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 - IGNITE

Funding

Other Collaborative groups,Australia New Zealand Gynaecological Oncology Group (ANZGOG)

Scientific enquiries

Dr George Au-Yeung

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 wit .... 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.
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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 cr .... 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.
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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 .... 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
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