Uterine Serous Carcinoma
Conditions
Keywords
Adavosertib, Phase 2b, open-label, single-arm
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.
Interventions
DRUGAdavosertib
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.
Sponsors
Parexel
AstraZeneca
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 130 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | up to 75 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Depth of Response | Up to 75 weeks | 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. |
| Progression Free Survival (PFS) | Up to 75 weeks | 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. |
| Progression Free Survival Rate at 6 Months (PFS6) | Up to 6 months | The progression free survival rate was assessed at 6 months by Kaplan-Meier estimate per RECIST v1.1. |
| Overall Survival (OS) | Up to 75 weeks | The time from date of first dose until the date of death due to any cause |
| Duration of Response (DoR) | up to 75 weeks | 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 |
| Lowest Concentration (Ctrough) of Adavosertib | Cycle 1, Day 5 and Cycle 2, Day 5 (pre-dose) (each cycle is 21 days) | Lowest plasma concentration of adavosertib was evaluated as pharmacokinetic paramerter. |
| Maximum Concentration (Cmax) of Adavosertib | Cycle 1, Day 5 and Cycle 2, Day 5 (2 hours post-dose) (each cycle is 21 days) | Maximum plasma concentration of adavosertib was evaluated as pharmacokinetic parameter. |
| Number of Participants With Treatment Emergent Adverse Events (AEs) | From baseline to post-treatment follow-up (30 days after last dose), approximately up to 114 weeks | 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. |
| Disease Control Rate (DCR) | Up to 75 weeks | 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. |
Countries
Canada, France, Italy, Spain, United States
Participant flow
Recruitment details
The study was conducted at 28 sites in 5 countries (United States, Canada, France, Italy and Spain) from 30-November-2020 to 07-February-2023.
Pre-assignment details
Participants had been through a screening period of 28 days, followed by assessments as per schedule of activities.
Participants by arm
| Arm | Count |
|---|---|
| Adavosertib Participants received adavosertib 300 mg administered orally, once daily on Days 1 to 5 followed by 2 days off and Days 8 to 12 (21 days treatment cycle). | 109 |
| Total | 109 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Other | 2 |
| Overall Study | Withdrawal by Subject | 16 |
Baseline characteristics
| Characteristic | Adavosertib |
|---|---|
| Age, Continuous | 68.8 years STANDARD_DEVIATION 7.05 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 98 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants |
| Race/Ethnicity, Customized Black African or American | 9 Participants |
| Race/Ethnicity, Customized Missing | 4 Participants |
| Race/Ethnicity, Customized Other | 3 Participants |
| Race/Ethnicity, Customized White | 92 Participants |
| Sex: Female, Male Female | 109 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 47 / 109 |
| other Total, other adverse events | 109 / 109 |
| serious Total, serious adverse events | 53 / 109 |
Outcome results
Primary
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.
Time frame: up to 75 weeks
Population: FAS, which included all participants who received at least one (non-zero) dose of study treatment. Here, overall number of participants analyzed signifies the participant with available data that were analyzed for the outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Adavosertib | Objective Response Rate (ORR) | 26 Percentage of participants |
Secondary
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.
Time frame: Up to 75 weeks
Population: FAS, which included all participants who received at least one (non-zero) dose of study treatment. Here, overall number of participants analyzed signifies the participant with available data that were analyzed for the outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Adavosertib | Depth of Response | -20.8 Percentage change | Standard Deviation 31.6 |
Secondary
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.
Time frame: Up to 75 weeks
Population: FAS, which included all subjects who received at least one (non-zero) dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Adavosertib | Disease Control Rate (DCR) | 51.4 Percentage of participants |
Secondary
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
Time frame: up to 75 weeks
Population: FAS, which included all participants who received at least one (non-zero) dose of study treatment and had a confirmed response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Adavosertib | Duration of Response (DoR) | 4.7 Months |
Secondary
Lowest Concentration (Ctrough) of Adavosertib
Lowest plasma concentration of adavosertib was evaluated as pharmacokinetic paramerter.
Time frame: Cycle 1, Day 5 and Cycle 2, Day 5 (pre-dose) (each cycle is 21 days)
Population: The pharmacokinetic analysis set included all dosed participants who had at least one measurable plasma concentration collected post-dose which was obtained without any deviation or event thought to significantly affect the pharmacokinetic analysis. Here, overall number of participants analyzed signifies in each row the participant with available data, that was analyzed for specific time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Adavosertib | Lowest Concentration (Ctrough) of Adavosertib | Cycle 1 Day 5 | 307.2 nanomole (nM) | Geometric Coefficient of Variation 105.6 |
| Adavosertib | Lowest Concentration (Ctrough) of Adavosertib | Cycle 2 Day 5 | 328.7 nanomole (nM) | Geometric Coefficient of Variation 70.3 |
Secondary
Maximum Concentration (Cmax) of Adavosertib
Maximum plasma concentration of adavosertib was evaluated as pharmacokinetic parameter.
Time frame: Cycle 1, Day 5 and Cycle 2, Day 5 (2 hours post-dose) (each cycle is 21 days)
Population: The pharmacokinetic analysis set included all dosed participants who had at least one measurable plasma concentration collected post-dose which was obtained without any deviation or event thought to significantly affect the pharmacokinetic analysis. Here, overall number of participants analyzed in each row signifies the participant with available data, that was analyzed for specific time points.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Adavosertib | Maximum Concentration (Cmax) of Adavosertib | Cycle 1 Day 5 | 1115.9 nM | Geometric Coefficient of Variation 82.1 |
| Adavosertib | Maximum Concentration (Cmax) of Adavosertib | Cycle 2 Day 5 | 1356.5 nM | Geometric Coefficient of Variation 59.3 |
Secondary
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.
Time frame: From baseline to post-treatment follow-up (30 days after last dose), approximately up to 114 weeks
Population: FAS, which included all participants who received at least one (non-zero) dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Adavosertib | Number of Participants With Treatment Emergent Adverse Events (AEs) | Any AE leading to dose modification of IP | 79 Participants |
| Adavosertib | Number of Participants With Treatment Emergent Adverse Events (AEs) | Any AE | 109 Participants |
| Adavosertib | Number of Participants With Treatment Emergent Adverse Events (AEs) | Any AE possibly related to treatment | 106 Participants |
| Adavosertib | Number of Participants With Treatment Emergent Adverse Events (AEs) | Any AE with outcome = death | 4 Participants |
| Adavosertib | Number of Participants With Treatment Emergent Adverse Events (AEs) | Any AE with outcome = death, possibly related to treatment | 1 Participants |
| Adavosertib | Number of Participants With Treatment Emergent Adverse Events (AEs) | Any AE of Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher | 75 Participants |
| Adavosertib | Number of Participants With Treatment Emergent Adverse Events (AEs) | Any AE of CTCAE grade 3 or higher, possibly related to treatment | 66 Participants |
| Adavosertib | Number of Participants With Treatment Emergent Adverse Events (AEs) | Any AE leading to discontinuation of IP | 19 Participants |
| Adavosertib | Number of Participants With Treatment Emergent Adverse Events (AEs) | Any AE leading to discontinuation of IP, possibly related to treatment | 16 Participants |
| Adavosertib | Number of Participants With Treatment Emergent Adverse Events (AEs) | Any serious adverse event (SAE) (including events with outcome = death) | 50 Participants |
| Adavosertib | Number of Participants With Treatment Emergent Adverse Events (AEs) | Any SAE (including events with outcome = death), possibly related to treatment | 29 Participants |
| Adavosertib | Number of Participants With Treatment Emergent Adverse Events (AEs) | Any SAE leading to discontinuation of investigational product (IP) | 10 Participants |
| Adavosertib | Number of Participants With Treatment Emergent Adverse Events (AEs) | Any SAE leading to discontinuation of IP, possibly related to treatment | 8 Participants |
| Adavosertib | Number of Participants With Treatment Emergent Adverse Events (AEs) | Any AE leading to dose reduction of IP | 62 Participants |
| Adavosertib | Number of Participants With Treatment Emergent Adverse Events (AEs) | Any AE leading to dose interruption of IP | 72 Participants |
| Adavosertib | Number of Participants With Treatment Emergent Adverse Events (AEs) | Any AE leading to dose interruption possibly related to treatment | 62 Participants |
| Adavosertib | Number of Participants With Treatment Emergent Adverse Events (AEs) | Any AE leading to dose reduction possibly related to treatment | 60 Participants |
Secondary
Overall Survival (OS)
The time from date of first dose until the date of death due to any cause
Time frame: Up to 75 weeks
Population: FAS, which included all participants who received at least one (non-zero) dose of study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Adavosertib | Overall Survival (OS) | 9.6 Months |
Secondary
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.
Time frame: Up to 75 weeks
Population: FAS, which included all participants who received at least one (non-zero) dose of study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Adavosertib | Progression Free Survival (PFS) | 2.8 Months |
Secondary
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.
Time frame: Up to 6 months
Population: FAS, which included all participants who received at least one (non-zero) dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Adavosertib | Progression Free Survival Rate at 6 Months (PFS6) | 18.1 Percentage |