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WEE1 Inhibitor AZD1775, External Beam Radiation Therapy, and Cisplatin in Treating Patients With Cervical, Vaginal, or Uterine Cancer

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ClinicalTrials.gov Identifier: NCT03345784
Recruitment Status : Recruiting
First Posted : November 17, 2017
Last Update Posted : March 20, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase I trial studies the side effects and best dose of WEE1 inhibitor AZD1775 when given together with external beam radiation therapy and cisplatin in treating patients with cervical, vaginal, or uterine cancer. WEE1 inhibitor AZD1775 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. External beam radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. 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. Giving WEE1 inhibitor AZD1775, external beam radiation therapy, and cisplatin may work better in treating patients with cervical, vaginal, or uterine cancer.

Condition or disease Intervention/treatment Phase
Endometrioid Adenocarcinoma Recurrent Cervical Carcinoma Stage I Uterine Corpus Cancer AJCC v7 Stage I Vaginal Cancer AJCC v6 and v7 Stage IA Uterine Corpus Cancer AJCC v7 Stage IB Cervical Cancer AJCC v6 and v7 Stage IB Uterine Corpus Cancer AJCC v7 Stage II Cervical Cancer AJCC v7 Stage II Uterine Corpus Cancer AJCC v7 Stage II Vaginal Cancer AJCC v6 and v7 Stage IIA Cervical Cancer AJCC v7 Stage IIB Cervical Cancer AJCC v6 and v7 Stage III Cervical Cancer AJCC v6 and v7 Stage III Uterine Corpus Cancer AJCC v7 Stage III Vaginal Cancer AJCC v6 and v7 Stage IIIA Cervical Cancer AJCC v6 and v7 Stage IIIA Uterine Corpus Cancer AJCC v7 Stage IIIB Cervical Cancer AJCC v6 and v7 Stage IIIB Uterine Corpus Cancer AJCC v7 Stage IIIC Uterine Corpus Cancer AJCC v7 Drug: Adavosertib Drug: Cisplatin Radiation: External Beam Radiation Therapy Other: Laboratory Biomarker Analysis Other: Pharmacological Study Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the recommended phase II dose (RP2D) and safety profile of WEE1 inhibitor AZD1775 (AZD1775) in combination with radiotherapy and concurrent cisplatin in patients with gynecological cancers.

SECONDARY OBJECTIVES:

I. To determine the acute and late toxicity of AZD1775 when administered to patients with gynecological cancer in combination with standard radiotherapy and concurrent cisplatin.

II. To evaluate the pharmacodynamic effects of AZD1775 when administered in combination with radiotherapy and concurrent cisplatin (in particular, for the 15 patients treated in an expansion cohort at the RP2D).

III. To obtain preliminary information about the progression-free survival of AZD1775 in combination with standard radiotherapy and concurrent cisplatin in women with gynecological cancer.

OUTLINE: This is a dose-escalation study of WEE1 inhibitor AZD1775.

Patients undergo external beam radiation therapy on days 1-5 and receive WEE1 inhibitor AZD1775 orally (PO) on days 1, 3, and 5 or days 1-5 and cisplatin intravenously (IV) over 1 hour on day 1 or 3. Courses repeat each week for up to 5 weeks in the absence of disease progression of unacceptable toxicity.

After completion of study treatment, patients are followed up at 28 days and then every 4 months for 2 years.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study of the Wee 1 Kinase (Wee 1) Inhibitor AZD1775 in Combination With Radiotherapy and Cisplatin in Cervical, Upper Vaginal and, Uterine Cancers (10041848, 10008224, 10008238, 10046888, 10014735)
Actual Study Start Date : October 23, 2017
Estimated Primary Completion Date : October 18, 2020
Estimated Study Completion Date : October 18, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Uterine Cancer
Drug Information available for: Cisplatin
U.S. FDA Resources

Arm Intervention/treatment
Experimental: Treatment (radiation therapy, cisplatin, AZD1775)
Patients undergo external beam radiation therapy on days 1-5 and receive WEE1 inhibitor AZD1775 PO on days 1, 3, and 5 or days 1-5 and cisplatin IV over 1 hour on day 1 or 3. Courses repeat each week for up to 5 weeks in the absence of disease progression of unacceptable toxicity.
Drug: Adavosertib
Given PO
Other Names:
  • AZD-1775
  • AZD1775
  • MK-1775
  • MK1775
Drug: Cisplatin
Given IV
Other Names:
  • Abiplatin
  • Blastolem
  • Briplatin
  • CDDP
  • Cis-diammine-dichloroplatinum
  • Cis-diamminedichloridoplatinum
  • Cis-diamminedichloro Platinum (II)
  • Cis-diamminedichloroplatinum
  • Cis-dichloroammine Platinum (II)
  • Cis-platinous Diamine Dichloride
  • Cis-platinum
  • Cis-platinum II
  • Cis-platinum II Diamine Dichloride
  • Cismaplat
  • Cisplatina
  • Cisplatinum
  • Cisplatyl
  • Citoplatino
  • Citosin
  • Cysplatyna
  • DDP
  • Lederplatin
  • Metaplatin
  • Neoplatin
  • Peyrone's Chloride
  • Peyrone's Salt
  • Placis
  • Plastistil
  • Platamine
  • Platiblastin
  • Platiblastin-S
  • Platinex
  • Platinol
  • Platinol- AQ
  • Platinol-AQ
  • Platinol-AQ VHA Plus
  • Platinoxan
  • Platinum
  • Platinum Diamminodichloride
  • Platiran
  • Platistin
  • Platosin
Radiation: External Beam Radiation Therapy
Undergo external beam radiation therapy
Other Names:
  • Definitive Radiation Therapy
  • EBRT
  • External Beam Radiotherapy
  • External Beam RT
  • external radiation
  • External Radiation Therapy
  • external-beam radiation
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies



Primary Outcome Measures :
  1. RP2D defined as the dose level with < 1/6 patients with dose limiting toxicities [ Time Frame: Up to week 5 ]

Secondary Outcome Measures :
  1. Objective response assessed by Response Evaluation Criteria in Solid Tumors 1.1 criteria [ Time Frame: Up to 2 years ]
  2. Pharmacodynamic effects of WEE1 inhibitor AZD1775 when given in combination with radiation therapy and cisplatin [ Time Frame: Up to 2 years ]
    Pharmacodynamic biomarkers will include: pCDC2, Ki67, γH2AX, pH3, and CC3. Associations between pharmacokinetic data with toxicity profiles will be performed primarily using descriptive statistics; however, logistic regression may be used if warranted.

  3. Progression-free survival [ Time Frame: From start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years ]
  4. Incidence of acute adverse events assessed by National Cancer Institute (NCI) Clinical Trials Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 2 years ]
    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.

  5. Incidence of late adverse events assessed by NCI CTCAE version 4.0 [ Time Frame: Up to 2 years ]
    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.



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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have one of the following biopsy proven gynecological cancer and a decision to treat with radiotherapy and concurrent cisplatin chemotherapy (RT-CT)

    • Newly diagnosed epithelial carcinoma of the cervix, cT1B-3B, N0/1, M0/1

      • Patient may have small volume metastatic disease in para-aortic or supraclavicular lymph nodes or at other metastatic sites as long as, in the best judgment of the treatment team, a radical course of pelvic radiotherapy is warranted to assure local disease control
    • Newly diagnosed epithelial carcinoma of the upper 1/3 vagina, T1-3, N0/1, M0/1

      • Patient may have small volume metastatic disease in para-aortic or supraclavicular lymph nodes or at other metastatic sites as long as, in the best judgment of the treatment team, a radical course of pelvic radiotherapy is warranted to assure local disease control
    • Newly diagnosed endometrioid adenocarcinoma of the uterus, cT1-3, N0/1, M0 unsuitable for primary surgery because of the extent of local disease; these patients are eligible if a prior decision has been made to treat radically with neoadjuvant chemoradiation followed by surgery or further radiotherapy (including brachytherapy) depending on response
    • Central pelvis or sidewall recurrence of epithelial carcinoma of the cervix of endometrioid adenocarcinoma of the uterus after previous surgery without previous pelvic radiotherapy

      • Patient may have small volume metastatic disease in para-aortic or supraclavicular lymph nodes or at other metastatic sites as long as, in the best judgment of the treatment team, a radical course of pelvic radiotherapy is warranted to assure local disease control
  • Patients must be planned to receive whole pelvic radiotherapy to a total dose of 45 Gy or greater
  • Patients must be able to receive weekly cisplatin
  • 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
  • Prothrombin time (PT)/partial thromboplastin time (PTT)/international normalized ratio (INR) =< 1.5 upper limit of normal (ULN)
  • Total bilirubin =< 1.5 x institutional upper limits of normal; unless due to Gilbert's syndrome
  • Aspartate aminotransferases (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 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 level
  • 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 radiotherapy or chemotherapy for their current gynecological cancer
  • Patients who received prior pelvic radiotherapy for any indication
  • Patients requiring para-aortic radiotherapy
  • Patients who are receiving any other investigational agents or anticancer therapy concurrently or within 4 weeks (ie 28 days)
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD1775 or cisplatin
  • Patients taking the following prescription or non-prescription drugs or other products (i.e. grapefruit juice) are ineligible: sensitive 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
  • 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 and cisplatin; these potential risks may also apply to other agents used in this study
  • 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 (within the last 3 months) which might limit the absorption of the study drug

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03345784


Locations
United States, California
University of California Davis Comprehensive Cancer Center Recruiting
Sacramento, California, United States, 95817
Contact: Vanessa A. Kennedy    916-734-3089      
Principal Investigator: Vanessa A. Kennedy         
United States, Colorado
University of Colorado Hospital Recruiting
Aurora, Colorado, United States, 80045
Contact: Bradley R. Corr    720-848-0650      
Principal Investigator: Bradley R. Corr         
United States, North Carolina
Duke University Medical Center Suspended
Durham, North Carolina, United States, 27710
Canada, Ontario
University Health Network-Princess Margaret Hospital Recruiting
Toronto, Ontario, Canada, M5G 2M9
Contact: Amit M. Oza    416-946-4501    clinical.trials@uhn.on.ca   
Principal Investigator: Amit M. Oza         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Stephanie Lheureux University Health Network Princess Margaret Cancer Center LAO

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03345784     History of Changes
Obsolete Identifiers: NCT01958658
Other Study ID Numbers: NCI-2017-00038
NCI-2017-00038 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2013-01765
PHL-087
10132 ( Other Identifier: University Health Network Princess Margaret Cancer Center LAO )
10132 ( Other Identifier: CTEP )
UM1CA186644 ( U.S. NIH Grant/Contract )
First Posted: November 17, 2017    Key Record Dates
Last Update Posted: March 20, 2018
Last Verified: November 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Uterine Cervical Neoplasms
Uterine Neoplasms
Vaginal Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Uterine Cervical Diseases
Endometrial Neoplasms
Ovarian Neoplasms
Adenocarcinoma
Carcinoma, Endometrioid
Carcinoma
Uterine Diseases
Genital Diseases, Female
Vaginal Diseases
Ovarian Diseases
Adnexal Diseases
Gonadal Disorders
Endocrine System Diseases
Cisplatin
Antineoplastic Agents