Patient case: 54-year-old male with Gastric cancer. Genetic variant: PIK3CA (E545K). Other conditions: Depression.

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

Summary: This pilot phase I/II trial studies the side effects and best dose of olaparib when given together with ramucirumab and how well they work in treating patients with gastric or gastroesophageal junction cancer that has spread to other places in the body, has come back, or cannot be removed by surgery. Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as ramucirumab, may interfere with the ability of tumor cells to grow and spread. Giving olaparib and ramucirumab may work better in treating patients with gastric or gastroesophageal junction cancer.

Detailed description: 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 rate (ORR). (Phase II).
  SECONDARY OBJECTIVES:
  I. To estimate median progression-free survival (PFS). II. To estimate median overall survival (OS). III. To measure the prevalence of the BROCA-HR biomarker in our study population.
  IV. To determine toxicity of olaparib and ramucirumab combination. V. To evaluate the effects of this regimen on quality of life scores by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30).
  TERTIARY OBJECTIVES:
  I. To assess the correlation between the Myriad homologous recombination deficiency (HRD) assay results, the signature 3 status, and mutations in BROCA-HR panel.
  II. To evaluate the association between findings from BROCA-HR panel, the Myriad HRD assay, and signature 3 results with response to therapy.
  III. To determine results of immunoassay for poly-ADP-ribosylated (PAR) substrates in tumor tissue.
  IV. To create a PDX model to study DNA repair in gastric tumors treated with PARP inhibitors (PARPi) from both pre-treatment biopsy and repeat biopsy after 16 weeks of treatment.
  V. Biobank additional tumor tissue for future genomic analysis. VI. Biobank peripheral blood for future genomic analysis and assessment of circulating tumor deoxyribonucleic acid (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 6 weeks thereafter.

Eligibility: 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 with measurable lymph node metastases
  -  For patients with nonregional lymph node metastases are eligible, but lymph node metastases must be measurable by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
  -  For patients with locally recurrent, unresectable disease if there is at least one lymph node metastasis either regional or non-regional that is measurable by RECIST v1.1
  -  For patients who have received prior radiation treatment the measurable lesions must be outside the radiation field
  -  The patient must have measurable disease by RECIST v1.1
  -  The patient must have experienced disease progression during or within 4 months after the last dose of chemotherapy for metastatic disease, or during or within 6 months after the last dose of adjuvant chemotherapy
  -  The patient must have experienced disease progression as outlined above after treatment with 1 or more prior chemotherapies
  -  All previous treatments are acceptable as long as they did not contain ramucirumab or PARP inhibitors
  -  Elevation in tumor markers without radiographic evidence of disease progression is not satisfactory for progression on previous treatment
  -  Patients who did not tolerate previous chemotherapy regimens are eligible as long as there is disease progression within 4 months after the last dose of therapy
  -  The patient has a life expectancy of >= 12 weeks
  -  The patient has resolution to grade =< 1 (or grade =< 2 for neuropathy) by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), of all clinically significant toxic effects of prior chemotherapy, surgery, radiotherapy, or hormonal therapy (with the exception of alopecia)
  -  Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1 (Karnofsky >= 60%)
  -  Leukocytes >= 3,000/mcL
  -  Absolute neutrophil count >= 1,500/mcL
  -  Platelets >= 100,000/mcL
  -  Hemologic > 9 g/dL
  -  Total bilirubin =< 1.5 x the institutional upper limit of normal (ULN)
  -  Aspartate aminotransferases (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN
  -  Creatinine =< 1.5 x institutional ULN OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  -  Proteinuria urinary protein is =< 1+ on dipstick or routine urinalysis, or a 24-hour urine collection for protein < 1000 mg of protein in 24 hours
  -  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; patients on full dose anti-coagulation 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 varices)
  -  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 randomization; 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; men 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 4 months after completion of olaparib and ramucirumab administration
  -  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
  -  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 either by mouth or feeding tube, 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
  -  Patients cannot have received any other investigational agents within the past 3 weeks
  -  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
  -  History of hypertensive crisis or hypertensive encephalopathy within 3 years
  -  A major surgical procedure, open biopsy, non-healing wound, ulcer or significant traumatic injury within 28 days prior to starting ramucirumab (percutaneous, endobronchial, and endoscopic biopsies are allowed)
  -  The patient has received chemotherapy, radiotherapy, immunotherapy, or targeted therapy for gastric cancer within 2 weeks of enrollment
  -  The patient has received any investigational therapy within 4 weeks of enrollment
  -  The patient has received prior therapy with ramucirumab or any PARP inhibitor
  -  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
  -  Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with olaparib and ramucirumab
  -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
  -  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 > 3 years
  -  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
  -  Participants receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 are ineligible; dihydropyridine calcium-channel blockers are permitted for management of hypertension
  -  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

Relevance to patient case: not relevant