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Adavosertib Before Surgery in Treating Patients With Advanced High Grade Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

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ClinicalTrials.gov Identifier: NCT02659241
Recruitment Status : Recruiting
First Posted : January 20, 2016
Last Update Posted : May 10, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
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. 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.

Condition or disease Intervention/treatment Phase
Carcinomatosis Elevated Serum CA-125 Tumor Antigen High Grade Fallopian Tube Serous Adenocarcinoma High Grade Ovarian Serous Adenocarcinoma Primary Peritoneal High Grade Serous Adenocarcinoma Stage III Fallopian Tube Cancer AJCC v7 Stage III Ovarian Cancer AJCC v6 and v7 Stage III Primary Peritoneal Cancer AJCC v7 Stage IIIA Fallopian Tube Cancer AJCC v7 Stage IIIA Ovarian Cancer AJCC v6 and v7 Stage IIIA Primary Peritoneal Cancer AJCC v7 Stage IIIB Fallopian Tube Cancer AJCC v7 Stage IIIB Ovarian Cancer AJCC v6 and v7 Stage IIIB Primary Peritoneal Cancer AJCC v7 Stage IIIC Fallopian Tube Cancer AJCC v7 Stage IIIC Ovarian Cancer AJCC v6 and v7 Stage IIIC Primary Peritoneal Cancer AJCC v7 Stage IV Fallopian Tube Cancer AJCC v6 and v7 Stage IV Ovarian Cancer AJCC v6 and v7 Stage IV Primary Peritoneal Cancer AJCC v7 Drug: Adavosertib Other: Laboratory Biomarker Analysis Early Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: A Pilot Study of Wee1 Inhibition Induction Prior to Tumor Reductive Surgery in Ovarian Cancer
Actual Study Start Date : February 4, 2016
Estimated Primary Completion Date : February 4, 2020
Estimated Study Completion Date : February 4, 2021


Arm Intervention/treatment
Experimental: Basic Science (adavosertib)
Patients receive adavosertib PO 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.
Drug: Adavosertib
Given PO
Other Names:
  • AZD-1775
  • AZD1775
  • MK-1775
  • MK1775

Other: Laboratory Biomarker Analysis
Correlative studies




Primary Outcome Measures :
  1. Change in level of deoxyribonucleic acid (DNA) copy number in p53-related pathways [ Time Frame: Baseline up to 28 days ]
    Descriptive statistics and graphical methods will be used to summarize the change in DNA copy number from pre-treatment to post-treatment with adavosertib. These changes for untreated patients will also be summarized. A paired t-test will be used to test that mean changes from pre-treatment to post-treatment are different from 0 if the changes are found to be normally distributed. Otherwise, median changes from pre-treatment to post-treatment will be tested with a Wilcoxon signed-rank test. A 2-sample t-test will be used to compare mean changes between treated and untreated patients if the changes are normally distributed. Otherwise, median changes will be compared between treated and untreated patients with a Wilcoxon rank sum test.

  2. Change in level of mutation in p53-related pathways [ Time Frame: Baseline up to 28 days ]
  3. Change in level of ribonucleic acid (RNA) expression in p53-related pathways [ Time Frame: Baseline up to 28 days ]
    Descriptive statistics and graphical methods will be used to summarize the change in RNA protein expression from pre-treatment to post-treatment with adavosertib. These changes for untreated patients will also be summarized. A paired t-test will be used to test that mean changes from pre-treatment to post-treatment are different from 0 if the changes are found to be normally distributed. Otherwise, median changes from pre-treatment to post-treatment will be tested with a Wilcoxon signed-rank test. A 2-sample t-test will be used to compare mean changes between treated and untreated patients if the changes are normally distributed. Otherwise, median changes will be compared between treated and untreated patients with a Wilcoxon rank sum test. RNA protein expression will also be determined as present/absent. An exact binomial test will be used to assess the proportion of patients treated with adavosertib that exhibit an increase (or decrease) in RNA protein expression greater than 50%.

  4. Change in level of protein expression in p53-related pathways [ Time Frame: Baseline up to 28 days ]
    McNemar's test will be used to compare changes based on protein expression results. Fisher's exact test will be used to compare protein expression results between treated and untreated patients.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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 oestrogen 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
  • The use of statins including atorvastatin are prohibited and patients should be moved on to non-breast cancer resistance protein (BCRP) alternatives

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02659241


Contacts
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Contact: Shannon Westin 713-794-4314 swestin@mdanderson.org

Locations
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United States, Texas
Memorial Hermann Memorial City Medical Center Recruiting
Houston, Texas, United States, 77024
Contact: Nicole D. Fleming    713-792-3245    nfleming@mdanderson.org   
Principal Investigator: Nicole D. Fleming         
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Shannon N. Westin    713-794-4314      
Principal Investigator: Shannon N. Westin         
The Woman's Hospital of Texas Recruiting
Houston, Texas, United States, 77054
Contact: Nicole D. Fleming    713-792-3245    nfleming@mdanderson.org   
Principal Investigator: Nicole D. Fleming         
MD Anderson in Katy Recruiting
Houston, Texas, United States, 77094
Contact: Nicole D. Fleming    713-792-3245    nfleming@mdanderson.org   
Principal Investigator: Nicole D. Fleming         
MD Anderson League City Recruiting
Nassau Bay, Texas, United States, 77058
Contact: Nicole D. Fleming    713-792-3245    nfleming@mdanderson.org   
Principal Investigator: Nicole D. Fleming         
MD Anderson in Sugar Land Recruiting
Sugar Land, Texas, United States, 77478
Contact: Nicole D. Fleming    713-792-3245    nfleming@mdanderson.org   
Principal Investigator: Nicole D. Fleming         
MD Anderson in The Woodlands Recruiting
The Woodlands, Texas, United States, 77384
Contact: Nicole D. Fleming    713-792-3245    nfleming@mdanderson.org   
Principal Investigator: Nicole D. Fleming         
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Shannon N Westin M.D. Anderson Cancer Center

Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT02659241     History of Changes
Other Study ID Numbers: 2015-0519
NCI-2016-00118 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2015-0519 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
First Posted: January 20, 2016    Key Record Dates
Last Update Posted: May 10, 2019
Last Verified: May 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Adenocarcinoma
Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Fallopian Tube Neoplasms
Peritoneal Neoplasms
Carcinoma
Cystadenocarcinoma, Serous
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Fallopian Tube Diseases
Abdominal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Peritoneal Diseases
Cystadenocarcinoma
Neoplasms, Cystic, Mucinous, and Serous
MK-1775
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action