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
