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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Seromucinous Carcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Undifferentiated Carcinoma; Ovarian Carcinosarcoma; Ovarian Brenner Tumor; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Surface Papillary Adenocarcinoma
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Other: Questionnaire Administration; Drug: Gemcitabine Hydrochloride; Other: Placebo Administration; Drug: Adavosertib

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.

• Study Type: Interventional
• Enrollment (Actual): 124
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / 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.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Other: Questionnaire Administration; Ancillary studies; Drug: Gemcitabine Hydrochloride; Given IV; Other Names: Gemzar; dFdCyd; Difluorodeoxycytidine Hydrochloride; Gemcitabine HCI; LY-188011; LY188011; Drug: Adavosertib; Given PO; Other Names: AZD-1775; AZD1775; MK-1775; MK1775
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.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Other: Questionnaire Administration; Ancillary studies; Drug: Gemcitabine Hydrochloride; Given IV; Other Names: Gemzar; dFdCyd; Difluorodeoxycytidine Hydrochloride; Gemcitabine HCI; LY-188011; LY188011; Other: Placebo Administration; Given PO

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival	To evaluate the progression free survival (PFS) of subjects with recurrent platinum-resistant ovarian, fallopian tube or primary peritoneal cancer receiving gemcitabine in combination with AZD1775 compared to subjects receiving gemcitabine in combination with placebo. Progression is defined, using the Response Evaluation Criteria In Solid Tumors (RECIST v1.1) guideline, as at least a 20% increase in the sum of the diameters of target lesions or the appearance of one or more new lesions.	From start of treatment until date of progression or death, whichever occurs first, up to 1 year follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response	To evaluate the objective response per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) of patients receiving gemcitabine combined with AZD1775 compared to patients receiving gemcitabine in combination with placebo. RECIST v1.1 criteria used for evaluation of target lesions: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), at least a 30% decrease in the sum of the diameters of target lesions; Progressive Disease (PD), at least a 20% increase in the sum of the diameters of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. The Best Overall Response is the best response recorded from the start of the treatment until disease progression/recurrence .	From start of treatment, every 6-8 weeks, until time of progression or death, whichever occurs first, up to 1 year follow-up
Response According to CA125 Criteria	To evaluate the GCIG CA125 response rate of patients receiving gemcitabine combined with AZD1775 compared to patients receiving gemcitabine in combination with placebo. A response according to CA-125 has occurred if there is at least a 50% reduction in CA-125 levels from a pre-treatment sample. The response must be confirmed and maintained for at least 28 days.	From start of treatment, every 4 weeks, until time of progression or death, whichever occurs first, up to 1 year follow-up
Overall Survival	To evaluate the overall survival of patients receiving gemcitabine combined with AZD1775 compared to patients receiving gemcitabine in combination with placebo.	From start of study treatment, every 12 weeks, until death, up to 22 months follow-up
Number of Participants With Grade 3 or 4 Adverse Events Related to Study Treatment	To evaluate the safety and tolerability of the combination of gemcitabine combined with AZD1775 in patients with recurrent, platinum-resistant ovarian, fallopian tube or primary peritoneal cancer.	From start of treatment until AE resolution, stabilization, or improvement to less than grade 2, up to 1 year follow-up
TP53 Mutations	To evaluate TP53 mutations (presence of mutation and type of mutation) as potential predictive factors of benefit (defined as response or PFS prolongation) to AZD1775 and gemcitabine treatment. TP53 status was assessed using Sanger sequencing.	Baseline
p53 Protein Expression	To evaluate p53 protein expression by immunohistochemistry as potential predictive factors of benefit (defined as response or PFS prolongation) to AZD1775 and gemcitabine treatment. Evaluating p53 expression in patients with high-grade serous ovarian cancer and in patients with high-grade serous ovarian cancer with TP53 mutations.	Baseline

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient Reported Outcomes	Will be assessed using Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE). Each symptomatic AE is assessed with respect to 1 to 3 of the following attributes: frequency (F), severity (S) and/or interference (I) with usual or daily activities, and a recall period of 'the past 7 days'. PRO-CTCAE responses are scored from 0 to 4 with scores of 3 and 4 corresponding to high frequency, severity and/or interference. Results show the number of patients in each arm reporting high scores (3-4) for symptomatic AEs occurring in >30% of patients	First 3 months
TP53 Mutations in Circulating Tumor Deoxyribonucleic Acid	TP53 mutations in circulating tumor deoxyribonucleic acid will be evaluated by TAm-Seq.	Baseline
Change in Levels of Circulating Deoxyribonucleic Acid TP53 Mutations by TAm-Seq	Levels of circulating deoxyribonucleic acid TP53 mutations will be correlated with response. *No results for this outcome measure	Baseline to up to 1 year
Changes in pCDC2 in Skin and Tumor Tissue	Validation of pCDC2 as a pharmacodynamic marker of therapy. *No results for this outcome measure	Baseline and at day 2 or 9 (course 1)
Changes in gH2AX in Skin and Tumor Tissue	Validation of gH2AX as a pharmacodynamic marker of therapy. *No results for this outcome measure	Baseline and at day 2 or 9 (course 1)
Changes in pCDC2	Changes in pCDC2 will be correlated with survival outcomes and response rate. *No results for this outcome measure	Baseline and at day 2 or 9 (course 1)
Changes in pH2AX	Changes in pH2AX will be correlated with survival outcomes and response rate. *No results for this outcome measure	Baseline and at day 2 or 9 (course 1)

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Amit M Oza, University Health Network-Princess Margaret Hospital

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): July 21, 2014
• Primary Completion (Actual): February 3, 2022
• Study Completion (Estimated): February 20, 2025

Study Registration Dates

• First Submitted: March 28, 2014
• First Submitted That Met QC Criteria: March 28, 2014
• First Posted (Estimated): April 2, 2014

Study Record Updates

• Last Update Posted (Actual): March 8, 2024
• Last Update Submitted That Met QC Criteria: March 7, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Uterine Neoplasms; Genital Neoplasms, Female; Endocrine System Diseases; Disease Attributes; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Fallopian Tube Diseases; Neoplasms, Complex and Mixed; Neoplasms, Connective Tissue; Sarcoma; Neoplasms, Cystic, Mucinous, and Serous; Ovarian Neoplasms; Endometrial Neoplasms; Neoplasms, Fibrous Tissue; Neoplasms, Fibroepithelial; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Carcinoma; Recurrence; Adenocarcinoma; Fallopian Tube Neoplasms; Carcinosarcoma; Cystadenocarcinoma, Serous; Carcinoma, Endometrioid; Cystadenocarcinoma; Cystadenocarcinoma, Mucinous; Adenocarcinoma, Papillary; Brenner Tumor; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Adavosertib; Gemcitabine
• Other Study ID Numbers: NCI-2014-00620 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); UM1CA186644 (U.S. NIH Grant/Contract); U10CA180821 (U.S. NIH Grant/Contract); N01CM00071 (U.S. NIH Grant/Contract); N01CM00038 (U.S. NIH Grant/Contract); N01CM00032 (U.S. NIH Grant/Contract); UM1CA186705 (U.S. NIH Grant/Contract); PHL-093; NCI 9568; 9568 (Other Identifier: CTEP)