Clinical trial NCT04590248: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Uterine Serous Carcinoma
Keywords: Adavosertib
Phase 2b
open-label
single-arm
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Parexel
First posted: 2020-10-19
Enrollment: 109
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: up to 75 weeks
Secondary outcomes:
measure: Duration of Response (DoR)
timeFrame: up to 75 weeks
measure: Depth of Response
timeFrame: Up to 75 weeks
measure: Progression Free Survival (PFS)
timeFrame: Up to 75 weeks
measure: Progression Free Survival Rate at 6 Months (PFS6)
timeFrame: Up to 6 months
measure: Overall Survival (OS)
timeFrame: Up to 75 weeks
measure: Disease Control Rate (DCR)
timeFrame: Up to 75 weeks
measure: Lowest Concentration (Ctrough) of Adavosertib
timeFrame: Cycle 1, Day 5 and Cycle 2, Day 5 (pre-dose) (each cycle is 21 days)
measure: Maximum Concentration (Cmax) of Adavosertib
timeFrame: Cycle 1, Day 5 and Cycle 2, Day 5 (2 hours post-dose) (each cycle is 21 days)
measure: Number of Participants With Treatment Emergent Adverse Events (AEs)
timeFrame: From baseline to post-treatment follow-up (30 days after last dose), approximately up to 114 weeks
Other outcomes:
Locations:
city: Burbank
country: United States
facility: Research Site
state: California
city: Duarte
country: United States
facility: Research Site
state: California
city: La Jolla
country: United States
facility: Research Site
state: California
city: West Hollywood
country: United States
facility: Research Site
state: California
city: Aurora
country: United States
facility: Research Site
state: Colorado
city: Iowa City
country: United States
facility: Research Site
state: Iowa
city: Covington
country: United States
facility: Research Site
state: Louisiana
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: Rochester
country: United States
facility: Research Site
state: Minnesota
city: New Brunswick
country: United States
facility: Research Site
state: New Jersey
city: Bronx
country: United States
facility: Research Site
state: New York
city: New York
country: United States
facility: Research Site
state: New York
city: Spokane
country: United States
facility: Research Site
state: Washington
city: Vancouver
country: United States
facility: Research Site
state: Washington
city: Toronto
country: Canada
facility: Research Site
city: Dijon cedex
country: France
facility: Research Site
city: Marseille
country: France
facility: Research Site
city: Nice
country: France
facility: Research Site
city: Pierre Benite
country: France
facility: Research Site
city: Saint Herblain
country: France
facility: Research Site
city: Milan
country: Italy
facility: Research Site
city: Napoli
country: Italy
facility: Research Site
city: Roma
country: Italy
facility: Research Site
city: A Coruña
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Pozuelo de Alarcón
country: Spain
facility: Research Site
Study officials:
affiliation: Dana-Farber Cancer Institute
name: Joyce Liu, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.