| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Recurrent or persistent Uterine Serous Carcinoma (USC) in patients who have previously received at least 1 prior platinum-based chemotherapy regimen for the treatment of USC |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10038604 |
| E.1.2 | Term | Reproductive system and breast disorders |
| E.1.2 | System Organ Class | 10038604 - Reproductive system and breast disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10029104 |
| E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of adavosertib by the assessment of objective response rate (ORR). |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate efficacy of adavosertib by assessment of Duration of Response (DoR)
- To evaluate efficacy of adavosertib by assessment of depth of response.
- To evaluate the efficacy of adavosertib by assessment of Progression Free Survival (PFS).
- To evaluate the efficacy of adavosertib by assessment of Proportion of patients alive and progression free at 6 months (PFS6)
- To evaluate the efficacy of adavosertib by assessment of Overall Survival (OS)
- To evaluate the efficacy of adavosertib by assessment of Disease Control Rate (DCR)
- To evaluate the pharmacokinetics of Adavosertib
- To assess the safety and tolerability of adavosertib in participants with USC. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Capable of giving signed informed consent and has given signed
informed consent as described in Appendix C which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
2. Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional
genetic research that supports Genomic Initiative.
3. Participant must be aged > = 18 years of age inclusive, at the time of signing the informed consent
4. Histologically confirmed recurrent or persistent USC. For the purposes of this study, participants with endometrial carcinoma of mixed histology where the serous component comprises at least 10% of the tumour will be considered eligible. Participants with carcinosarcomas are not eligible.
5. Evidence of measurable disease as per RECIST v1.1 defined as at least
one lesion, not previously irradiated, that can be accurately measured in at least one dimension (longest diameter to be recorded) as = 10 mm with computed tomography (CT) scan or magnetic resonance imaging (MRI) (except lymph nodes which must have short axis = 15 mm) and which is suitable for accurate repeated measurements.
6. At least 1 prior platinum-based chemotherapy regimen for the management of USC (there is no restriction on the number of prior lines of systemic therapy that a participant may have previously received, and the platinum-based chemotherapy may have been given in the adjuvant setting). Chemotherapy administered only in conjunction with primary radiotherapy as a radiosensitiser should not count as a systemic regimen.
Prior anticancer therapies (IOs, eg, immune checkpoint inhibitors,
vascular endothelial growth factor (VEGF) inhibitors and HER2 targeted therapy) are allowed.
Participants who have known MSI-H or dMMR tumours will not be eligible unless they have already received prior therapy with pembrolizumab or another PD-1/PD-L1 immune checkpoint inhibitor, in territories where this treatment is available for this indication, or are deemed not to be a candidate for immune checkpoint therapy.
7. Eastern Cooperative Oncology Group (ECOG) performance status 0-1
8. Life expectancy = 12 weeks.
9. Participants must have normal organ and marrow function at baseline,
as defined below by laboratory values within 7 days prior to study drug(s) administration:
- Absolute neutrophil count (ANC) >= 1.5 × 10^9 /L
- Haemoglobin (Hb) >= 9 g/dL
- Platelet count >= 100 × 10^9 /L
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
>= 3 x upper limit of normal (ULN) or <= 5 x ULN if known hepatic metastases
- Serum bilirubin within normal limits (WNL) or <=1.5 x ULN in patients
with liver metastases; or total bilirubin = 3.0 x ULN with direct bilirubin
WNL in patients with documented Gilbert's Syndrome
- Serum creatinine <= 1.5 x ULN, or measured creatinine clearance (CrCl)
>= 45 mL/min as estimated using either the Cockcroft-Gault method, a 24-hour urine test or another validated test as per local practice (confirmation of creatinine clearance is only required when creatinine is > 1.5 x institutional ULN).
10. Consent to submit and provide a mandatory FFPE tumour sample for
central testing. The site must confirm that the FFPE sample is available prior to dosing
11. Female patients who are not of childbearing potential and women of
childbearing potential who agree to use adequate contraceptive measures from the time of signing the ICF and until 1 month after study treatment discontinuation, who are not breastfeeding, and who have a negative serum or urine pregnancy test during screening and confirmed on Cycle 1, Day 1 (prior to the start of study treatment). |
|
| E.4 | Principal exclusion criteria |
1. Any underlying medical condition that would impair the ability of the
participant to receive study treatment, as judged by the investigator.
2. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
3. Common Terminology Criteria for Adverse Events (CTCAE) v5.0 Grade > 1 toxicity from prior therapy (except alopecia, anorexia or CTCAE grade 2 peripheral neuropathy).
4. Unable to swallow oral medications
5. History of another primary malignancy (exceptions are detailed in Section 5.2 of the Protocol)
6. Spinal cord compression or metastases unless asymptomatic, stable,
and not requiring steroids for at least 4 weeks prior to start of study intervention.
7. Patients with current (or within 28 days prior to Cycle 1, Day 1) signs
or symptoms of bowel obstruction, including sub-occlusive disease, related to underlying disease.
8. Any of the following cardiac diseases currently or within the last 6
months:
- Unstable angina pectoris
- Acute myocardial infarction
- Congestive heart failure >= Class 2 (as defined by New York Heart
Association)
- Conduction abnormality not controlled with pacemaker or medication
- Significant ventricular or supraventricular arrhythmias (patients with
chronic rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible)
9. History of Torsades de pointes unless all risk factors that contributed
to Torsades have been corrected.
10. a) Resting corrected QTc interval using the Fridericia formula (QTcF) > 480 msec (as calculated per institutional standards) obtained from an
electrocardiogram (ECG) (NOTE: if one ECG demonstrates a QTcF > 480 msec, then a mean QTcF of <= 480 msec obtained from 3 ECGs 2-5
minutes apart, is required at study entry), or b) congenital long QT syndrome.
11. Immunocompromised patients, eg, patients who are known to be serologically positive for human immunodeficiency virus (HIV).
12. Patients with known active hepatitis (ie, hepatitis B or C):
- Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen (HBsAg) result. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible
- Patients positive for hepatitis C virus (HCV) antibody are eligible only if
polymerase chain reaction is negative for HCV RNA
13. Use of 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 PD-1/PD-L1 inhibitors, a minimum of 28 days since last dose is required.
Patients on luteinising-hormone releasing hormone analogue treatment
for more than 6 months are allowed entry into the study and may continue at the discretion of the investigator.
14. Palliative radiotherapy with a limited field of radiation within 2 weeks or with wide field of radiation or to more than 30% of bone marrow within 4 weeks prior to the first dose of study intervention.
15. Major surgical procedures <= 28 days, or minor surgical procedures <=
7 days, prior to beginning study treatment. No waiting period required following port-a-cath or other central venous access placement.
16. Prior receipt of a cell cycle checkpoint inhibitor (eg, CHK1, WEE1, or ATR inhibition)
17. Has had prescription or non-prescription drugs or other products
known to be moderate to strong inhibitors/inducers of CYP3A4. If the
drug could be discontinued, then a wash out of >= 2 weeks prior to Day 1 of dosing is required and the drug will be withheld throughout the study until 2 weeks after the last dose of study drug.
18. Use of herbal medications 7 days prior to first dose of study treatment.
FOR MORE EXCLUSION CRITERIA, PLEASE REFER TO THE PROTOCOL |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall Response Rate (ORR) is defined as the proportion of participants 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After start of treatment (Cycle 1, Day 1), scans will be repeated every 6 weeks (±7 days) for the first 48 weeks and every 9 weeks (±7 days) thereafter, until objective radiological disease progression by investigator assessment using RECIST v1.1 |
|
| E.5.2 | Secondary end point(s) |
1. Duration of Response (DoR) is defined as the time from the date of first documented response until date of documented progression per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as assessed by Blinded Independent Central Review (BICR), or death in the absence of disease progression.
2. Depth of response is defined as the best percentage change from baseline in Target Lesions.
3. Progression-free survival (PFS) is defined as time from date of first dose until progression per RECIST v1.1 as assessed by BICR, or death due to any cause.
4. Disease control rate (DCR) is defined as the percentage of participants who have a best overall response of CR (confirmed response) or PR (partial response) or who have stable disease for at least 5 weeks after start of treatment (to allow for an early assessment within the assessment window).
5. Overall survival (OS) is defined as time from date of first dose until the date of death due to any cause
6. Progression free at 6 months (PFS6) is defined as the proportion of participants alive and progression free at 6 months, and will be reported as the Kaplan-Meier estimate of PFS per RECIST v1.1 as assessed by BICR at 6 months
7. Plasma concentration of adavosertib
8. Safety will be evaluated in terms of AEs, vital signs, clinical laboratory assessments, ECGs, and AEs leading to dose interruptions, dose reductions, and dose discontinuations. Vital signs parameters include systolic and diastolic blood pressure, and
pulse as well as heart rate, body temperature, body weight, height, and BMI.
Laboratory parameters include clinical chemistry and haematology
parameters as well as urinalysis. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-6: After start of treatment (Cycle 1, Day 1), scans will be repeated
every 6 weeks (±7 days) for the first 48 weeks and every 9 weeks (±7 days) thereafter, until objective radiological disease progression by investigator assessment using RECIST v1.1.
7: Pre dose and 2 hours post dose on Day 5 of Cycles 1 and 2
8: From baseline to post treatment follow-up (30 days after last dose) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Samples collected for the Genomic initiative are considered primary use and will be whole exome or whole genome sequenced. Analysis will be performed for both known and novel health related genes and this broad genetic research will not restrict to disease or drug. Sequencing data generated is for research purposes only and cannot be used for clinical decision making and there will not be any clinical endpoints delivered to the study, as a result of testing performed |
| I campioni raccolti per l'iniziativa Genomic sono considerati di uso primario e sarà sequenziato l'intero esoma o l'intero genoma.L'analisi verrà effettuata sia per geni noti che per geni nuovi relativi allo stato di salute e questa ampia ricerca genetica non si limiterà solo alle malattie o ai farmaci. I dati di sequenziamento generati sono solo a scopo di ricerca e non possono essere utilizzati per il processo decisionale clinico e non ci sarà alcun endpoint clinico rilasciato per lo studio e |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 23 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| France |
| Germany |
| Italy |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 23 |
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