A Pilot Study of Wee1 Inhibition Induction Prior to Tumor Reductive Surgery in Ovarian Cancer
The goal of this clinical research study is to learn if certain characteristics of DNA (the genetic material in cells) affects how ovarian, fallopian tube, or primary peritoneal carcinomas respond to therapy with AZD1775. Researchers also want to learn if treatment with AZD1775 affects the DNA in cancer cells.
Disease Group: Fallopian Tube,Ovary,Peritoneum
Treatment Agent: AZD1775
Treatment Location: Both at MDACC & and Other Sites
Sponsor: AstraZeneca,Institutional Moonshots Fund,UTMDACC Andrew Sabin Fellows Award
Primary To explore baseline levels and effects of AZD1775 on DNA copy number, mutation, and level of RNA and protein expression (together described as “molecular results”) in p53-related pathways before and after treatment in women with primary advanced high grade serous ovarian, fallopian tube, or primary peritoneal cancer. Secondary 1. To correlate molecular results to clinical endpoints including response and survival. 2. To correlate molecular results to pathologic endpoints including tumor volume and apoptosis. 3. 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. 4. To determine the toxicity of AZD1775 given preoperatively, with a focus on postoperative wound healing. 5. To determine the feasibility of treating preoperatively with AZD1775.
IRB Review and Approval Date: 02/04/2016
Recruitment Status: Open
Projected Accrual: 30
1) Patients with presumed advanced-stage high grade serous ovarian,
fallopian tube, or primary peritoneal carcinoma, based on the presence
of carcinomatosis, and/or elevated CA125, and/or ovarian mass(es), or at
the discretion of the treating physician.
2) Medically able to undergo primary cytoreductive surgery, at least 14 days and up to 28 days after starting study drug, as determined by treating physician.
3) No prior therapy for high-grade serous ovarian, fallopian tube, or primary peritoneal carcinoma.
4) 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).
5) Patients must have normal organ and marrow function (measured within 7 days prior to the initiation of therapy) as defined below: a. Absolute neutrophil count >/= 1,500/mcL; b. Hemoglobin >/= 9gm/dL; c. Platelets >/= 100,000/mcL; d. Total Bilirubin </= 1.5X ULN; e. AST and ALT </= 2.5x upper limit of normal unless the liver is involved with tumor, in that case, AST and ALT must be </= 5x upper limit of normal; f. Creatinine clearance > 50 mL/min (assessed by Cockcroft Gault estimation) and creatinine < 1.5 x ULN.
6) Patients must have an ECOG performance status of 0 or 1.
7) 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, vasectomised 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 oestrogen and/or a progestational agent
8) (Continued from previous criterion) 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.
9) It is unknown if AZD1775 will be present in human breast milk. For this reason, women must not breast-feed while taking the study medications.
10) Patients must be able to understand and willing to sign an informed consent.
11) Patients must be at least 18 years of age.
1) Prior treatment for ovarian, fallopian tube, or primary peritoneal cancer
2) Current receipt of any other investigational agents or any additional anti-cancer agents for this or any other disease
3) Known central nervous system (CNS) disease other than neurologically stable, treated brain metastases -- defined as metastasis having no evidence of progression or haemorrhage after treatment for at least 2 weeks
4) 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.
5) 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.
6) Significant symptom burden from presumed diagnosis including large volume ascites, pain requiring narcotic medication, or shortness of breath on exertion
7) 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
8) Corrected QT interval (QTc) >470 msec (as calculated by Fridericia correction formula) at study entry or congenital long QT syndrome
9) Caution should be exercised when inhibitors or substrates of P-gP, substrates of CYP1A2 with a narrow therapeutic range, sensitive substrates of CYP2C19 or CYP2C19 substrates with a narrow therapeutic range are administered with AZD1775.
10) 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.
11) Any known hypersensitivity or contraindication to the components of study treatment
12) Pregnant or breast-feeding
13) 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.
14) 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.
15) Subject has had prescription or non-prescription drugs or other products known to be sensitive 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.
16) AZD1775 is an inhibitor of breast cancer resistance protein (BCRP). The use of statins including Atorvastatin which are substrates for BCRP are therefore prohibited and patients should be moved on to non-BCRP alternatives.
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