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

NCT ID: NCT02101775

Last Updated: 2025-09-29

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 124 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-07-21
• Study Completion Date: 2026-02-20

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.

Detailed Description

PRIMARY OBJECTIVES:

I. To evaluate the progression free survival (PFS) of subjects with recurrent platinum-resistant ovarian, fallopian tube or primary peritoneal cancer receiving gemcitabine (gemcitabine hydrochloride) in combination with AZD 1775 (MK-1775 [WEE1 inhibitor MK-1775]) compared to subjects receiving gemcitabine in combination with placebo.

SECONDARY OBJECTIVES:

I. To evaluate the objective response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 of patients receiving gemcitabine combined with AZD 1775 (MK-1775) compared to patients receiving gemcitabine in combination with placebo.

II. To evaluate the Gynecologic Cancer Intergroup (GCIG) cancer antigen (CA)125 response rate of patients receiving gemcitabine combined with AZD 1775 (MK-1775) compared to patients receiving gemcitabine in combination with placebo.

III. To evaluate the overall survival of patients (max 1-year [yr] follow-up) receiving gemcitabine combined with AZD 1775 (MK-1775) compared to patients receiving gemcitabine in combination with placebo.

IV. To evaluate the safety and tolerability of the combination of gemcitabine combined with AZD 1775 (MK-1775) in patients with recurrent, platinum-resistant ovarian, fallopian tube or primary peritoneal cancer.

V. To evaluate tumor protein p53 (TP53) mutations (presence of mutation and type of mutation) as potential predictive factors of benefit (defined as response or progression-free survival [PFS] prolongation) to AZD 1775 (MK-1775) and gemcitabine treatment.

VI. To evaluate p53 protein expression by immunohistochemistry as potential predictive factors of benefit (defined as response or PFS prolongation) to AZD 1775 (MK-1775) and gemcitabine treatment.

TERTIARY OBJECTIVES:

I. To evaluate patient reported outcomes using Patient-Reported Outcomes (PRO)-Common Terminology Criteria for Adverse Events (CTCAE).

II. To evaluate the concordance of TP53 mutations in the tumor specimen and TP53 mutations determined by tagged-amplicon deep sequencing (Tam-Seq) in circulating tumor DNA.

III. To correlate the levels circulating DNA TP53 mutations by Tam-Seq with response.

IV. Validation of phosphorylated-cyclin-dependent cycle 2 (pCDC2) and gamma-H2A histone family, member X (H2AX) in skin and tumor tissue as a pharmacodynamic marker of therapy.

V. To correlate changes in pCDC2 and gamma-H2AX with survival outcomes and response rate.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive WEE1 inhibitor MK-1775 orally (PO) on days 1, 2, 8, 9, 15, and 16 and gemcitabine hydrochloride intravenously (IV) over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: 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.

After completion of study treatment, patients are followed up every 6-8 weeks (after the 30-37 day safety visit) for up to 1 year.

Conditions

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; Ovarian Undifferentiated Carcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

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.

Group Type: EXPERIMENTAL

Adavosertib

Intervention Type: DRUG

Given PO

Gemcitabine Hydrochloride

Intervention Type: DRUG

Given IV

Laboratory Biomarker Analysis

Intervention Type: OTHER

Correlative studies

Pharmacological Study

Intervention Type: OTHER

Correlative studies

Questionnaire Administration

Intervention Type: OTHER

Ancillary studies

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.

Group Type: ACTIVE_COMPARATOR

Gemcitabine Hydrochloride

Intervention Type: DRUG

Given IV

Laboratory Biomarker Analysis

Intervention Type: OTHER

Correlative studies

Pharmacological Study

Intervention Type: OTHER

Correlative studies

Placebo Administration

Intervention Type: OTHER

Given PO

Questionnaire Administration

Intervention Type: OTHER

Ancillary studies

Interventions

Adavosertib

Given PO

Intervention Type: DRUG

Gemcitabine Hydrochloride

Given IV

Intervention Type: DRUG

Laboratory Biomarker Analysis

Correlative studies

Intervention Type: OTHER

Pharmacological Study

Correlative studies

Intervention Type: OTHER

Placebo Administration

Given PO

Intervention Type: OTHER

Questionnaire Administration

Ancillary studies

Intervention Type: OTHER

Other Intervention Names

AZD 1775; AZD-1775; AZD1775; MK 1775; MK-1775; MK1775; dFdCyd; Difluorodeoxycytidine Hydrochloride; Gemcitabine HCI; Gemzar; LY 188011; LY-188011; LY188011

Eligibility 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Amit M Oza

Role: PRINCIPAL_INVESTIGATOR

University Health Network-Princess Margaret Hospital

Locations

City of Hope Comprehensive Cancer Center

Duarte, California, United States

City of Hope South Pasadena

South Pasadena, California, United States

University of Chicago Comprehensive Cancer Center

Chicago, Illinois, United States

Decatur Memorial Hospital

Decatur, Illinois, United States

Indiana University/Melvin and Bren Simon Cancer Center

Indianapolis, Indiana, United States

Mayo Clinic in Rochester

Rochester, Minnesota, United States

Fox Chase Cancer Center

Philadelphia, Pennsylvania, United States

University of Pittsburgh Cancer Institute (UPCI)

Pittsburgh, Pennsylvania, United States

BCCA-Cancer Centre for the Southern Interior

Kelowna, British Columbia, Canada

BCCA-Vancouver Cancer Centre

Vancouver, British Columbia, Canada

London Regional Cancer Program

London, Ontario, Canada

Ottawa Hospital and Cancer Center-General Campus

Ottawa, Ontario, Canada

University Health Network Princess Margaret Cancer Center P2C

Toronto, Ontario, Canada

University Health Network-Princess Margaret Hospital

Toronto, Ontario, Canada

CHUM - Centre Hospitalier de l'Universite de Montreal

Montreal, Quebec, Canada

National University Hospital Singapore

Singapore, , Singapore

Countries

United States; Canada; Singapore

References

Lheureux S, Cristea MC, Bruce JP, Garg S, Cabanero M, Mantia-Smaldone G, Olawaiye AB, Ellard SL, Weberpals JI, Wahner Hendrickson AE, Fleming GF, Welch S, Dhani NC, Stockley T, Rath P, Karakasis K, Jones GN, Jenkins S, Rodriguez-Canales J, Tracy M, Tan Q, Bowering V, Udagani S, Wang L, Kunos CA, Chen E, Pugh TJ, Oza AM. Adavosertib plus gemcitabine for platinum-resistant or platinum-refractory recurrent ovarian cancer: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet. 2021 Jan 23;397(10271):281-292. doi: 10.1016/S0140-6736(20)32554-X.

Reference Type: DERIVED

PMID: 33485453 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

NCI-2014-00620

Identifier Type: REGISTRY

Identifier Source: secondary_id

PHL-093

Identifier Type: -

Identifier Source: secondary_id

NCI 9568

Identifier Type: -

Identifier Source: secondary_id

9568

Identifier Type: OTHER

Identifier Source: secondary_id

9568

Identifier Type: OTHER

Identifier Source: secondary_id

N01CM00032

Identifier Type: NIH

Identifier Source: secondary_id

View Link

N01CM00038

Identifier Type: NIH

Identifier Source: secondary_id

View Link

N01CM00071

Identifier Type: NIH

Identifier Source: secondary_id

View Link

U10CA180821

Identifier Type: NIH

Identifier Source: secondary_id

View Link

UM1CA186644

Identifier Type: NIH

Identifier Source: secondary_id

View Link

UM1CA186705

Identifier Type: NIH

Identifier Source: secondary_id

View Link

NCI-2014-00620

Identifier Type: -

Identifier Source: org_study_id

NCT02151292

Identifier Type: -

Identifier Source: nct_alias