AZD1775, Cisplatin, and Radiation Therapy in Treating Patients With Cervical Cancer
Conditions
Stage IB Cervical Cancer - Stage IIA Cervical Cancer - Stage IIB Cervical Cancer - Stage IIIA Cervical Cancer - Stage IIIB Cervical Cancer
Conditions: official terms
Uterine Cervical Neoplasms
Study Type
Interventional
Study Phase
Phase 1
Study Design
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Intervention
Name: Cisplatin Type: Drug
Name: External Beam Radiation Therapy Type: Radiation
Name: Internal Radiation Therapy Type: Radiation
Name: Laboratory Biomarker Analysis Type: Other
Name: Pharmacological Study Type: Other
Name: Pulsed-Dose Rate Brachytherapy Type: Radiation
Name: WEE1 Inhibitor MK-1775 Type: Drug
Overall Status
Recruiting
Summary
This phase I trial studies the side effects and best dose of WEE1 inhibitor MK-1775 (AZD1775) when given together with cisplatin and radiation therapy in treating patients with cervical cancer. WEE1 inhibitor MK-1775 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill tumor cells. Giving WEE1 inhibitor MK-1775 together with cisplatin and radiation therapy may be a better treatment for patients with cervical cancer.
Detailed Description
PRIMARY OBJECTIVES:

I. To determine the recommended phase II dose (RP2D) and safety profile of AZD1775 (MK-1775) in combination with cisplatin and radiation in patients with cervical cancer (phase I).

SECONDARY OBJECTIVES:

I. To evaluate the pharmacodynamic effects of AZD1775 (MK-1775) drugs when administered in combination with cisplatin and radiation (in particular, for the 15 patients treated in an expansion cohort at the RP2D). Pharmacodynamic biomarkers will include: phosphorylated cell division cycle protein 2 homolog (pCDC2), antigen Ki-67 (Ki67), gamma H2A histone family, member X (gH2AX), phosphorylated (phospho)-histone 3 (pH3), and cleaved caspase-3 (CC3).

II. To obtain preliminary information about the progression-free survival of AZD1775 (MK-1775) in combination with standard radiation and chemotherapy in women with locally advanced high-risk cervix cancer.

III. To determine the acute and late toxicity of AZD1775 (MK-1775) when administered to patients with cervix cancer in combination with standard radiation and concurrent chemotherapy.

IV. To correlate the serum pharmacokinetic parameters—maximum concentration (Cmax), time to peak concentration (Tmax), 8-hours concentration (C8), and area under the curve (AUC) (0-8)—with the drug concentration in the tumor tissue (for patients in the expansion cohort).

OUTLINE: This is a dose-escalation study of WEE1 inhibitor MK-1775. Patients are assigned to 1 of 3 treatment groups.

COHORT I: Patients receive WEE1 inhibitor MK-177 orally (PO) twice daily (BID) on days 1-2, 8-9, 15-16, 22-23, and 29-30.

COHORT II: Patients receive WEE1 inhibitor MK-177 PO BID on days 4-5, 11-12, 18-19, 25-26, and 32-33 or on days 3-5, 10-12, 17-19, 24-26, and 31-33.

COHORT III: Patients receive WEE1 inhibitor MK-177 PO BID on days 1-5, 8-12, 15-19, 22-26, and 29-33.

In all cohorts, patients also receive cisplatin intravenously (IV) over 1 hour on days 1, 8, 15, 22, and 29 and undergo of pelvic external beam radiation therapy 5 days a week for 5 weeks followed by pulsed-dose rate or high-dose rate brachytherapy 5 days a week in weeks 6-8.

After completion of study treatment, patients are followed up at 4 weeks, at 3, 6, and 12 months.
Criteria for eligibility
Healthy Volunteers: No
Maximum Age: N/A
Minimum Age: 18 Years
Gender: Female
Criteria: Inclusion Criteria:

- Patients must have biopsy-proven epithelial carcinoma of the cervix, T1B-3B, N0/1, M0/1 with visible or palpable disease and a decision to treat radically with radiotherapy and concurrent cisplatin chemotherapy (RT-CT)

- T1B-3B: during the dose escalation phase of the study, high risk patients (tumor > 5 cm or node positive or metastatic) ONLY will be enrolled

- M0/1: during the dose escalation phase, patients with asymptomatic metastatic disease of little extent will be eligible provided they were candidates for treatment of the primary tumor with radiotherapy and concurrent cisplatin chemotherapy

- Patients must be planned to received radiotherapy to 40 Gray (Gy) or greater

- Patients must be able to receive weekly cisplatin

- No prior anticancer treatment to treat the current cervical cancer is allowed

- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky >= 60%)

- Life expectancy of greater than 3 months

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin =< 9 g/dL

- 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)/international normalized ratio (INR) =< 1.5 upper limit of normal (ULN)

- Total bilirubin within normal institutional limits

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.5 x institutional upper limit of normal

- Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

- Patients with elevated creatinine secondary to hydronephrosis may be eligible if renal function returns to normality after placing an internal stent or nephrostomy

- Patients must be able to swallow whole capsules

- Women of child-bearing potential must agree to use two birth control methods (two barrier methods or a barrier method plus a hormonal method) or abstinence prior to study entry, for the duration of study participation prior to study entry, for the duration of study participation, and for 4 months after coming off study, should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients who have received any anticancer treatment for their cervical cancer

- Patients who are receiving any other investigational agents concurrently or within 4 weeks

- Patients with para-aortic lymph node metastases above the bifurcation of the aorta/inferior vena cava (IVC), as determined by compute tomography (CT), magnetic resonance (MR) or positron emission tomography (PET) imaging criteria

- History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD1775 (MK-1775) or cisplatin

- 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

- As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product

- 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

- Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with AZD1775 (MK-1775) and cisplatin

- Patients with another uncontrolled malignancy; patients with a previous malignancy, treated curatively and without evidence of disease relapse are eligible

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible

- History of active clinically significant bleeding

- History of bowel obstruction or malabsorption syndromes
Locations
Tom Baker Cancer Centre
Calgary, Alberta, Canada
Status: Recruiting
Contact: Prafull Ghatage - 403-521-3721 - prafull.ghatage@albertahealthservices.ca
Cross Cancer Institute
Edmonton, Alberta, Canada
Status: Recruiting
Contact: Katia S. Tonkin - 780-432-8514 - Katia.Tonkin@albertahealthservices.ca
London Regional Cancer Program
London, Ontario, Canada
Status: Recruiting
Contact: Stephen A. Welch - 519-685-8640 - stephen.welch@lhsc.on.ca
Victoria Hospital
London, Ontario, Canada
Status: Recruiting
Contact: David P. D'Souza - 519-685-8650 - david.dsouza@lhsc.on.ca
University Health Network-Princess Margaret Hospital
Toronto, Ontario, Canada
Status: Recruiting
Contact: Amit M. Oza - 416-946-2818 - amit.oza@uhn.ca
CHUM - Hopital Notre-Dame
Montreal, Quebec, Canada
Status: Recruiting
Contact: Diane Provencher - 514-890-8000 - diane.provencher.chum@ssss.gouv.qc.ca
Start Date
September 2013
Sponsors
National Cancer Institute (NCI)
Source
National Cancer Institute (NCI)
Record processing date
ClinicalTrials.gov processed this data on July 28, 2015
ClinicalTrials.gov page