AZD1775, Cisplatin, and Radiation Therapy in Treating Patients With Cervical Cancer

Stage IIB Cervical Cancer Clinical Trial

Official title:

A Phase I Study of the Wee 1 Kinase (Wee 1) Inhibitor AZD1775 (MK-1775) in Combination With Cisplatin and Radiation in Cervical Cancer (10041848, 10008224, 10008328)

Clinical Trial Details — Status: Suspended

Administrative data

• NCT number: NCT01958658
• Other study ID #: NCI-2013-01765
• Secondary ID: NCI-2013-01765PH
• Status: Suspended
• Phase: Phase 1
• First received: October 7, 2013
• Last updated: July 10, 2017
• Start date: September 5, 2013

Study information

• Verified date: May 2017
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Other known NCT identifiers

• NCT01925326

Recruitment information / eligibility

• Status: Suspended
• Enrollment: 57
• Est. primary completion date: June 30, 2021
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Stage IB Cervical Cancer
• Stage IIA Cervical Cancer
• Stage IIB Cervical Cancer
• Stage IIIA Cervical Cancer
• Stage IIIB Cervical Cancer
• Uterine Cervical Neoplasms

Intervention

Drug:
• Cisplatin
Given IV

Radiation:
• External Beam Radiation Therapy
Undergo external beam radiation therapy
• Internal Radiation Therapy
Undergo pulsed-dose rate or high-dose rate brachytherapy

Other:
• Laboratory Biomarker Analysis
Correlative studies
• Pharmacological Study
Correlative studies

Radiation:
• Pulsed-Dose Rate Brachytherapy
Undergo pulsed-dose rate or high-dose rate brachytherapy

Drug:
• WEE1 Inhibitor AZD1775
Given PO

Locations

Country	Name	City	State
Canada	Tom Baker Cancer Centre	Calgary	Alberta
Canada	Cross Cancer Institute	Edmonton	Alberta
Canada	London Regional Cancer Program	London	Ontario
Canada	Victoria Hospital	London	Ontario
Canada	CHUM - Hopital Notre-Dame	Montreal	Quebec
Canada	University Health Network-Princess Margaret Hospital	Toronto	Ontario

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	RP2D defined as the dose level with < 1/6 patients with dose-limiting toxicity as assessed by the National Cancer Institute (NCI) Clinical Trials Common Terminology Criteria for Adverse Events (CTCAE) version 4.0	Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Adverse events will be summarized using all adverse events experienced, although a subanalysis may be conducted including only those adverse events in which the treating physician deems possibly, probably or definitely attributable to one or both study treatments.	Up to 5 weeks
Primary	Safety profile of MK-1775 in combination with cisplatin and radiation therapy as assessed by the NCI CTCAE version 4.0 (Phase I)	Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Adverse events will be summarized using all adverse events experienced, although a subanalysis may be conducted including only those adverse events in which the treating physician deems possibly, probably or definitely attributable to one or both study treatments	Up to 1 year
Secondary	Objective response to treatment using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1		Up to 1 year
Secondary	Pharmacodynamic effects of AZD1775 (MK-1775)	Standard descriptive statistics, such as the mean, median, range and proportion, will be used to summarize the patient sample and to estimate parameters of interest. Ninety-five percent confidence intervals will be provided for estimates of interest where possible.	Baseline and at day 2-5 of week 1 or 2
Secondary	Pharmacokinetic (PK) parameters of AZD1775 (MK-1775)	PK parameters will be calculated by non-compartmental methods.	Baseline, at 1, 2, and 6 hours between day 1 and day 5
Secondary	Progression-free survival using RECIST version 1.1		From the start of treatment to time to progression or death, whichever occurs first, assessed up to 1 year