Adavosertib Before Surgery in Treating Patients With Advanced High Grade Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Adavosertib Before Surgery in Treating Patients With Advanced High Grade Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
This pilot early phase I trial studies how adavosertib affects the tumor deoxyribonucleic
 acid (DNA) of patients undergoing surgery for high grade (fast growing or aggressive)
 ovarian, fallopian tube, or primary peritoneal cancer that has spread to other places in the
 body (advanced). Certain characteristics in the DNA of these patients may affect how well
 they respond to treatment. Learning how adavosertib affects DNA in tumor cells may help
 doctors plan effective treatment.
PRIMARY OBJECTIVE:

 I. To explore baseline levels and effects of adavosertib (AZD1775) on DNA copy number,
 mutation, and level of ribonucleic acid (RNA) and protein expression (together described as
 "molecular results") in tumor protein p53 (p53)-related pathways before and after treatment
 in women with primary advanced high grade serous ovarian, fallopian tube, or primary
 peritoneal cancer.

 SECONDARY OBJECTIVES:

 I. To correlate molecular results to clinical endpoints including response and survival.

 II. To correlate molecular results to pathologic endpoints including tumor volume and
 apoptosis.

 III. To compare DNA copy number and level of RNA and protein expression in p53-related
 pathways in tissue from patients treated with AZD1775 to those untreated with AZD1775 in the
 preoperative period.

 IV. To determine the toxicity of AZD1775 given preoperatively, with a focus on postoperative
 wound healing.

 V. To determine the feasibility of treating preoperatively with AZD1775.

 OUTLINE:

 Patients receive adavosertib orally (PO) once daily (QD) on days 1-5. Patients then undergo
 standard of care laparoscopy. Patients may also receive adavosertib PO QD on days 8-12,
 15-19, and 22-26 for up to 28 days based on surgery schedule.

 After completion of study treatment, patients are followed up at 30 days and then every 3
 months thereafter.
Inclusion Criteria:

 -  Patients with presumed advanced-stage high grade serous ovarian, fallopian tube, or
 primary peritoneal carcinoma, based on the presence of carcinomatosis, and/or elevated
 cancer antigen (CA)125, and/or ovarian mass(es), or at the discretion of the treating
 physician

 -  Medically able to undergo primary cytoreductive surgery, at least 13 days and up to 28
 days after starting study drug, as determined by treating physician

 -  No prior therapy for high-grade serous ovarian, fallopian tube, or primary peritoneal
 carcinoma

 -  Patients must be able to swallow and tolerate oral medications and not have
 gastrointestinal illnesses that would preclude absorption of AZD1775 (e.g.
 uncontrolled nausea, vomiting, or diarrhea; malabsorption syndrome; ulcerative
 disease); Note: patient may not have a percutaneous endoscopic gastrostomy (PEG) tube
 or be receiving total parenteral nutrition (TPN)

 -  Absolute neutrophil count >= 1,500/mcL (within 7 days prior to initiation of therapy)

 -  Hemoglobin >= 9 gm/dL (within 7 days prior to initiation of therapy)

 -  Platelets >= 100,000/mcL (within 7 days prior to initiation of therapy)

 -  Total bilirubin =< 1.5 x upper limit of normal (ULN) (within 7 days prior to
 initiation of therapy)

 -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper
 limit of normal unless the liver is involved with tumor, in that case, AST and ALT
 must be =< 5 x upper limit of normal (within 7 days prior to initiation of therapy)

 -  Creatinine clearance > 50 mL/min (assessed by Cockcroft Gault estimation) and
 creatinine < 1.5 x ULN (within 7 days prior to initiation of therapy)

 -  Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of
 0 or 1

 -  Women of childbearing potential (WoCBP) may be included only if acceptable
 contraception is in place for two weeks before study entry, for the duration of the
 study and for 90 days after the last dose of AZD1775; WoCBP are defined as those who
 are not surgically sterile (ie, bilateral tubal ligation, bilateral oophorectomy, or
 complete hysterectomy) or postmenopausal (defined as 12 months with no menses without
 an alternative medical cause); acceptable methods of contraception include true
 abstinence in line with the preferred and usual lifestyle choice of the patient, tubal
 ligation, vasectomized partner, barrier methods (eg, cap plus spermicide, sponge plus
 spermicide, diaphragm plus spermicide, or male condom plus a spermicide), intrauterine
 device methods (eg, Copper T or Levonorgestrel-releasing intrauterine system), or
 hormonal methods (eg, any registered and marketed contraceptive agent that contains an
 estrogen and/or a progestational agent and that is administered via the oral,
 subcutaneous, transdermal, intrauterine, or intramuscular route as an implant, hormone
 shot or injection, combined pill, minipill or patch); all methods of contraception
 (with the exception of total abstinence) should be used in combination with the use of
 a condom by their male sexual partner for intercourse; periodic abstinence, the rhythm
 method, and the withdrawal method are not acceptable methods of birth control; all
 WoCBP must have a negative pregnancy test within 3 days prior to study the initiation
 of therapy; should a woman become pregnant or suspect she is pregnant while
 participating in this study, she should inform her treating physician immediately

 -  Women must not breast-feed while taking the study medications

 -  Patients must be able to understand and willing to sign an informed consent

 Exclusion Criteria:

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

 -  Current receipt of any other investigational agents or any additional anti-cancer
 agents for this or any other disease

 -  Known central nervous system (CNS) disease other than neurologically stable, treated
 brain metastases -- defined as metastasis having no evidence of progression or
 hemorrhage after treatment for at least 2 weeks

 -  Presence of other active cancers; patients with stage I cancer who have received
 definitive local treatment within the last 3 years, and whom are considered unlikely
 to recur, are eligible; all patients with previously treated in-situ carcinoma (i.e.,
 non-invasive) are eligible, as are patients with prior non-melanoma skin cancers

 -  Major surgical procedures =< 28 days of beginning study treatment, or minor surgical
 procedures =< 7 days (minor procedures done at time of laparoscopy are allowed); no
 waiting required following port-a-cath placement

 -  Significant symptom burden from presumed diagnosis including large volume ascites,
 pain requiring narcotic medication, or shortness of breath on exertion

 -  Myocardial infarction within 6 months before starting therapy, symptomatic congestive
 heart failure (New York Heart Association > class II), unstable angina, or unstable
 cardiac arrhythmia requiring medication

 -  Corrected QT interval (QTc) > 470 msec (as calculated by Fridericia correction
 formula) at study entry or congenital long QT syndrome

 -  Caution should be exercised when inhibitors or substrates of P-glycoprotein (P-gP),
 substrates of cytochrome P450 family 1 subfamily A member 2 (CYP1A2) with a narrow
 therapeutic range, sensitive substrates of cytochrome P450 family 2 subfamily C member
 19 (CYP2C19) or CYP2C19 substrates with a narrow therapeutic range are administered
 with AZD1775

 -  Herbal preparations are not allowed throughout the study; these herbal medications
 include, but are not limited to: St. John's wort, kava, ephedra (ma huang), gingko
 biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng; not willing
 to avoid grapefruit, grapefruit juices, grapefruit hybrids, Seville oranges, pummelos,
 and exotic citrus fruits from 14 days prior to the dose of study medication and during
 the entire study due to potential CYP3A4 interaction with the study medication; orange
 juice is allowed

 -  Any known hypersensitivity or contraindication to the components of study treatment

 -  Pregnant or breast-feeding

 -  As judged by the investigator, any evidence of severe or uncontrolled systemic
 diseases (e.g., severe hepatic impairment, interstitial lung disease [bilateral,
 diffuse, parenchymal lung disease], uncontrolled chronic renal diseases
 [glomerulonephritis, nephritic syndrome, Fanconi syndrome or renal tubular acidosis]),
 serious active infection or current unstable or uncompensated respiratory or cardiac
 conditions, or uncontrolled hypertension (blood pressure >= 140/90), active bleeding
 diatheses or active infection including hepatitis B, hepatitis C, and human
 immunodeficiency virus; screening for chronic conditions and infectious diseases is
 not required

 -  As judged by the investigator, the patient is unsuitable to participate in the study
 and the patient is unlikely to comply with study procedures, restrictions, and
 requirements

 -  Subject has had prescription or non-prescription drugs or other products known to be
 sensitive cytochrome P450 family 3 subfamily A member 4 (CYP3A4) substrates or CYP3A4
 substrates with a narrow therapeutic index, or to be moderate to strong inhibitors /
 inducers of CYP3A4 which cannot be discontinued two weeks prior to day 1 of dosing and
 withheld throughout the study until 2 weeks after the last dose of study drug;
 co-administration of aprepitant or fosaprepitant during this study is prohibited

 -  AZD1775 is an inhibitor of breast cancer resistance protein (BCRP).; the use of
 statins including atorvastatin are prohibited and patients should be moved on to
 non-breast cancer resistance protein (BCRP) alternatives