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Gemcitabine Hydrochloride With or Without WEE1 Inhibitor MK-1775 in Treating Patients With Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

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ClinicalTrials.gov Identifier: NCT02101775
Recruitment Status : Active, not recruiting
First Posted : April 2, 2014
Last Update Posted : June 5, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This randomized phase II clinical trial studies how well gemcitabine hydrochloride and WEE1 inhibitor MK-1775 work compared to gemcitabine hydrochloride alone in treating patients with ovarian, primary peritoneal, or fallopian tube cancer that has come back after a period of time. Gemcitabine hydrochloride may prevent tumor cells from multiplying by damaging their deoxyribonucleic acid (DNA, molecules that contain instructions for the proper development and functioning of cells), which in turn stops the tumor from growing. The protein WEE1 may help to repair the damaged tumor cells, so the tumor continues to grow. WEE1 inhibitor MK-1775 may block the WEE1 protein activity and may increase the effectiveness of gemcitabine hydrochloride by preventing the WEE1 protein from repairing damaged tumor cells without causing harm to normal cells. It is not yet known whether gemcitabine hydrochloride with or without WEE1 inhibitor MK-1775 may be an effective treatment for recurrent ovarian, primary peritoneal, or fallopian tube cancer.

Condition or disease Intervention/treatment Phase
Ovarian Brenner Tumor Ovarian Carcinosarcoma Ovarian Clear Cell Cystadenocarcinoma Ovarian Endometrioid Adenocarcinoma Ovarian Mucinous Cystadenocarcinoma Ovarian Seromucinous Carcinoma Ovarian Serous Cystadenocarcinoma Ovarian Serous Surface Papillary Adenocarcinoma Recurrent Fallopian Tube Carcinoma Recurrent Ovarian Carcinoma Recurrent Primary Peritoneal Carcinoma Undifferentiated Ovarian Carcinoma Drug: Adavosertib Drug: Gemcitabine Hydrochloride Other: Laboratory Biomarker Analysis Other: Pharmacological Study Other: Placebo Other: Questionnaire Administration Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Official Title: A Randomized Placebo-Controlled Phase II Trial Comparing Gemcitabine Monotherapy to Gemcitabine in Combination With AZD 1775 (MK 1775) in Women With Recurrent, Platinum Resistant Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancers
Actual Study Start Date : July 21, 2014
Estimated Primary Completion Date : December 31, 2018


Arm Intervention/treatment
Experimental: Arm I (WEE1 inhibitor MK-1775, gemcitabine hydrochloride)
Patients receive WEE1 inhibitor MK-1775 PO on days 1, 2, 8, 9, 15, and 16 and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: Adavosertib
Given PO
Other Names:
  • AZD-1775
  • AZD1775
  • MK-1775
  • MK1775

Drug: Gemcitabine Hydrochloride
Given IV
Other Names:
  • dFdCyd
  • Difluorodeoxycytidine Hydrochloride
  • Gemzar
  • LY-188011
  • LY188011

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Pharmacological Study
Correlative studies

Other: Questionnaire Administration
Ancillary studies

Active Comparator: Arm II (placebo, gemcitabine hydrochloride)
Patients receive placebo PO on days 1, 2, 8, 9, 15, and 16 and gemcitabine hydrochloride as patients in Arm I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: Gemcitabine Hydrochloride
Given IV
Other Names:
  • dFdCyd
  • Difluorodeoxycytidine Hydrochloride
  • Gemzar
  • LY-188011
  • LY188011

Other: Laboratory Biomarker Analysis
Correlative studies

Other: Pharmacological Study
Correlative studies

Other: Placebo
Given PO
Other Names:
  • placebo therapy
  • PLCB
  • sham therapy

Other: Questionnaire Administration
Ancillary studies




Primary Outcome Measures :
  1. Progression free survival [ Time Frame: Time from start of treatment to time to progression or death, whichever occurs first, assessed up to 1 year ]
    Progression free survival will be evaluated according to Response Evaluation Criteria in Solid Tumors version 1.1.


Secondary Outcome Measures :
  1. Objective response [ Time Frame: Up to 1 year ]
    Objective response will be evaluated according to Response Evaluation Criteria in Solid Tumors version 1.1.

  2. CA125 response rate [ Time Frame: Up to 1 year ]
    The Gynecologic Cancer InterGroup CA125 response rate will be assessed.

  3. Overall survival [ Time Frame: Up to 1 year ]
    Survival estimates will be computed using the Kaplan-Meier method.

  4. Incidence of grade 3 or 4 serious adverse events, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 1 year ]
    Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest.

  5. TP53 mutations [ Time Frame: Baseline ]
    Presence and type of TP53 mutations will be assessed by Sanger sequencing.

  6. p53 protein expression [ Time Frame: Baseline ]
    Expression of p53 protein in archival tumor tissue will be measured by immunohistochemistry.


Other Outcome Measures:
  1. Patient reported outcomes [ Time Frame: Up to 1 year ]
    Will be assessed using Patient Reported Outcomes-Common Terminology Criteria for Adverse Events.

  2. TP53 mutations in circulating tumor deoxyribonucleic acid [ Time Frame: Baseline ]
    TP53 mutations in circulating tumor deoxyribonucleic acid will be evaluated by TAm-Seq.

  3. Change in levels of circulating deoxyribonucleic acid TP53 mutations by TAm-Seq [ Time Frame: Baseline to up to 1 year ]
    Levels of circulating deoxyribonucleic acid TP53 mutations will be correlated with response.

  4. Changes in pCDC2 in skin and tumor tissue [ Time Frame: Baseline and at day 2 or 9 (course 1) ]
    Validation of pCDC2 as a pharmacodynamic marker of therapy.

  5. Changes in gH2AX in skin and tumor tissue [ Time Frame: Baseline and at day 2 or 9 (course 1) ]
    Validation of gH2AX as a pharmacodynamic marker of therapy.

  6. Changes in pCDC2 [ Time Frame: Baseline and at day 2 or 9 (course 1) ]
    Changes in pCDC2 will be correlated with survival outcomes and response rate.

  7. Changes in pH2AX [ Time Frame: Baseline and at day 2 or 9 (course 1) ]
    Changes in pH2AX will be correlated with survival outcomes and response rate.



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 must have histologically or cytologically confirmed epithelial ovarian, primary peritoneal and fallopian tube carcinoma; all histologic subtypes of epithelial ovarian cancer are eligible, but only patients with high grade serous ovarian cancer will be considered for the statistical analysis; non-high grade serous cancers will be allowed in an exploratory cohort
  • Patients must be platinum-resistant (platinum-free interval < 6 months) or have platinum-refractory disease as per Gynecologic Cancer Intergroup Committee (GCIC) criteria; disease progression has to be radiologic or clinical; biomarker progression with CA125 after a platinum based regimen would not be sufficient evidence of disease progression; the patients must have had radiological progression to that regimen
  • Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as > 10 mm with computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
  • There is no limitation in the number of prior lines of therapy
  • Patients must have completed any prior chemotherapy, radiotherapy or major surgery at least 4 weeks before receiving study treatment; ongoing toxicities related to treatment must be =< grade 1 and patients with grade 2 alopecia or peripheral neuropathy can also be included; palliative radiation to < 10% of bone marrow is permissible if completed within one week of commencing study treatment as long as the toxicities secondary to palliative radiotherapy are limited to grade 1; the lesions that have received radiation treatment immediately before will be excluded as target lesions; previously irradiated lesions can be considered as targeted lesions, as long as there is prove of radiological progression
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Life expectancy of greater than 3 months
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Hemoglobin >= 90 g/L

    • Blood transfusions are allowed at any time during the screening, treatment or follow-up period, according to the center recommendations
  • Prothrombin time (PT), partial thromboplastin time (PTT) and international normalized ratio (INR) =< 1.5 upper limit of normal (ULN)
  • Total bilirubin =< 1.5 x institutional upper limit of normal; unless due to Gilbert's syndrome
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional upper limit of normal (5 x if liver metastases)
  • Creatinine =< 1.5 × institutional upper limit of normal OR creatinine clearance >= 40 mL/min/1.73 m^2 for patients with creatinine levels above 1.5 x institutional limit of normal
  • Patients must be able to tolerate oral medication and not have evidence of active bowel obstruction

    • Note: patients can have a history of prior bowel obstruction, provided the patient is not having symptoms of bowel obstruction at the time of enrolment and the bowel obstruction is not anticipated to recur during the participation in the study
  • Patients must have disease amenable to biopsy and must be willing to undergo a paired biopsy for correlative analyses (the first biopsy within 28 days prior to start of treatment and the second biopsy while on treatment)
  • Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately

    • Women of childbearing potential include women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal; postmenopause is defined as amenorrhea >= 12 consecutive months; Note: women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti-estrogens, ovarian suppression or any other reversible reason
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Patients who previously received gemcitabine for the treatment of recurrent disease
  • Patients who are receiving any other investigational agents
  • Patients with clinically or radiologically unstable brain metastases are excluded from this clinical trial

    • Note: patients with stable brain metastases after treatment, for at least 3 months prior to enrolling on this trial, could participate in the study; patients should be off, or on a stable dose of steroids
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD 1775 (MK-1775) or gemcitabine
  • Patients taking the following prescription or non-prescription drugs or other products (i.e. grapefruit juice) are ineligible: sensitive cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) substrates, CYP3A4 substrates with a narrow therapeutic index, moderate to potent inhibitors/inducers of CYP3A4; patients would be eligible if the medications can be discontinued two weeks prior to day 1 of dosing and withheld throughout the study until 2 weeks after the last dose of study medication
  • Pregnant and breastfeeding women are excluded from this study
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
  • Uncontrolled intercurrent illness including, but not limited to, myocardial infarction within 6 months, congestive heart failure, symptomatic congestive heart failure, unstable angina pectoris, active cardiomyopathy, unstable ventricular arrhythmia, uncontrolled hypertension, uncontrolled psychotic disorders, serious infections, active peptic ulcer disease, active liver disease or cerebrovascular disease with previous stroke, or psychiatric illness/social situations that would limit compliance with study requirements

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): NCT02101775


Locations
United States, California
City of Hope Comprehensive Cancer Center
Duarte, California, United States, 91010
City of Hope South Pasadena
South Pasadena, California, United States, 91030
United States, Illinois
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, United States, 60637
Decatur Memorial Hospital
Decatur, Illinois, United States, 62526
United States, Indiana
Indiana University/Melvin and Bren Simon Cancer Center
Indianapolis, Indiana, United States, 46202
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, Pennsylvania
Fox Chase Cancer Center
Philadelphia, Pennsylvania, United States, 19111
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, United States, 15232
Canada, British Columbia
BCCA-Cancer Centre for the Southern Interior
Kelowna, British Columbia, Canada, V1Y 5L3
BCCA-Vancouver Cancer Centre
Vancouver, British Columbia, Canada, V5Z 4E6
Canada, Ontario
London Regional Cancer Program
London, Ontario, Canada, N6A 4L6
Ottawa Hospital and Cancer Center-General Campus
Ottawa, Ontario, Canada, K1H 8L6
University Health Network Princess Margaret Cancer Center P2C
Toronto, Ontario, Canada, M5G 2M9
University Health Network-Princess Margaret Hospital
Toronto, Ontario, Canada, M5G 2M9
Canada, Quebec
CHUM - Hopital Notre-Dame
Montreal, Quebec, Canada, H2L 4M1
Singapore
National University Hospital Singapore
Singapore, Singapore, 119074
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Amit Oza University Health Network-Princess Margaret Hospital

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02101775     History of Changes
Obsolete Identifiers: NCT02151292
Other Study ID Numbers: NCI-2014-00620
NCI-2014-00620 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NCI 9568
PHL-093
9568 ( Other Identifier: University Health Network-Princess Margaret Hospital )
9568 ( Other Identifier: CTEP )
N01CM00032 ( U.S. NIH Grant/Contract )
N01CM00038 ( U.S. NIH Grant/Contract )
N01CM00071 ( U.S. NIH Grant/Contract )
UM1CA186644 ( U.S. NIH Grant/Contract )
UM1CA186705 ( U.S. NIH Grant/Contract )
First Posted: April 2, 2014    Key Record Dates
Last Update Posted: June 5, 2018
Last Verified: June 2018

Additional relevant MeSH terms:
Carcinoma
Adenocarcinoma
Fallopian Tube Neoplasms
Ovarian Neoplasms
Neoplasms, Glandular and Epithelial
Cystadenocarcinoma
Carcinoma, Endometrioid
Carcinosarcoma
Mixed Tumor, Mullerian
Cystadenocarcinoma, Serous
Cystadenocarcinoma, Mucinous
Brenner Tumor
Adenocarcinoma, Papillary
Neoplasms by Histologic Type
Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Fallopian Tube Diseases
Adnexal Diseases
Genital Diseases, Female
Endocrine Gland Neoplasms
Ovarian Diseases
Endocrine System Diseases
Gonadal Disorders
Neoplasms, Cystic, Mucinous, and Serous
Endometrial Neoplasms
Uterine Neoplasms
Neoplasms, Complex and Mixed
Sarcoma