Neoplasms

All Conditions

Symptoms and General Pathology

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Rare Diseases

Carcinoma

Adenocarcinoma

Recurrence

Uterine Cervical Neoplasms

Vaginal Neoplasms

Uterine Neoplasms

Genital Neoplasms, Female

Carcinoma, Endometrioid

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Urogenital Neoplasms

Uterine Cervical Diseases

Uterine Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Vaginal Diseases

Endometrial Neoplasms

Ovarian Neoplasms

Ovarian Diseases

Adnexal Diseases

Gonadal Disorders

Endocrine System Diseases

Vaginal Cancer

Ovarian Cancer

Antineoplastic Agents

All Drugs and Chemicals

Cisplatin

Adavosertib

Enzyme Inhibitors

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.

External Beam Radiation Therapy

Stephanie Lheureux

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.

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.

Testing AZD1775 inC Combination With Radiotherapy and Chemotherapy in Cervical, Upper Vaginal and Uterine Cancers

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)

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.

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

To evaluate the pharmacodynamic effects of AZD1775 drugs when administered in combination with radiotherapy and concurrent cisplatin. 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.

To obtain preliminary information about the progression-free survival of AZD1775 in combination with radiotherapy and concurrent cisplatin in women with locally advanced gynecological cancer. Progression is defined a clinical or radiological using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

National Cancer Institute (NCI)

Through regular investigator assessment, regular laboratory testing, etc. Frequency and severity of adverse events were tabulated using counts and proportions.

Patients undergo external beam radiation therapy (45-50Gy) on days 1-5, receive 100mg AZD1775 PO on days 1, 3, and 5, and receive 40 mg/m2 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.

Treatment (Radiation Therapy, AZD1775 3 Days/Week, Cisplatin) Dose Level 1

Patients undergo external beam radiation therapy (45-50Gy) on days 1-5, receive 100mg AZD1775 PO on days 3 and 5, and receive 40 mg/m2 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.

Treatment (Radiation Therapy, AZD1775 2 Days/Week, Cisplatin) Dose Level -1

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Canada

United States

Region of Enrollment

0-Normal activity. Fully active, able to carry on all pre-disease performance w/o restriction. 1-Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory \& able to carry out work of a light/sedentary nature. 2-In bed \<50% of the time. Ambulatory \& capable of all self-care, but unable to carry out any work activities. Up \& about \>50% of waking hours. 3-In bed \>50% of the time. Capable of only limited self-care, confined to bed/chair \>50% of waking hours. 4-100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed /chair. 5-Dead.

ECOG Performance Status

Primary Site

Prior Therapy

Describes the extent of cancer in the body. The extent increases with stage.

FIGO Stage

The grade of a cancer tells you how much the cancer cells look like normal cells. Lower grades look most like normal cells while higher grades look more abnormal.

Grade

Histology

The main limitation of our study is the small number of patients enrolled due to premature closure; yet the study showed the limiting toxicities of this triplet combination.

Dr. Stephanie Lheureux, PI

Patients undergo external beam radiation therapy on days 1-5, receive AZD1775 PO on days 1, 3, and 5, and receive 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.

Patients undergo external beam radiation therapy on days 1-5, receive AZD1775 PO on days 3 and 5, and receive 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.

Participants that were evaluable for response.

Recommended Phase 2 Dose Defined as the Dose Level With < 1/6 Patients With Dose Limiting Toxicities

All Grade 1-2 Toxicities

Related Grade 1-2 Toxicities

All Grade 3-4 Toxicities

Related Grade 3-4 Toxicities

Frequency and Severity of AZD1775 Toxicity Events in Patients With Gynecological Cancer in Combination With Standard RT and Concurrent Cisplatin

Not analyzed as samples were not collected, therefore no data are available.

Pharmacodynamic Effects of AZD1775 in Combination With RT and Concurrent Cisplatin

4 Months Post Treatment

2 Years Post Treatment

Progression-free Survival

Overall Study

Spots Global Cancer Trial Database for stage i vaginal cancer ajcc v6 and v7