A Study of Adavosertib as Treatment for Uterine Serous Carcinoma

Study Overview
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Brief Summary
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This Phase 2b study aims to evaluate the efficacy and safety of adavosertib, an inhibitor of the tyrosine kinase WEE1, in subjects with recurrent or persistent uterine serous carcinoma (USC) who have previously received at least 1 prior platinum-based chemotherapy regimen for the management of USC.

Detailed Description
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This Phase 2b, open-label, single-arm, multi-center study will assess the efficacy and safety of adavosertib in eligible subjects with histologically confirmed recurrent or persistent USC, evidence of measurable disease as per Response Evaluation Criteria in Solid Tumors.(RECIST) v1.1, and who have received at least 1 prior platinum-based chemotherapy regimen for the management of USC. Subjects with carcinosarcomas are not eligible.

Official Title
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A Phase 2b, Open-label, Single-arm, Multi-centre Study Assessing the Efficacy and Safety of Adavosertib as Treatment for Recurrent or Persistent Uterine Serous Carcinoma

Conditions
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Uterine Serous Carcinoma

Intervention / Treatment
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* Drug: Adavosertib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must be aged ≥ 18 years of age inclusive, at the time of signing the informed consent. Histologically confirmed recurrent or persistent USC. Subjects with carcinosarcomas are not eligible. Evidence of measurable disease as per RECIST v1.1. At least 1 prior platinum-based chemotherapy regimen for the management of USC. Prior receipt of immune checkpoint inhibitors, vascular endothelial growth factor (VEGF) inhibitors and human epidermal growth factor receptor 2 (HER2) targeted therapy is allowed. There is no restriction on the number of prior lines of systemic therapy. Eastern Cooperative Oncology Group performance (ECOG) status 0-1. Life expectancy ≥ 12 weeks. Subjects must have normal organ and marrow function at baseline, within 7 days prior to study drug administration. Consent to submit and provide a mandatory Formalin-fixed paraffin-embedded tumor sample for central testing. Female subjects who are not of childbearing potential and women of childbearing potential who agree to use adequate contraceptive measures. Exclusion Criteria: Any underlying medical condition and uncontrolled intercurrent illness that would impair the ability of the subject to receive study treatment, as judged by the investigator. With the exception of alopecia, any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 at the time of starting study treatment. Unable to swallow oral medications. Spinal cord compression or metastases unless asymptomatic, stable, and not requiring steroids for at least 4 weeks prior to start of study intervention. Subjects with current signs or symptoms of bowel obstruction, including sub-occlusive disease, related to underlying disease. Any of the following cardiac diseases currently or within the last 6 months: Unstable angina pectoris Acute myocardial infarction Congestive heart failure Conduction abnormality not controlled with pacemaker or medication Significant ventricular or supraventricular arrhythmias History of Torsades de pointes unless all risk factors that contributed to Torsades have been corrected. a) Resting corrected QTc interval using the Fridericia formula (QTcF) > 480 msec, or b) congenital long QT syndrome. Immunocompromised subjects. Subjects with known active hepatitis (ie, hepatitis B or C). Prior treatment with any of the following: Cell cycle checkpoint inhibitor. Anticancer treatment drug ≤ 21 days (≤ 6 weeks for nitrosoureas or mitomycin C) or use of an investigational product within 5 half-lives prior to the first dose of adavosertib. For Programmed cell death-1 receptor (PD-1) /Programmed death-ligand 1 (PD-L1) inhibitors, a minimum of 28 days since last dose is required. Prescription or non-prescription drugs known as moderate to strong inhibitors / inducers of CYP3A4 within 2 weeks prior to the first dose of study treatment. Herbal medications 7 days prior to first dose of study treatment. Palliative radiotherapy with a limited field of radiation within 2 weeks or with wide field of radiation within 4 weeks prior to the first dose of study intervention. Major surgical procedures ≤ 28 days, or minor surgical procedures ≤ 7 days, prior to beginning study. Subjects with a known hypersensitivity or contraindication to adavosertib or any of the excipients of the product. Currently pregnant or breast-feeding.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Adavosertib<br>Subjects will receive adavosertib 300 mg administered orally, once daily on Days 1 to 5 and Days 8 to 12 of a 21-day treatment cycle. | Drug: Adavosertib<br>* The subjects will receive oral adavosertib 300 mg, once daily on Days 1 to 5 and Days 8 to 12 of a 21-day treatment cycle.<br>* Other names: AZD1775;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 for target lesions (TLs) and assessed by computed tomography (CT) or magnetic resonance imaging (MRI): Complete response (CR), Disappearance of all target lesions; Partial response (PR), >=30% decrease in the sum of the diameters of TL, taking as reference the baseline sum of diameters. | up to 75 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DoR) | The time from the date of first documented response until date of documented progression per RECIST v1.1 as assessed by BICR, or death in the absence of disease progression | up to 75 weeks | 
| Depth of Response | Depth of response is defined as best percentage change from baseline in target lesion size, which is the maximum reduction from baseline or the minimum increase from baseline in the absence of a reduction. A negative change denotes a reduction in target lesion size. | Up to 75 weeks | 
| Progression Free Survival (PFS) | The time from first dose until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdraws from study drug or receives another anticancer therapy prior to progression. PFS was assessed per RECIST v1.1 using CT or MRI scans by BICR. | Up to 75 weeks | 
| Progression Free Survival Rate at 6 Months (PFS6) | The progression free survival rate was assessed at 6 months by Kaplan-Meier estimate per RECIST v1.1. | Up to 6 months | 
| Overall Survival (OS) | The time from date of first dose until the date of death due to any cause | Up to 75 weeks | 
| Disease Control Rate (DCR) | The percentage of participants who have a best overall response of confirmed response (CR) or partial response (PR) or who have stable disease for at least 5 weeks after start of treatment, based on BICR. | Up to 75 weeks | 
| Lowest Concentration (Ctrough) of Adavosertib | Lowest plasma concentration of adavosertib was evaluated as pharmacokinetic paramerter. | Cycle 1, Day 5 and Cycle 2, Day 5 (pre-dose) (each cycle is 21 days) | 
| Maximum Concentration (Cmax) of Adavosertib | Maximum plasma concentration of adavosertib was evaluated as pharmacokinetic parameter. | Cycle 1, Day 5 and Cycle 2, Day 5 (2 hours post-dose) (each cycle is 21 days) | 
| Number of Participants With Treatment Emergent Adverse Events (AEs) | The number of participants with treatment emergent adverse events (AEs) were assessed as variable of safety and tolerability. The adverse events reported here were treatment emergent. | From baseline to post-treatment follow-up (30 days after last dose), approximately up to 114 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adavosertib, Phase 2b, open-label, single-arm