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Trial registered on ANZCTR


Registration number
ACTRN12619001185156
Ethics application status
Approved
Date submitted
12/08/2019
Date registered
22/08/2019
Date last updated
11/06/2024
Date data sharing statement initially provided
22/08/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Targeting Cyclin E1 altered high grade serous ovarian cancer (HGSC)
Scientific title
A Phase II signal-seeking trial targeting recurrent high grade serous ovarian cancer (HGSC) with Cyclin E1 (CCNE1) over-expression with and without gene amplification to determine the clinical benefit rate.
Secondary ID [1] 298996 0
Nil known
Universal Trial Number (UTN)
Trial acronym
IGNITE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Ovarian Cancer 314002 0
Cancer of the falllopian tube 314003 0
Primary peritoneal cancer 314052 0
Condition category
Condition code
Cancer 312392 312392 0 0
Ovarian and primary peritoneal

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients will be recruited to one of two cohorts based on the results of the pre-screening tissue testing:
Cohort 1: Cyclin E1 over-expressed and amplified; or
Cohort 2: Cyclin E1 over-expressed and non-amplified
Cohort 3: Cyclin E1 over-expressed treated with ceralasertib

Cohort 1 & 2: Patients will receive 300mg of adavosertib in the form of a daily oral tablet to be taken on Days 1-5 and then Days 8-12 of each 21-day cycle, for a maximum duration of 24 months (based on clinical response at the discretion of the investigator). Adherence to the intervention is recorded through to use of patient diaries that are to be brought to each of the patient's clinic visits (every 21 days while receiving adavosertib) along with any unused drug tablets remaining for that cycle also being brought to clinic.

Cohort 3: Ceralasertib will be administered orally 160 mg twice daily, starting on Day 1 until Day 14, in each 28 day treatment cycle, for a maximum duration of 24 months (based on clinical response at the discretion of the investigator). Adherence to the intervention is recorded through to use of patient diaries that are to be brought to each of the patient's clinic visits along with any unused drug tablets remaining for that cycle also being brought to clinic.

Intervention code [1] 315263 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 321026 0
To determine the clinical benefit rate (CBR, defined as absence of progression for = 18 weeks by RECIST 1.1 among patients with measurable disease and GCIG CA-125 criteria among patients without measurable disease)
Timepoint [1] 321026 0
18 weeks post-intervention commencement
Primary outcome [2] 338506 0
To determine the 16 week ORR of ceralasertib as a single agent in women with recurrent platinum resistant HGSC with Cyclin E1 over-expression regardless of copy number status.
ORR will be determined by RECIST 1.1 among patients with measurable disease. In patients with GCIG CA-125 evaluable disease only, at least 50% reduction as per GCIG criteria will be considered as a response. Patients who died before 16 weeks will be considered as not having responded at 16 weeks.
Timepoint [2] 338506 0
Primary outcome [3] 338507 0
To determine the 16 week ORR of ceralasertib as a single agent in women with recurrent platinum resistant HGSC with Cyclin E1 over-expression regardless of copy number status.
ORR will be determined by RECIST 1.1 among patients with measurable disease. In patients with GCIG CA-125 evaluable disease only, at least 50% reduction as per GCIG criteria will be considered as a response. Patients who died before 16 weeks will be considered as not having responded at 16 weeks.
Timepoint [3] 338507 0
16 weeks post-intervention commencement
Secondary outcome [1] 373732 0
To determine the frequency and severity of adverse events with study drug in the study population (according to CTCAE v5.0, overall and per cohort) through patient reported adverse events or any patient hospitalisations outside of the treatment schedule.
Timepoint [1] 373732 0
Daily from Day 1 of Cycle 1 until End of Treatment.
Secondary outcome [2] 373733 0
To determine progression free survival.
Timepoint [2] 373733 0
Collected 2 years after last patient has commenced treatment
Secondary outcome [3] 373734 0
To determine the best overall response (BOR) rate according to RECIST 1.1 among patients with measurable disease and GCIG CA-125 criteria among patients without measurable disease
Timepoint [3] 373734 0
Collected 2 years after last patient has commenced treatment
Secondary outcome [4] 373735 0
To determine the duration of response (DoR) according to RECIST 1.1 among patients with measurable disease and GCIG CA-125 criteria among patients without measurable disease
Timepoint [4] 373735 0
Collected 2 years after last patient has commenced treatment
Secondary outcome [5] 373737 0
To compare the time to progression on study drug compared to the time to progression on the most recent line of chemotherapy prior to study enrolment.
Timepoint [5] 373737 0
Collected 2 years after last patient has commenced treatment
Secondary outcome [6] 373948 0
To determine overall survival.
Timepoint [6] 373948 0
Collected 2 years after last patient has commenced treatment

Eligibility
Key inclusion criteria
1. Patient has provided written informed consent for the Main part of the study
2. Patient continues to meet all pre-screening inclusion criteria
3. Patient’s tumour has a confirmed Cyclin E over-expression defined by IHC
- Tumours with Cyclin E over-expression will have CCNE1 copy number assessed by FISH
4. Patient has platinum resistant HGSC, defined as progressive disease by imaging < 6 months from last date of most recent platinum-based therapy, or symptomatic, rising CA-125 based on GCIG criteria
a. Patients who are refractory (progress during or within 4 weeks) to 2nd or subsequent lines of platinum-based chemotherapy are eligible.
b. Patients who are primary platinum refractory (progress during or within 4 weeks of 1st line chemotherapy) are considered ineligible
5. Patient has recurrent disease which is measurable by RECIST 1.1 and/or evaluable disease by GCIG CA-125 criteria
- The number of patients with only GCIG CA-125 evaluable disease is capped at 10 in each cohort
6. Patient has adequate bone marrow, liver and renal function with baseline laboratory values within 7 days prior to registration:
- Absolute neutrophil count (ANC) greater than or equal to 1.5 x 109/L
- Haemoglobin (HgB) greater than or equal to 90 g/L with no requirement for transfusions in last 28 days prior to registration
- Platelets greater than or equal to 100 x 109/L
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 2.5 x upper limit of normal (ULN) or less than or equal to 5 x ULN if known hepatic metastases.
• Alkaline phosphatase (ALP) < 2.5 x ULN
• Adequate synthetic liver function e.g., INR less than or equal to 1.5 x ULN
- Serum bilirubin within normal limits (WNL) or less than or equal to 1.5 x ULN in patients with liver metastases; or total bilirubin less than or equal to 3.0 x ULN with direct bilirubin WNL in patients with documented Gilbert’s Syndrome.
- Creatinine clearance (CrCl) greater than or equal to 45 mL/min, estimated by Cockgroft-Gault equation. Confirmation of creatinine clearance is required for all patients regardless of serum creatinine
7. Females of childbearing potential must practice highly effective methods of birth control for the duration of the study and for at least 6 months after last study drug.
8. Patient has consented to the use of their collected archival FFPE specimen and peripheral blood samples as detailed in the protocol for translational research, including but not limited to DNA, RNA and protein-based biomarker detection.
Minimum age
18 Years
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patient has had prior treatment with Wee1 kinase or ATR inhibition
2. Patient has a diagnosis of ataxia telangiectasia (Cohort 3 only)
3. Use of anti-cancer treatment drug less than or equal to 21 days or 5 half-lives (whichever is shorter) prior to registration; for drugs for which 5 half-lives is less than or equal to 21 days, a minimum of 10 days between termination of the prior treatment and registration into the study is required
For cohort 3: the minimum washout period for immunotherapy is 42 days
- Patients on luteinizing hormone-releasing hormone (LHRH) analogue treatment for more than 6 months are allowed entry into the study and may continue at the discretion of the investigator.
4. Patient has had previous radiation therapy completed less than or equal to 7 days prior to registration. (For cohort 3): palliative radiotherapy must have been completed 21 or more days before planned Cycle 1 Day 1 of study treatment. Patients receiving radiation to more than 30% of bone marrow or wide field radiotherapy must have completed 28 or more days before planned Cycle 1 Day 1 of study treatment.
5. Patient has had major surgical procedures less than or equal to 28 days prior to registration, or minor surgical procedures less than or equal to 7 days prior to registration:
- No waiting period required following port-a-cath or other central venous access placement
6. Patient has persistent Grade > 1 toxicity from prior therapy (except alopecia or anorexia)
7. Patient has an inability to swallow oral medications; Note: Patients may not have a percutaneous endoscopic gastrostomy (PEG) tube or be receiving total parenteral nutrition (TPN)
- Patients with symptoms of subacute or acute bowel obstruction in three months prior to Cycle 1 Day 1 of main study are excluded
8. Patient has known malignant central nervous system (CNS) disease other than neurologically stable, treated brain metastases, defined as metastasis having no evidence of progression or hemorrhage for at least 2 weeks after treatment:
- Patients must be off any systemic corticosteroids for the treatment of brain metastases for at least 14 days prior to registration
9. Patient has had prescription or non-prescription drugs or other products known to be moderate to strong inhibitors/inducers of CYP3A4.
10. Patient has taken the following herbal preparations within 7 days prior to registration:
- St. John's wort, kava, ephedra (ma hung), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto and ginseng.
11. Patient has known hypersensitivity or contraindication to the components of the study drug(s)
12. Patient has any of the following cardiac diseases currently or within the last 6 months as defined by New York Heart Association (NYHA) greater than or equal to class 2:
- Unstable angina pectoris
- Congestive heart failure with LVEF <55%
- Acute myocardial infarction
- 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)
- Mean resting corrected QTc interval using the Fridericia formula (QTcF) > 470 msec (as calculated per institutional standards) obtained from 3 electrocardiograms (ECGs) 2-5 minutes apart at study entry, or congenital long QT syndrome
- History of Torsades de pointes unless all risk factors that contributed to Torsades have been corrected
- Patients with relative hypotension (BP <100/60mmHg) or clinically relevant orthostatic hypotension including fall in systolic BP > 20mmHg
13. Pregnant or breastfeeding women
14. Patient has serious active infection at the time of registration, or another serious underlying medical condition that would impair the ability of the patient to receive study treatment
15. Patients with confirmed COVID-19 infection by PCR test who have not made a full recovery
16. Patient has received any live attenuated vaccination within 30 days prior to Cycle 1 Day 1 study treatment
17. Patient has a presence of other active invasive cancers that do not harbor CCNE1 amplification
18. Patient has a known positive test result for human immunodeficiency virus (HIV) or active hepatitis B or C virus infection
19. Serious underlying medical condition that would impair the ability of the patient to receive study treatment

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis
Cohort 1 & 2:
Simon's two-stage design (Simon, 1989) will be implemented separately for each cohort: CCNE1 over-expressed and amplified and CCNE1 over-expressed and non-amplified. The null hypothesis that the true clinical benefit rate is 5% will be tested against a one-sided alternative. In the first stage, 10 patients will be accrued to each cohort. If there are no patients with clinical benefit in these 10 patients, no further patients will be recruited to that cohort. Otherwise, 19 additional patients will be accrued for that cohort for a total of 29. This design yields a type I error rate of 0.05 and power of 0.8 when the true clinical benefit rate is 20%.
A drop-out rate of up to 10% is expected; therefore, we aim to recruit a total of 32 patients in each cohort.
An additional 32 patients will be recruited to the non-amplified cohort (i.e. 64 non-amplified and 32 amplified patients will be recruited in total).

Cohort 3:
An optimal Simon's two-stage design (Simon, 1989) will be implemented for Cohort 3 – ceralasertib treated patients. The null hypothesis that the true 16 week overall response rate is 5% will be tested against a one-sided alternative hypothesis. In the first stage, 10 patients will be accrued. If there are no responders in these 10 patients evaluable for 16 week overall response rate, no further patients will be recruited to that cohort. Otherwise, 19 additional patients will be accrued for that cohort for a total of 29. This design yields a type I error rate of 0.05 and power of 0.8 when the true overall response rate is 20%.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/03/2020
Actual
26/03/2020
Date of last participant enrolment
Anticipated
31/12/2025
Actual
Date of last data collection
Anticipated
31/12/2028
Actual
Sample size
Target
96
Accrual to date
71
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 14511 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [2] 14512 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [3] 14513 0
Prince of Wales Hospital - Randwick
Recruitment hospital [4] 14514 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment hospital [5] 14515 0
Westmead Hospital - Westmead
Recruitment hospital [6] 14516 0
Orange Health Service - Orange
Recruitment hospital [7] 14517 0
Sunshine Hospital - St Albans
Recruitment hospital [8] 14518 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [9] 14519 0
Mater Adult Hospital - South Brisbane
Recruitment hospital [10] 19986 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [11] 19987 0
Royal Hobart Hospital - Hobart
Recruitment postcode(s) [1] 27523 0
3000 - Melbourne
Recruitment postcode(s) [2] 27524 0
6009 - Nedlands
Recruitment postcode(s) [3] 27525 0
2031 - Randwick
Recruitment postcode(s) [4] 27526 0
2050 - Camperdown
Recruitment postcode(s) [5] 27527 0
2145 - Westmead
Recruitment postcode(s) [6] 27528 0
2800 - Orange
Recruitment postcode(s) [7] 27529 0
3021 - St Albans
Recruitment postcode(s) [8] 27530 0
5042 - Bedford Park
Recruitment postcode(s) [9] 27531 0
4101 - South Brisbane
Recruitment postcode(s) [10] 34694 0
2065 - St Leonards
Recruitment postcode(s) [11] 34695 0
7000 - Hobart

Funding & Sponsors
Funding source category [1] 303534 0
Other Collaborative groups
Name [1] 303534 0
Australia New Zealand Gynaecological Oncology Group (ANZGOG)
Country [1] 303534 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australia New Zealand Gynaecological Oncology Group (ANZGOG)
Address
Level 6, Chris O'Brien Lifehouse
119-143 Missenden Road
CAMPERDOWN NSW 2050
Country
Australia
Secondary sponsor category [1] 303602 0
None
Name [1] 303602 0
Address [1] 303602 0
Country [1] 303602 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304061 0
Peter MacCallum Cancer Centre Human Research Ethics Committee
Ethics committee address [1] 304061 0
C/O HREC Secretariat
Victorian Comprehensive Cancer Centre
305 Grattan Street
MELBOURNE VIC 3000
Ethics committee country [1] 304061 0
Australia
Date submitted for ethics approval [1] 304061 0
30/09/2019
Approval date [1] 304061 0
12/11/2019
Ethics approval number [1] 304061 0
Ethics committee name [2] 304062 0
Bellberry Limited Human Research Ethics Committee
Ethics committee address [2] 304062 0
29 Glen Osmond Road
EASTWOOD SOUTH AUSTRALIA 5063
Ethics committee country [2] 304062 0
Australia
Date submitted for ethics approval [2] 304062 0
30/09/2019
Approval date [2] 304062 0
Ethics approval number [2] 304062 0

Summary
Brief summary
This study will determine if the use of adavosertib (cohort 1 & 2) or ceralasertib (cohort 3) as monotherapy provides clinical benefit to patients with high grade serous ovarian cancer

Who is it for?
You may be eligible to join this study if you are aged 18 and above and have platinum resistant high grade serous ovarian cancer with Cyclin E1 over-expression

Study details
Participants in this study are now being enrolled into an additional third cohort.
Cohort 1 and 2 enrolled 71 participants with Cyclin E1 over-expression (Non-amplified or Amplified). who received the same intervention: daily oral adavosertib tablet from Day 1-5 and Day 8-12 of a 21-day cycle for a maximum of 24 months.
Cohort 3 plans to enrol 32 participants with Cyclin E1 over-expression (Non-amplified or Amplified). Participants will receive twice daily oral ceralasertib tablets from day 1-14 of a 28 day cycle for a maximum of 24 months.
Patients will undergo 4-weekly appointments for their treatment duration, have bloods taken for translational research and may also be required to have a biopsy performed after the end of their first cycle. All participants will be monitored regularly in order to assess clinical response and treatment safety.

It is hoped that IGNITE will provide clinical benefit to patients with high grade serous ovarian cancer who have Cyclin E1 expression and will be able to provide a new treatment option for patients with this genetic fault.
Trial website
www.anzgog.org.au
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 95690 0
Dr George Au-Yeung
Address 95690 0
Peter MacCallum Cancer Centre
305 Grattan Street
Melbourne VIC 3000
Country 95690 0
Australia
Phone 95690 0
+61 3 8559 5000
Fax 95690 0
Email 95690 0
[email protected]
Contact person for public queries
Name 95691 0
George Au-Yeung
Address 95691 0
Peter MacCallum Cancer Centre
305 Grattan Street
Melbourne VIC 3000
Country 95691 0
Australia
Phone 95691 0
+61 3 8559 5000
Fax 95691 0
Email 95691 0
[email protected]
Contact person for scientific queries
Name 95692 0
George Au-Yeung
Address 95692 0
Peter MacCallum Cancer Centre
305 Grattan Street
Melbourne VIC 3000
Country 95692 0
Australia
Phone 95692 0
+61 3 8559 5000
Fax 95692 0
Email 95692 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Individual Participant Data will not be made available, as participant data is coded for privacy reasons.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.