Olaparib in Treating Patients With Newly Diagnosed BRCA-Mutant Ovarian, Primary Peritoneal, or Fallopian Cancer Before Surgery
Olaparib in Treating Patients With Newly Diagnosed BRCA-Mutant Ovarian, Primary Peritoneal, or Fallopian Cancer Before Surgery
This early phase I trial studies how well olaparib works in treating patients with newly
 diagnosed BRCA-mutant ovarian, primary peritoneal, or fallopian cancer before surgery.
 Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell
 growth.
PRIMARY OBJECTIVES:

 I. To determine the feasibility of daily olaparib given in the neoadjuvant setting in women
 with primary advanced high grade non-mucinous epithelial ovarian, fallopian tube, or primary
 peritoneal cancer.

 SECONDARY OBJECTIVES:

 I. Estimate efficacy of olaparib given in the neoadjuvant setting using response rate (by
 Response Evaluation Criteria in Solid Tumors [RECIST] in subjects with measurable disease).

 II. Estimate proportion of subjects able to proceed immediately to interval tumor reductive
 surgery (without chemotherapy).

 III. Determine progression-free survival (PFS). IV. Determine complete pathologic response
 rate at the time of surgery. V. Determine the toxicity of daily olaparib given in the
 neoadjuvant setting. VI. Evaluate the toxicity of chemotherapy given after neoadjuvant
 olaparib. VII. Measure longitudinal symptom burden of study subjects treated with neoadjuvant
 olaparib and chemotherapy after olaparib.

 EXPLORATORY OBJECTIVES:

 I. Explore deoxyribonucleic acid (DNA) copy number and level of ribonucleic acid (RNA) and
 protein expression in homologous recombination-related pathways before and after treatment
 with olaparib in women with primary advanced high grade non-mucinous epithelial ovarian,
 fallopian tube, or primary peritoneal cancer.

 II. Correlate molecular results to clinical endpoints including response and survival.

 OUTLINE:

 Patients receive olaparib orally (PO) twice daily (BID) on days 1-28. Treatment repeats every
 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity.
 After treatment, patients either undergo surgery then receive standard chemotherapy for up to
 4 cycles or receive standard chemotherapy within 14 days for up to 4 cycles then undergo
 surgery in the absence of disease progression or unacceptable toxicity at the discretion of
 the treating physician.

 After completion of study treatment, patients are followed up at 30 days.
Inclusion Criteria:

 -  Written informed consent and any locally-required authorization (e.g., Health
 Insurance Portability and Accountability Act [HIPAA] in the United States of America
 [USA]) obtained from the subject prior to performing any protocol-related procedures,
 including screening evaluations

 -  Histology showing high-grade epithelial non-mucinous ovarian, primary peritoneal, or
 fallopian tube cancer

 -  Documented BRCA pathway mutations

 -  No prior treatment for primary advanced (stage III or IV) epithelial ovarian, primary
 peritoneal, or fallopian tube carcinoma such as irradiation, chemotherapy, hormonal
 therapy, immunotherapy, investigational therapy, surgery, and/or other concurrent
 agents or therapies

 -  A disposition to neoadjuvant chemotherapy (NACT) with planned interval tumor reductive
 surgery after 3 complete cycles of treatment

 -  Have measurable disease based on RECIST version 1.1 or evaluable disease. Measurable
 disease is defined at least one lesion that can be accurately measured in at least one
 dimension (longest dimension to be recorded). Each "target" lesion must be > 20 mm
 when measured by conventional techniques, including palpation, plain x-ray, computed
 tomography (CT), and magnetic resonance imaging (MRI), or > 10 mm when measured by
 spiral CT. Evaluable disease includes nonmeasurable lesions, ascites, pleural effusion

 -  Peripheral neuropathy grade 0 or 1 by Common Terminology Criteria for Adverse Events
 (CTCAE) version (v)5.0

 -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

 -  Life expectancy of >= 16 weeks

 -  Postmenopausal or evidence of non-childbearing status for women of childbearing
 potential: 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 postmenopausal range
 for women under 50, radiation-induced oophorectomy with last menses > 1 year ago,
 chemotherapy-induced menopause with > 1 year interval since last menses, or surgical
 sterilization (bilateral oophorectomy or hysterectomy). Women of childbearing
 potential (WoCBP) must utilize acceptable contraception for two weeks before the first
 dose of olaparib, for the duration of the study, and for at least 6 months after the
 last dose of olaparib

 -  Hemoglobin >= 10.0 g/dL (with no blood transfusion in the past 28 days) (measured
 within 28 days prior to administration of study treatment)

 -  Absolute neutrophil count (ANC) >= 1.5 x 109/L (> 1500 per mm3) (measured within 28
 days prior to administration of study treatment)

 -  Platelet count >= 100 x 109/L (> 100,000 per mm3) (measured within 28 days prior to
 administration of study treatment)

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

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

 -  Serum creatinine clearance (CrCL) >= 51 mL/min by the Cockcroft-Gault formula or by
 24-hour urine collection for determination of CrCL (measured within 28 days prior to
 administration of study treatment)

 Exclusion Criteria:

 -  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

 -  Prior treatment for ovarian, fallopian tube, or primary peritoneal cancer

 -  Histology showing mucinous or low grade epithelial carcinoma

 -  Participation in another clinical study with an investigational product (IP) during
 the last 4 weeks

 -  History of another primary malignancy except for: malignancy treated with curative
 intent and with no known active disease >= 5 years before the first dose of study drug
 and of low potential risk for recurrence, adequately treated non-melanoma skin cancer
 or lentigo maligna without evidence of disease, and/or adequately treated carcinoma in
 situ without evidence of disease e.g., cervical cancer in situ

 -  Resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible
 cardiac conditions, as judged by the investigator (e.g., unstable ischemia,
 uncontrolled symptomatic arrhythmia, congestive heart failure, mean QT interval
 corrected for heart rate with Fridericia's correction (QTcF) prolongation > 500 ms,
 electrolyte disturbances, etc.), or patients with congenital long QT syndrome

 -  Any unresolved toxicity (> CTCAE grade 2) from previous anti-cancer therapy, excluding
 alopecia

 -  History of hypersensitivity to olaparib or its excipients

 -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
 infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
 angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active
 bleeding diatheses including any subject known to have evidence of acute or chronic
 hepatitis B, hepatitis C or human immunodeficiency virus (HIV) or otherwise
 immunocompromised subjects, or psychiatric illness/social situations that would limit
 compliance with study requirements or compromise the ability of the subject to give
 written informed consent

 -  History of leptomeningeal carcinomatosis

 -  Subjects who are pregnant and/or breast-feeding

 -  Any condition that, in the opinion of the investigator, would interfere with
 evaluation of study treatment or interpretation of subject safety or study results

 -  Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive
 of but not limited to surgery, radiation and/or corticosteroids. The subject 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 unless considered to have received definitive treatment for this and
 evidence of clinically stable disease for 28 days

 -  Subjects with uncontrolled seizures

 -  Patients with myelodysplastic syndrome/acute myeloid leukemia or with features
 suggestive of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML)

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

 -  Any previous treatment with PARP inhibitor, including olaparib

 -  Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin,
 clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
 saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g.
 ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout
 period prior to starting olaparib is 2 weeks

 -  Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin,
 rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's wort ) or
 moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required washout
 period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3
 weeks for other agents

 -  Major surgery within 2 weeks of starting study treatment and patients must have
 recovered from any effects of any major surgery

 -  Previous allogeneic bone marrow transplant or double umbilical cord blood
 transplantation (dUCBT)

 -  Whole blood transfusions in the last 120 days prior to entry to the study (packed red
 blood cells and platelet transfusions are acceptable outside of 28 days prior to
 treatment)

 -  Non-English speakers will be excluded from participating in the patient-reported
 outcomes component of the study