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

 -  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: serum bilirubin within normal limits (WNL) or =< 1.5 x ULN in
 patients with liver metastases; or total bilirubin =< 3.0 x ULN with direct bilirubin
 WNL in patients with documented Gilbert's syndrome

 -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
 [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]):
 Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x upper limit
 of normal (ULN) or =< 5 x ULN if known hepatic metastases

 -  Creatinine clearance (CrCl) >= 60 mL/min as calculated by the Cockcroft-Gault method

 -  Patients must be able to swallow whole capsules

 -  The effects of AZD1775 on the developing human fetus are unknown; the preclinical
 chromosomal aberrations assays have shown potential to induce chromosomal aberrations;
 in addition, cisplatin and radiotherapy are known to be teratogenic; for this reason,
 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 is participating in this
 study, she should inform her treating physician immediately

 -  Females with child-bearing potential must have had a negative serum pregnancy test
 result =< 28 days prior to the first dose of study treatment

 -  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 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

 -  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