Gemcitabine Hydrochloride With or Without WEE1 Inhibitor MK-1775 in Treating Patients With Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube Cancer
Study Details
Study Description
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 |
|---|---|---|
|
|
Phase 2 |
Detailed Description
PRIMARY OBJECTIVES:
- 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:
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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.
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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.
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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.
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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.
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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.
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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:
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To evaluate patient reported outcomes using Patient-Reported Outcomes (PRO)-Common Terminology Criteria for Adverse Events (CTCAE).
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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.
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To correlate the levels circulating DNA TP53 mutations by Tam-Seq with response.
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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.
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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 Design
Arms and Interventions
| 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:
Drug: Gemcitabine Hydrochloride
Given IV
Other Names:
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:
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Other: Placebo Administration
Given PO
Other: Questionnaire Administration
Ancillary studies
|
Outcome Measures
Primary Outcome Measures
- Progression free survival [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
- Objective response [Up to 1 year]
Objective response will be evaluated according to Response Evaluation Criteria in Solid Tumors version 1.1.
- CA125 response rate [Up to 1 year]
The Gynecologic Cancer InterGroup CA125 response rate will be assessed.
- Overall survival [Up to 1 year]
Survival estimates will be computed using the Kaplan-Meier method.
- 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 [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.
- TP53 mutations [Baseline]
Presence and type of TP53 mutations will be assessed by Sanger sequencing.
- p53 protein expression [Baseline]
Expression of p53 protein in archival tumor tissue will be measured by immunohistochemistry.
Other Outcome Measures
- Patient reported outcomes [Up to 1 year]
Will be assessed using Patient Reported Outcomes-Common Terminology Criteria for Adverse Events.
- TP53 mutations in circulating tumor deoxyribonucleic acid [Baseline]
TP53 mutations in circulating tumor deoxyribonucleic acid will be evaluated by TAm-Seq.
- Change in levels of circulating deoxyribonucleic acid TP53 mutations by TAm-Seq [Baseline to up to 1 year]
Levels of circulating deoxyribonucleic acid TP53 mutations will be correlated with response.
- Changes in pCDC2 in skin and tumor tissue [Baseline and at day 2 or 9 (course 1)]
Validation of pCDC2 as a pharmacodynamic marker of therapy.
- Changes in gH2AX in skin and tumor tissue [Baseline and at day 2 or 9 (course 1)]
Validation of gH2AX as a pharmacodynamic marker of therapy.
- Changes in pCDC2 [Baseline and at day 2 or 9 (course 1)]
Changes in pCDC2 will be correlated with survival outcomes and response rate.
- Changes in pH2AX [Baseline and at day 2 or 9 (course 1)]
Changes in pH2AX will be correlated with survival outcomes and response rate.
Eligibility Criteria
Criteria
Inclusion Criteria:
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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
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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
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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
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There is no limitation in the number of prior lines of therapy
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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
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Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
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Life expectancy of greater than 3 months
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Leukocytes >= 3,000/mcL
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Absolute neutrophil count >= 1,500/mcL
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Platelets >= 100,000/mcL
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Hemoglobin >= 90 g/L
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Blood transfusions are allowed at any time during the screening, treatment or follow-up period, according to the center recommendations
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Prothrombin time (PT), partial thromboplastin time (PTT) and international normalized ratio (INR) =< 1.5 upper limit of normal (ULN)
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Total bilirubin =< 1.5 x institutional upper limit of normal; unless due to Gilbert's syndrome
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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)
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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
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Patients must be able to tolerate oral medication and not have evidence of active bowel obstruction
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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
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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)
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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
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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
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Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
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Patients who previously received gemcitabine for the treatment of recurrent disease
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Patients who are receiving any other investigational agents
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Patients with clinically or radiologically unstable brain metastases are excluded from this clinical trial
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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
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History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD 1775 (MK-1775) or gemcitabine
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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
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Pregnant and breastfeeding women are excluded from this study
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Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
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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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | City of Hope Comprehensive Cancer Center | Duarte | California | United States | 91010 |
| 2 | City of Hope South Pasadena | South Pasadena | California | United States | 91030 |
| 3 | University of Chicago Comprehensive Cancer Center | Chicago | Illinois | United States | 60637 |
| 4 | Decatur Memorial Hospital | Decatur | Illinois | United States | 62526 |
| 5 | Indiana University/Melvin and Bren Simon Cancer Center | Indianapolis | Indiana | United States | 46202 |
| 6 | Mayo Clinic in Rochester | Rochester | Minnesota | United States | 55905 |
| 7 | Fox Chase Cancer Center | Philadelphia | Pennsylvania | United States | 19111 |
| 8 | University of Pittsburgh Cancer Institute (UPCI) | Pittsburgh | Pennsylvania | United States | 15232 |
| 9 | BCCA-Cancer Centre for the Southern Interior | Kelowna | British Columbia | Canada | V1Y 5L3 |
| 10 | BCCA-Vancouver Cancer Centre | Vancouver | British Columbia | Canada | V5Z 4E6 |
| 11 | London Regional Cancer Program | London | Ontario | Canada | N6A 4L6 |
| 12 | Ottawa Hospital and Cancer Center-General Campus | Ottawa | Ontario | Canada | K1H 8L6 |
| 13 | University Health Network Princess Margaret Cancer Center P2C | Toronto | Ontario | Canada | M5G 2M9 |
| 14 | University Health Network-Princess Margaret Hospital | Toronto | Ontario | Canada | M5G 2M9 |
| 15 | CHUM - Hopital Notre-Dame | Montreal | Quebec | Canada | H2L 4M1 |
| 16 | National University Hospital Singapore | Singapore | Singapore | 119074 |
Sponsors and Collaborators
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Amit M Oza, University Health Network-Princess Margaret Hospital
Study Documents (Full-Text)
More Information
Publications
None provided.- NCI-2014-00620
- NCI-2014-00620
- PHL-093
- NCI 9568
- 9568
- 9568
- N01CM00032
- N01CM00038
- N01CM00071
- U10CA180821
- UM1CA186644
- UM1CA186705
- NCT02151292