Study Evaluating the Efficacy of Maintenance Olaparib and Cediranib or Olaparib Alone in Ovarian Cancer Patients

  • STATUS
    Recruiting
  • End date
    Dec 18, 2023
  • participants needed
    618
  • sponsor
    University College, London
Updated on 22 August 2021
measurable disease
carcinoma
metastasis
neutrophil count
bevacizumab
cancer chemotherapy
recurrent disease
parp inhibitor
olaparib
fallopian tube
platinum-based chemotherapy
cancer antigen 125
endometrioid carcinoma
peritoneal cancer
tumor debulking
ovarian epithelial carcinoma
cancer of the ovary

Summary

ICON 9 will assess the efficacy, safety and tolerability of maintenance olaparib in combination with cediranib compared to maintenance olaparib alone following a response to platinum-based chemotherapy in women with relapsed platinum-sensitive ovarian, fallopian tube or peritoneal cancer. Prognostic and predictive factors will be studied from tumour and blood samples.

Description

ICON9 is an international multicentre randomised, phase III trial assessing maintenance treatment with olaparib and cediranib or olaparib alone in women with relapsed ovarian cancer whose disease progressed more than 6 months after first line chemotherapy. Women whose disease responds to platinum chemotherapy following 3 to 4 cycles can be registered for collection of germline BRCA test results if known, and somatic BRCA testing of archival tumour specimens or secondary debulking tissue if required. Patients who have completed treatment and whose disease has responded (partial or complete) to a minimum of 4 cycles of platinum based chemotherapy will be randomised to maintenance treatment of either olaparib and cediranib or olaparib alone.

The maintenance regimen may be continued beyond radiological progression until trial closure if the patient is deemed to still be deriving clinical benefit, but must be discontinued once subsequent treatment is instituted.

Details
Condition Ovarian disorder, Ovarian Cancer, Ovarian Function, Recurrent Ovarian Cancer, ovarian carcinomas, cancer, ovarian, cancer ovarian, cancer of the ovary, ovarian tumors
Treatment olaparib, Cediranib
Clinical Study IdentifierNCT03278717
SponsorUniversity College, London
Last Modified on22 August 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Provision of informed consent prior to any study specific procedures and the ability to comply with the protocol for the duration of the study, including undergoing treatment and scheduled visits and examinations
Females aged 18 years with previous histologically proven diagnosis of high grade serous or endometrioid carcinoma of the
Ovary
Fallopian tube
or peritoneum, progressing >6 months after day 1 of the last cycle of first-line platinum-based chemotherapy and requiring treatment with platinum-based chemotherapy on the basis of radiological evidence of disease or following surgical resection of recurrent disease
Patients must have had CT or MRI proven relapsed disease (measureable or non-measureable abnormalities supported by GCIG CA125 criteria of progression), or have had debulking surgery for first relapse
Patients showing response to chemotherapy mid-treatment (post 3 or 4 cycles), either by CA125, on a CT/MRI scan, or no evidence of progression having undergone surgical debulking, should be approached for ICON9 trial registration to allow for BRCA mutation status to be assessed (germline and/ or somatic)
Prior front-line maintenance therapy with bevacizumab is permitted
ECOG performance status 0-1
Formalin fixed, paraffin embedded (FFPE) tumour sample from the primary cancer or from secondary debulking surgery with adequate neoplastic cell content (>30%), must be available for central BRCA testing. For inclusion in i) the genetic HRD Test and ii) the biomarker research, patients must complete the consent form. Translational blood samples are also required, see Laboratory Manual for further details
Patients should have a life expectancy 16 weeks
Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days prior to study treatment and confirmed prior to treatment on day 1
Postmenopausal is defined as age 60 years, or
Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments
Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the post-menopausal range for women under 50
Radiation-induced oophorectomy with last menses >1 year ago
Chemotherapy-induced menopause with >1 year interval since last menses
Surgical sterilisation (bilateral oophorectomy or hysterectomy) 10. Adequately controlled blood pressure (systolic blood pressure [SBP] 140 mmHg; diastolic blood pressure [DBP] 90mmHg) on maximum of 2 antihypertensive medications. 11. Adequately controlled thyroid function, with no symptoms of thyroid dysfunction
Randomisation Inclusion Criteria
Patients must have received at least 4 cycles, and a maximum of 6 cycles of second-line platinum-based chemotherapy
In patients with measurable disease, end of treatment scans must have a RECIST v1.1 'partial response' or 'complete response' and meet one of the following CA125
requirements
If the first screening CA125 value is below the ULN the patient is eligible for randomisation and a second CA125 assessment is not required
If the first screening CA125 value is greater than ULN then a second assessment is required at least 7 days after the first to confirm eligibility. If the second CA125 value has risen by 15% then the patient will not be eligible
In patients with non-measurable disease, who have not undergone debulking surgery, they must have had a GCIG CA125 response to chemotherapy and meet one of the following CA125 requirements
If the first screening CA125 value is below the ULN the patient is eligible for randomisation and a second CA125 assessment is not required
If the first screening CA125 value is greater than ULN then a second assessment is required at least 7 days after the first to confirm eligibility. If the second CA125 value has risen by 15% then the patient will not be eligible
Patients who have had debulking surgery at first relapse must have no evidence of disease progression on imaging (CT or MRI) and meet one of the following CA125
requirements
If the first screening CA125 value is below the ULN the patient is eligible for randomisation and a second CA125 assessment is not required
If the first screening CA125 value is greater than ULN then a second assessment is required at least 7 days after the first to confirm eligibility. If the second CA125 value has risen by 15% then the patient will not be eligible
Expected to be able to commence treatment within 7 days post randomisation, and within 4-8 weeks post day 1 of the last cycle of chemotherapy
Adequate bone marrow function as defined below
Absolute Neutrophil Count (ANC) 1.5 x 109/l
Platelet (Plt) 100 x 109/l
Haemoglobin (Hb) 100g/l required and no packed blood transfusions in the 14 days prior to starting trial treatment
Adequate liver function as defined below
Serum bilirubin 1.5 x ULN (or 3 for cases of known Gilbert's syndrome)
Serum transaminases 3 x ULN
Serum transaminases 5 x ULN if liver metastasis present
Adequate renal function as defined below
Serum creatinine 1.5 x ULN and calculated glomerular filtration rate (GFR)
ml/min (calculated as per local practice)
\. Urine dipstick for proteinuria <2+. If urine dipstick is 2+ on two
occasions more than one week apart then a 24-hour urine must demonstrate 1 g
of protein in 24 hours or protein/creatinine ratio < 1.5
\. Germline and/or somatic BRCA mutation status must be known prior to
randomisation

Exclusion Criteria

Non-epithelial ovarian cancer, carcinosarcoma, clear cell carcinoma and mucinous carcinomas
Arterial thrombotic event (including transient ischemic attack, cerebrovascular accident, and peripheral arterial embolus) within the last 12 months
Patients unable to swallow orally administered medication and patients with gastrointestinal impairment that could affect ability to take, or absorption of oral medicines including sub-acute or complete bowel obstruction
Clinically significant signs and/or symptoms of bowel obstruction within 3 months prior to starting treatment
History of intra-abdominal abscess within 3 months prior to starting treatment
History of GI perforation. Patients with a history of abdominal fistula will be considered eligible if the fistula was surgically repaired, there has been no evidence of fistula for at least 6 months prior to starting treatment, and patient is deemed to be at low risk of recurrent fistula
Symptomatic or clinically significant inflammatory bowel disease (Crohn's disease or ulcerative colitis)
Patients with an ileostomy will be excluded
Evidence of severe or uncontrolled cardiac disease
Myocardial infarct or unstable angina within the last 6 months
New York Health Association (NHYA) grade 2 congestive heart failure
Cardiac ventricular arrhythmias requiring medication
History of 2nd or 3rd degree atrioventricular conduction defects
Resting ECG with QTcF > 470msec on 2 or more time points within a 24 hour period or family history of long QT syndrome
Evidence of active bleeding or bleeding diathesis
Significant haemorrhage of >30ml in a single episode within the last 3 months
or any haemoptysis (>5ml fresh blood in last 4 weeks)
\. Malignancy treated within the last 5 years except: adequately treated
non-melanoma skin cancer, curatively treated in situ cancer of the cervix
ductal carcinoma in situ (DCIS) of the breast, Stage 1, grade 1 endometrial
carcinoma
\. Previous treatment with VEGFR tyrosine kinase inhibitors or PARP
inhibitors are not permitted
\. Patients with a known hypersensitivity to excipients of cediranib or
olaparib
\. Persisting grade 2 CTCAE toxicity (except alopecia and neuropathy) from
previous anti-cancer treatment
\. Major surgery within 14 days before anticipated start of treatment and
patients must have recovered from any effects of major surgery
\. Inability to attend or comply with treatment or follow-up scheduling
\. Evidence of any other disease, metabolic dysfunction, physical
examination finding or laboratory finding giving reasonable suspicion of a
disease or condition that contra-indicated the use of an investigation drug or
puts the patients at high risk for treatment-related complications
\. Pregnant or breast-feeding women are excluded. Women of childbearing
potential will be excluded unless effective methods of contraception are used
from signing of the informed consent, throughout the period of taking study
treatment and for at least 6 weeks after last dose of trial drug(s)
\. Treatment with any other investigational agent, or participation in
another interventional clinical trial within 28 days prior to enrolment
\. Concomitant use of known CYP3A4 inhibitors (such as ketoconazole
itraconazole, protease inhibitors boosted with ritonavir or cobicistat
indinavir, saquinavir, nelfinavir, boceprevir, telaprevir, telithromycin and
clarithromycin or moderate CYP3A inhibitors (e.g. Ciprofloxacin, erythromycin
diltiazem, fluconazole, verapamil). The required washout period prior to
starting olaparib is 2 weeks
\. Concomitant use of known strong (e.g. phenobarbital, enzalutamide
phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and
St John's Wort) or moderate CYP3A inducers (eg. bosentan, efavirenz
modafinil). The required washout period prior to starting olaparib is 5 weeks
for enzalutamide or phenobarbital and 3 weeks for other agents
\. Patients with myelodysplastic syndrome/acute myeloid leukaemia
\. Other psychological, psychiatric, social or medical condition, physical
examination finding or a laboratory abnormality that the Investigator
considers would make the patient a poor trial candidate or could interfere
with protocol compliance or the interpretation of trial results
\. Patients with known active hepatitis (i.e. Hepatitis B or C) due to risk
of transmitting the infection through blood or other body fluids
\. Immunocompromised patients e.g., patients who are known to be
serologically positive for human immunodeficiency virus (HIV) and are
receiving antiviral therapy
\. Patients with symptomatic uncontrolled brain or meningeal metastases. A
scan to confirm the absence of brain metastases is not required. The patient
can receive a stable dose of corticosteroids before and during the study as
long as these were started at least 4 weeks prior to treatment
\. Patients with spinal cord compression unless considered to have received
definitive treatment for this and evidence of clinically stable disease for 28
days
\. Previous allogenic bone marrow transplant or double umbilical cord blood
transplantation (dUCBT)
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