatinine clearance >= 60 mL/min/1.73 m^2, within 28 days prior to
administration of study treatment

- Proteinuria with urinary protein is =< 1+ on dipstick or routine urinalysis, or a
24-hour urine collection for protein < 1000 mg of protein in 24 hours, within 28 days
prior to administration of study treatment

- Coagulation parameters (international normalized ratio [INR], activated partial
thromboplastin time [aPTT]) =< 1.25 x institutional limits, except where a lupus
anti-coagulant has been confirmed or the patient is on warfarin; patients on full dose
anticoagulation must be on a stable dose for at least 14 days. If receiving warfarin,
the patient must have an INR =< 3.0 without any evidence of active bleeding within 14
days prior to first dose of study treatment or a pathologic condition that carries a
high risk of bleeding (tumor involvement with major blood vessels or varicies), within
28 days prior to administration of study treatment

- Postmenopausal or evidence of non-childbearing status for women of childbearing
potential a negative urine or serum pregnancy test within 28 days of study treatment
and confirmed prior to treatment on day 1; postmenopausal is defined as:

- Amenorrheic for 1 year or more following cessation of exogenous hormonal
treatments

- Luteinizing hormone (LH )and follicle stimulating hormone (FSH) levels in the
post menopausal range for women under 50

- Radiation-induced oophorectomy with last menses > 1 year ago

- Chemotherapy-induced menopause with > 1 year interval since last menses

- Surgical sterilization (bilateral oophorectomy or hysterectomy)

- Women of child-bearing potential and men must agree to use adequate contraception
including hormonal, barrier, or abstinence; contraception must be started prior to
study enrollment; female patients of childbearing potential must have a negative serum
pregnancy test within 7 days prior to treatment; should a woman become pregnant or
suspect she is pregnant while she or her partner is participating in this study, she
should inform her treating physician immediately; both men and women treated or
enrolled on this protocol must also agree to use adequate contraception prior to the
study, for the duration of the study participation, and for 3 months after completion
of olaparib and ramucirumab administration; male patients and their partners, who are
sexually active and of childbearing potential, must agree to the use of two highly
effective forms of contraception in combination, throughout the period of taking study
treatment and for 3 months after last dose of study drug(s) to prevent pregnancy in a
partner

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

- The patient must be willing to undergo a biopsy prior to treatment

- For inclusion into optional exploratory genetic and biomarker research, patients must
fulfill the following criteria:

- Provision of informed consent for genetic research

- Provision of informed consent for biomarker research

- If a patient declines to participate in the optional exploratory genetic
research or the optional biomarker research, there will be no penalty or
loss of benefit to the patient; the patient will not be excluded from other
parts of the study

- The patient must be willing to undergo repeat biopsy at week 16 (for the first 20
patients in the phase 2 part of the study)

- Patients must be able to tolerate oral medications by mouth, and not have a
gastrointestinal illness that would preclude absorption of olaparib

- Adequately controlled blood pressure (BP) < 140 mmHg (systolic) and < 90 mmHg
(diastolic) taken in the clinic setting by a medical professional within 2 weeks prior
to starting study; patients with hypertension may be managed with up to a maximum of 3
antihypertensive medications; a cardiologist or blood pressure specialist must
evaluate patients who are on 3 antihypertensive medications within 4 weeks of
enrollment

- Patients who have the following risk factors are considered to be at increased risk
for cardiac toxicity and must have documented left ventricular ejection fraction
(LVEF) by echocardiogram greater than institution's lower limit of normal (or 55% if
threshold for normal not otherwise specified by institutional guidelines) obtained
within 3 months

- Prior treatment with anthracyclines

- Prior treatment with trastuzumab

- A New York Heart Association (NYHA) classification of II controlled with
treatment

- Prior central thoracic radiation therapy (RT), including RT to the heart.

- History of myocardial infarction within 12 months (patients with history of
myocardial infarction within 6 months are excluded)

Exclusion Criteria:

- Patients with untreated brain metastases are excluded from this clinical trial because
of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events;
a scan to confirm the absence of brain metastases is not required; the patient can
receive a stable dose of corticosteroids before and during the study as long as these
were started at least 4 weeks prior to treatment; patients with spinal cord
compression are also excluded unless considered to have received definitive treatment
for this and evidence of clinically stable disease for 28 days

- Patients who have not recovered from adverse events due to prior anti-cancer therapy
(i.e., have residual toxicities > Common Terminology Criteria for Adverse Events
(CTCAE) grade 1 or baseline, with the exception of alopecia)

- Patients unable to swallow orally administered medication and patients with
gastrointestinal disorders likely to interfere with absorption of the study medication

- The patient has experienced any grade 3-4 gastrointestinal bleeding within 3 months
prior to randomization

- The patient has experienced any arterial thrombotic events, including but not limited
to myocardial infarction, transient ischemic attack, cerebrovascular accident, or
unstable angina, within 6 months prior to enrollment

- The patient has an ongoing or active infection, symptomatic congestive heart failure,
unstable angina pectoris, symptomatic or poorly controlled cardiac arrhythmia,
uncontrolled thrombotic or hemorrhagic disorder, or any other serious uncontrolled
medical disorder in the opinion of the investigator

- The patient has an ongoing or active psychiatric illness or social situation that
would limited compliance with study requirements

- Clinically significant peripheral vascular disease or vascular disease (abdominal
aortic aneurysm > 5 cm) or aortic dissection; if known history of abdominal aortic
aneurysm with >= 4 cm in diameter, all of the following must be met

- An ultrasound within the last 6 months required to document that it is =< 5 cm

- Patient must be asymptomatic from the aneurysm

- Blood pressure must be well controlled as defined in this protocol

- The patient has uncontrolled or poorly controlled hypertension despite standard
medical management as defined in this protocol

- NYHA classification of III or IV

- A resting electrocardiogram (EKG) with a corrected QT (QTC) >= 470 msec detected on 2
or more time points within a 2 hour period or family history of long QT syndrome; if
the EKG demonstrates QTC >= 470 msec, the patient will only be eligible if a repeat
EKG demonstrates QTC =< 470 msec

- History of hypertensive crisis or hypertensive encephalopathy within 3 years

- Major surgery within 28 days of starting study treatment and patients must have
recovered from any effects of any major surgery

- An open biopsy, non-healing wound, ulcer or significant traumatic injury within 28
days prior to starting treatment (percutaneous, endobronchial, and endoscopic biopsies
are allowed)

- The patient has received chemotherapy, radiotherapy (except for palliative reasons),
immunotherapy, or targeted therapy for gastric cancer within 3 weeks of study
treatment

- The patient has received any investigational therapy within 4 weeks of enrollment

- The patient has received prior therapy with bevacizumab, ramucirumab or any PARP
inhibitor, including olaparib

- Patients must not have evidence of coagulopathy or bleeding diathesis; therapeutic
anticoagulation for prior thromboembolic events is permitted; the clinical indication
for therapeutic anticoagulation must be clearly documented prior to enrollment and
must be discussed with the principal investigator (PI); patients on greater than or
equal to 2 anti-thrombotic agents, including but not limited to anti-platelet agents
(nonsteroidal anti-inflammatory drugs [NSAIDS]/aspirin, clopidogrel), heparin, low
molecular weight heparin, warfarin and a direct thrombin inhibitor will be excluded

- The patient has elective or planned major surgery to be performed during the course of
the clinical trial

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to olaparib and ramucirumab

- Patients with a known hypersensitivity to olaparib or any of the excipients of the
product

- Patients with a known hypersensitivity to the combination/comparator agent

- Pregnant or breast feeding women are excluded from this study

- Immunocompromised patients, this includes human immunodeficiency virus (HIV)-positive
patients

- Patients with a known history of hepatitis B (defined as hepatitis B surface antigen
[HBsAg] reactive) or known active hepatitis C virus (defined as detectable hepatitis C
virus [HCV] ribonucleic acid [RNA]) infection; Note: no testing for hepatitis B and
hepatitis C is required unless mandated by local health authority

- The patient has known and active alcohol or drug dependency

- The patient has a concurrent active malignancy other than treated non-melanoma skin
cancers or in situ neoplasm; a patient with a prior history of malignancy is eligible,
provided that they have been free of disease for >= 5 years

- Patients may not have had a prior allogeneic bone marrow transplant or double
umbilical cord blood transplantation (dUCBT)

- Patients may not have features suggestive of myelodysplastic syndrome (MDS) or acute
myelogenous leukemia (AML) on peripheral blood smear or bone marrow biopsy, if
clinically indicated

- Patients may not have current signs and/or symptoms of bowel obstruction within 1
month prior to starting study drugs, except if it was a temporary incident (improved
within < 24 hours [hr] with medical management)

- History of hemoptysis within the last 1 month

- History of abdominal fistula, intra-abdominal abscess, or gastrointestinal perforation
within the last 3 months

- Dependency on IV hydration > 1 day per week within the screening period

- Participants receiving any medications or substances that are strong inhibitors or
inducers of CYP3A4/5 are ineligible; the required washout period prior to starting
treatment is 2 weeks for CYP3A inhibitors, 3 weeks for CYP3A inducers, and 5 weeks for
enzalutamide; dihydropyridine calcium-channel blockers are permitted for management of
hypertension

- Whole blood transfusions in the last 120 days prior to entry to the study (packed red
blood cells and platelet transfusions are acceptable

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

- Previous enrollment in the present study

- Current use of natural herb products or other complementary alternative medications;
if used previously, patients must have at least 1-week washout and must stop using
them while participating in this study