A Study of Adavosertib as Treatment for Uterine Serous Carcinoma (ADAGIO)

• ClinicalTrials.gov Identifier: NCT04590248
• Recruitment Status: Completed
• First Posted: October 19, 2020
• Last Update Posted: February 23, 2023
• Sponsor: AstraZeneca
• Collaborator: Parexel
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: September 22, 2020
• First Posted Date: October 19, 2020
• Last Update Posted Date: February 23, 2023
• Actual Study Start Date: November 30, 2020
• Actual Primary Completion Date: May 23, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 15, 2020)

Objective response rate (ORR) [ Time Frame: From baseline to approximately 24 months ]

The percentage of subjects with measurable disease at baseline who have a confirmed complete response (CR) or partial response (PR), as determined by Blinded Independent Central Review (BICR) per RECIST v1.1

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 15, 2020)

• Duration of response (DoR) [ Time Frame: From baseline to approximately 24 months ]
  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
• Depth of response [ Time Frame: From baseline to approximately 24 months ]
  Absolute change and percentage change from baseline will be based on RECIST v1.1 target lesions measurements
• Progression free survival (PFS) [ Time Frame: From baseline to approximately 24 months ]
  The time from first dose until the date of objective disease progression or death (by any cause in the absence of progression), derived using RECIST v1.1 assessments based on BICR data
• PFS6 [ Time Frame: From baseline up to 6 months ]
  The proportion of subjects alive and progression free at 6 months by Kaplan-Meier estimate
• Overall survival (OS) [ Time Frame: From baseline to approximately 24 months ]
  The time from date of first dose until the date of death due to any cause
• Disease control rate (DCR) [ Time Frame: From baseline to approximately 24 months ]
  The percentage of subjects who have a best response of confirmed CR or PR or who have stable disease for at least 5 weeks after start of treatment, based on BICR data
• Lowest concentration (Ctrough) of adavosertib [ Time Frame: Pre-dose (60 minutes prior to dosing) on Day 5 of Cycles 1 and 2 (each cycle is 21 days) ]
  Lowest plasma concentration of adavosertib before next dose
• Maximum concentration (Cmax) of adavosertib [ Time Frame: 2 hours post-dose on Day 5 of Cycles 1 and 2 (each cycle is 21 days) ]
  Maximum plasma concentration of adavosertib after oral dosing
• Number of subjects with adverse events (AE) and serious AEs [ Time Frame: From baseline to post-treatment follow-up (30 days after last dose) ]
  Assessment of AEs, vital signs, clinical laboratory values, electrocardiogram findings, and AEs leading to dose interruptions, dose reductions, and dose discontinuations

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Adavosertib as Treatment for Uterine Serous Carcinoma
• Official Title: 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
• Brief Summary: 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: 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.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Uterine Serous Carcinoma

Intervention

Drug: Adavosertib

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.

Other Name: AZD1775

Study Arms

Experimental: Adavosertib

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.

Intervention: Drug: Adavosertib

• Publications *: Liu J, Oza AM, Colombo N, Oaknin A. ADAGIO: a phase IIb international study of the Wee1 inhibitor adavosertib in women with recurrent or persistent uterine serous carcinoma. Int J Gynecol Cancer. 2022 Jan;32(1):89-92. doi: 10.1136/ijgc-2021-003144. Epub 2021 Oct 29.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 6, 2022): 109
• Original Estimated Enrollment (submitted: October 15, 2020): 120
• Actual Study Completion Date: February 7, 2023
• Actual Primary Completion Date: May 23, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Subjects must be aged ≥ 18 years of age inclusive, at the time of signing the informed consent.
2. Histologically confirmed recurrent or persistent USC. Subjects with carcinosarcomas are not eligible.
3. Evidence of measurable disease as per RECIST v1.1.
4. 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.
5. Eastern Cooperative Oncology Group performance (ECOG) status 0-1.
6. Life expectancy ≥ 12 weeks.
7. Subjects must have normal organ and marrow function at baseline, within 7 days prior to study drug administration.
8. Consent to submit and provide a mandatory Formalin-fixed paraffin-embedded tumor sample for central testing.
9. Female subjects who are not of childbearing potential and women of childbearing potential who agree to use adequate contraceptive measures.

Exclusion Criteria:

1. 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.
2. 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.
3. Unable to swallow oral medications.
4. Spinal cord compression or metastases unless asymptomatic, stable, and not requiring steroids for at least 4 weeks prior to start of study intervention.
5. Subjects with current signs or symptoms of bowel obstruction, including sub-occlusive disease, related to underlying disease.

6. 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
7. History of Torsades de pointes unless all risk factors that contributed to Torsades have been corrected.
8. a) Resting corrected QTc interval using the Fridericia formula (QTcF) > 480 msec, or b) congenital long QT syndrome.
9. Immunocompromised subjects.
10. Subjects with known active hepatitis (ie, hepatitis B or C).

11. 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.
12. 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.
13. Major surgical procedures ≤ 28 days, or minor surgical procedures ≤ 7 days, prior to beginning study.
14. Subjects with a known hypersensitivity or contraindication to adavosertib or any of the excipients of the product.
15. Currently pregnant or breast-feeding.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years to 130 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, France, Italy, Spain, United States
• Removed Location Countries: Germany

Administrative Information

• NCT Number: NCT04590248
• Other Study ID Numbers: D601HC00002
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)

Time Frame

AstraZeneca will meet or exceed data availability as per the commitments made to the European Federation of Pharmaceutical Industries and Associations Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Access Criteria

When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

• URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

• Current Responsible Party: AstraZeneca
• Original Responsible Party: Same as current
• Current Study Sponsor: AstraZeneca
• Original Study Sponsor: Same as current
• Collaborators: Parexel

Investigators

• Principal Investigator: Joyce Liu, MD, MPH; Dana-Farber Cancer Institute

• PRS Account: AstraZeneca
• Verification Date: February 2023