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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01958658
First received: October 7, 2013
Last updated: September 16, 2014
Last verified: August 2014
  Purpose

This phase I trial studies the side effects and the 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.


Condition Intervention Phase
Stage IB Cervical Cancer
Stage IIA Cervical Cancer
Stage IIB Cervical Cancer
Stage IIIA Cervical Cancer
Stage IIIB Cervical Cancer
Drug: WEE1 inhibitor MK-1775
Drug: cisplatin
Radiation: external beam radiation therapy
Radiation: pulsed-dose rate brachytherapy
Radiation: brachytherapy
Other: pharmacological study
Other: laboratory biomarker analysis
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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)

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • 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 [ Time Frame: Up to 5 weeks ] [ Designated as safety issue: Yes ]
    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.

  • Safety profile of MK-1775 in combination with cisplatin and radiation therapy as assessed by the NCI CTCAE version 4.0 (Phase I) [ Time Frame: Up to 1 year ] [ Designated as safety issue: Yes ]
    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


Secondary Outcome Measures:
  • Objective response to treatment using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
  • Progression-free survival using RECIST version 1.1 [ Time Frame: From the start of treatment to time to progression or death, whichever occurs first, assessed up to 1 year ] [ Designated as safety issue: No ]
  • Pharmacokinetic (PK) parameters of AZD1775 (MK-1775) [ Time Frame: Baseline, at 1, 2, and 6 hours between day 1 and day 5 ] [ Designated as safety issue: No ]
    PK parameters will be calculated by non-compartmental methods.

  • Pharmacodynamic effects of AZD1775 (MK-1775) [ Time Frame: Baseline and at day 2-5 of week 1 or 2 ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 57
Study Start Date: August 2014
Estimated Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort I (MK-1775, cisplatin, radiation therapy)
Patients receive WEE1 inhibitor MK-177 PO BID on days 1-2, 8-9, 15-16, 22-23, and 29-30. Patients also receive cisplatin IV over 1 hour on days 1, 8, 15, 22, and 29 and undergo 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.
Drug: WEE1 inhibitor MK-1775
Given PO
Other Names:
  • AZD1775
  • MK-1775
Drug: cisplatin
Given IV
Other Names:
  • CACP
  • CDDP
  • CPDD
  • DDP
Radiation: external beam radiation therapy
Undergo external beam radiation therapy
Other Name: EBRT
Radiation: pulsed-dose rate brachytherapy
Undergo pulsed-dose rate or high-dose rate brachytherapy
Other Names:
  • PDR brachytherapy
  • PDR curietherapy
  • pulsed-dose rate curietherapy
Radiation: brachytherapy
Undergo pulsed-dose rate or high-dose rate brachytherapy
Other Names:
  • low-LET implant therapy
  • radiation brachytherapy
  • therapy, low-LET implant
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Correlative studies
Experimental: Cohort II (MK-1775, cisplatin, radiation therapy)
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. Patients also receive cisplatin IV over 1 hour on days 1, 8, 15, 22, and 29 and undergo 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.
Drug: WEE1 inhibitor MK-1775
Given PO
Other Names:
  • AZD1775
  • MK-1775
Drug: cisplatin
Given IV
Other Names:
  • CACP
  • CDDP
  • CPDD
  • DDP
Radiation: external beam radiation therapy
Undergo external beam radiation therapy
Other Name: EBRT
Radiation: pulsed-dose rate brachytherapy
Undergo pulsed-dose rate or high-dose rate brachytherapy
Other Names:
  • PDR brachytherapy
  • PDR curietherapy
  • pulsed-dose rate curietherapy
Radiation: brachytherapy
Undergo pulsed-dose rate or high-dose rate brachytherapy
Other Names:
  • low-LET implant therapy
  • radiation brachytherapy
  • therapy, low-LET implant
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Correlative studies
Experimental: Cohort III (MK-1775, cisplatin, radiation therapy)
Patients receive WEE1 inhibitor MK-177 PO BID on days 1-5, 8-12, 15-19, 22-26, and 29-33. Patients also receive cisplatin IV over 1 hour on days 1, 8, 15, 22, and 29 and undergo 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.
Drug: WEE1 inhibitor MK-1775
Given PO
Other Names:
  • AZD1775
  • MK-1775
Drug: cisplatin
Given IV
Other Names:
  • CACP
  • CDDP
  • CPDD
  • DDP
Radiation: external beam radiation therapy
Undergo external beam radiation therapy
Other Name: EBRT
Radiation: pulsed-dose rate brachytherapy
Undergo pulsed-dose rate or high-dose rate brachytherapy
Other Names:
  • PDR brachytherapy
  • PDR curietherapy
  • pulsed-dose rate curietherapy
Radiation: brachytherapy
Undergo pulsed-dose rate or high-dose rate brachytherapy
Other Names:
  • low-LET implant therapy
  • radiation brachytherapy
  • therapy, low-LET implant
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Correlative studies

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 (γH2AX), 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 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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 requiring radiation to the para-aortic lymph nodes are ineligible
  • 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
  • Willingness to undergo biopsy for p53 immunohistochemistry and correlative analyses
  • 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 that required radiation treatment to the para-aortic lymph nodes are excluded
  • 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; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
  • History of active clinically significant bleeding
  • History of bowel obstruction or malabsorption syndromes which might limit the absorption of the study drug
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01958658

Locations
Canada, Alberta
Tom Baker Cancer Centre Recruiting
Calgary, Alberta, Canada, T2N 4N2
Contact: Prafull Ghatage    403-521-3721    prafull.ghatage@albertahealthservices.ca   
Principal Investigator: Prafull Ghatage         
Canada, Ontario
London Regional Cancer Program Recruiting
London, Ontario, Canada, N6A 4L6
Contact: Stephen A. Welch    519-685-8640    stephen.welch@lhsc.on.ca   
Principal Investigator: Stephen A. Welch         
Victoria Hospital Recruiting
London, Ontario, Canada, N6K 1C2
Contact: David P. D'Souza    519-685-8650    david.dsouza@lhsc.on.ca   
Principal Investigator: David P. D'Souza         
University Health Network-Princess Margaret Hospital Recruiting
Toronto, Ontario, Canada, M5G 2M9
Contact: Helen J. Mackay    416-946-2253    helen.mackay@uhn.ca   
Principal Investigator: Helen J. Mackay         
Sponsors and Collaborators
Investigators
Principal Investigator: Helen Mackay Princess Margaret Hospital Phase 2 Consortium
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01958658     History of Changes
Obsolete Identifiers: NCT01925326
Other Study ID Numbers: NCI-2013-01765, NCI-2013-01765, PHL-087, 9407, N01CM00032
Study First Received: October 7, 2013
Last Updated: September 16, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Uterine Cervical Neoplasms
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Uterine Cervical Diseases
Uterine Diseases
Genital Diseases, Female
Cisplatin
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Radiation-Sensitizing Agents

ClinicalTrials.gov processed this record on September 22, 2014