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

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

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.

Study Overview

• Status: Completed
• Conditions: Uterine Serous Carcinoma
• Intervention / Treatment: Drug: Adavosertib

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
• Enrollment (Actual): 109
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Toronto, Canada, M5G 2M9
    • Research Site
• France
  • Dijon cedex, France, 21079
    • Research Site
  • Marseille, France, 13273
    • Research Site
  • Nice, France, 6189
    • Research Site
  • Pierre Benite, France, 69495
    • Research Site
  • Saint Herblain, France, 44805
    • Research Site
• Italy
  • Milan, Italy, 20141
    • Research Site
  • Napoli, Italy, 80131
    • Research Site
  • Roma, Italy, 00168
    • Research Site
• Spain
  • A Coruña, Spain, 15009
    • Research Site
  • Barcelona, Spain, 08035
    • Research Site
  • Barcelona, Spain, 08036
    • Research Site
  • Pozuelo de Alarcón, Spain, 28223
    • Research Site
• United States
  • California
    • Burbank, California, United States, 91505
      • Research Site
    • Duarte, California, United States, 91010
      • Research Site
    • La Jolla, California, United States, 92093
      • Research Site
    • West Hollywood, California, United States, 90048
      • Research Site
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Research Site
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Research Site
  • Louisiana
    • Covington, Louisiana, United States, 70433
      • Research Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Research Site
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Research Site
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Research Site
  • New York
    • Bronx, New York, United States, 10467
      • Research Site
    • New York, New York, United States, 10065
      • Research Site
  • Washington
    • Spokane, Washington, United States, 99202
      • Research Site
    • Vancouver, Washington, United States, 98684
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 130 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	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 Names: AZD1775

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Parexel
• Investigators: Principal Investigator: Joyce Liu, MD, MPH, Dana-Farber Cancer Institute

Publications and helpful links

General 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.

Helpful Links

• D601HC00002_CSR_Synopsis_redacted
• Statistical Analysis Plan (SAP)
• CSP

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2020
• Primary Completion (Actual): May 23, 2022
• Study Completion (Actual): February 7, 2023

Study Registration Dates

• First Submitted: September 22, 2020
• First Submitted That Met QC Criteria: October 15, 2020
• First Posted (Actual): October 19, 2020

Study Record Updates

• Last Update Posted (Actual): August 14, 2023
• Last Update Submitted That Met QC Criteria: August 11, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: open-label; Phase 2b; single-arm; Adavosertib
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Cystadenocarcinoma; Neoplasms, Cystic, Mucinous, and Serous; Carcinoma; Cystadenocarcinoma, Serous; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Adavosertib
• Other Study ID Numbers: D601HC00002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD 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.

IPD Sharing 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.

IPD Sharing 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.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No