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)
Overview
- Phase
- Phase 1
- Status
- Terminated
- Enrollment
- 10
- Locations
- 8
- Primary Endpoint
- Recommended Phase 2 Dose Defined as the Dose Level With < 1/6 Patients With Dose Limiting Toxicities
Overview
Brief Summary
This phase I trial studies the side effects and best dose of adavosertib when given together with external beam radiation therapy and cisplatin in treating patients with cervical, vaginal, or uterine cancer. Adavosertib 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 adavosertib, external beam radiation therapy, and cisplatin may work better in treating patients with cervical, vaginal, or uterine cancer.
Detailed Description
PRIMARY OBJECTIVE:
I. To determine the recommended phase II dose (RP2D) and safety profile of adavosertib (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, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or clinical progression, of AZD1775 in combination with standard radiotherapy and concurrent cisplatin in women with gynecological cancer.
OUTLINE: This is a dose-escalation study of adavosertib.
Patients undergo external beam radiation therapy on days 1-5 and receive adavosertib orally (PO) on days 1, 3, and 5 or once daily (QD) on days 1-5 and cisplatin intravenously (IV) over 1 hour on day 1 or 3. Cycles 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 Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- Female
- Accepts Healthy Volunteers
- No
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
- •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%)
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 who have a mean resting correct corrected QT (QTc) interval using the Fridericia formula (QTcF) \> 470 msec (as calculated per institutional standards) obtained from 3 electrocardiograms (ECGs) 2-5 minutes apart at study entry, or congenital long QT syndrome; AZD1775 should not be given to patients who have a history of Torsades de pointes unless all risk factors contributed to Torsades have been corrected; AZD1775 has not been studied in patients with ventricular arrhythmias or recent myocardial infarction
- •Patients requiring para-aortic radiotherapy
- •Patients who are receiving any other investigational agents or anticancer therapy concurrently or within 4 weeks (i.e. 28 days)
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD1775 or cisplatin
- •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 because AZD1775 and chemoradiation are agents with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD1775 and cisplatin, breastfeeding must 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 because of the potential for pharmacokinetic interactions with AZD1775; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
Arms & Interventions
Treatment (radiation therapy, adavosertib, cisplatin)
Patients undergo external beam radiation therapy on days 1-5 and receive adavosertib PO on days 1, 3, and 5 or QD on days 1-5 and cisplatin IV over 1 hour on day 1 or 3. Cycles repeat each week for up to 5 weeks in the absence of disease progression of unacceptable toxicity.
Intervention: Adavosertib (Drug)
Treatment (radiation therapy, adavosertib, cisplatin)
Patients undergo external beam radiation therapy on days 1-5 and receive adavosertib PO on days 1, 3, and 5 or QD on days 1-5 and cisplatin IV over 1 hour on day 1 or 3. Cycles repeat each week for up to 5 weeks in the absence of disease progression of unacceptable toxicity.
Intervention: Cisplatin (Drug)
Treatment (radiation therapy, adavosertib, cisplatin)
Patients undergo external beam radiation therapy on days 1-5 and receive adavosertib PO on days 1, 3, and 5 or QD on days 1-5 and cisplatin IV over 1 hour on day 1 or 3. Cycles repeat each week for up to 5 weeks in the absence of disease progression of unacceptable toxicity.
Intervention: External Beam Radiation Therapy (Radiation)
Outcomes
Primary Outcomes
Recommended Phase 2 Dose Defined as the Dose Level With < 1/6 Patients With Dose Limiting Toxicities
Time Frame: Up to week 5
To determine the recommended phase II dose (RP2D) and safety profile of AZD1775 in combination with radiotherapy and concurrent cisplatin in patients with gynecological cancers.
Secondary Outcomes
- Progression-free Survival(From start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years)
- Frequency and Severity of AZD1775 Toxicity Events in Patients With Gynecological Cancer in Combination With Standard RT and Concurrent Cisplatin(Up to 2 years)
- Pharmacodynamic Effects of AZD1775 in Combination With RT and Concurrent Cisplatin(Up to 2 years)