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About
This is a multi-center, prospective, open-label, phase II trial. Patients with suspected advanced ovarian cancer planned to undergo diagnostic laparoscopy for histologic confirmation and evaluation of disease spread will be registered into the trial after providing a 1st written informed consent.
Full description
In total, 60 patients are planned to be enrolled in 2 consecutive cohorts (30 patients per cohort) into the trial.
After histologic confirmation of high-grade epithelial non-mucinous, non-clear cell ovarian cancer, patients will be treated in two consecutive cohorts (A, B) of 30 patients each, with
A) olaparib alone or B) olaparib in combination with durvalumab
Treatment allocation will take place in two consecutive cohorts rather than by randomization. This will allow to evaluate the safety and feasibility in a stepwise approach. A trial steering committee (TSC) meeting will take place between the cohorts to review safety and feasibility prior to starting the second cohort. The safety follow-up of the first cohort will take 90 days as of the first dose of therapy.
The window-of-opportunity treatment phase will be followed by primary debulking surgery and standard of care platinum based first-line chemotherapy at the discretion of the investigator.
After completion of first-line chemotherapy patients who have not progressed during first-line chemotherapy will receive the indicated standard maintenance treatment according to the national S3-guideline and treating physician's choice. For patients who have received all possible licensed treatment regimens according to the national guideline or for whom further licensed treatment options are contraindicated, Olaparib may be offered as investigational maintenance therapy for up to 24 months.
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
WoO pre-treatment (screening phase):
Patients with presumed and previously untreated advanced stage ovarian cancer planned to undergo laparoscopy for histologic diagnosis and treatment planning
Patients willing and able to comply with the study protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
Patients able and willing to provide fresh frozen biopsy samples from laparoscopy as well as primary debulking for translational endpoints as well as serial liquid biopsies
Patients able and willing to provide formaldehyde-fixed paraffin embedded (FFPE) tissue samples from laparoscopy and primary debulking surgery
Patients aged ≥18 years
Patients must be capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol
Provision of signed and dated, written ICF for the mandatory biomarker and genetic re-search as well as the clinical/therapeutic part of the study prior to any mandatory study specific procedures, sampling, and analyses
Eastern cooperative oncology group (ECOG) performance status 0-1 (see Appendix 1)
Patients must have a life expectancy ≥16 weeks
Ability to take oral medication
Postmenopausal or evidence of non-childbearing status for women of childbearing potential (WOCBP): negative serum pregnancy test within 28 days of study treatment and confirmed neagtive urine or serum pregnancy test prior to treatment on day 1.
Postmenopausal is defined as:
Women of childbearing potential (WOCBP) and their partners, who are sexually active, must agree to the use of 2 highly effective forms of contraception in combination. This should be started from the signing of the informed consent and continue throughout the period of taking study treatment and for at least 6 months after last dose of study drug(s), or they must totally/truly abstain from any form of sexual intercourse.
WoO treatment phase:
Confirmed advanced (FIGO IIB/III/IV) high-grade, non-mucinous, non-clear cell epithelial ovarian, fallopian tube or primary peritoneal cancer or known (BReast CAncer) BRCA mutation and any histologic type
Planned primary debulking surgery after confirmation of diagnosis and disease evaluation during laparoscopy
Body weight >30kg
Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below:
Estimated creatinine clearance=((140-age [years])*weight (kg))/(serum creatinine (mg/dL)*72)(* 0,85) 17. Patients must have successfully contributed blood and tissue samples as per requirements.
Exclusion criteria
Medical conditions:
Disease requiring urgent surgical intervention
Evidence of significant uncontrolled concomitant disease that could affect compliance with the study protocol
Significant uncontrolled symptom burden (e.g. but not necessarily limited to large volume ascites, shortness of breath on exertion, pain requiring opioid medication, signs of (sub)ileus
Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, recent (within 3 months) myocardial infarction, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
Other malignancy unless curatively treated with no evidence of disease for ≥5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), stage 1, grade 1 endometrial carcinoma. Patients with a history of localized triple negative breast cancer may be eligible, provided they completed their adjuvant chemotherapy more than three years prior to registration, and that the patient remains free of recurrent or metastatic disease (optional criteria that is dependent on the patient population under investigation).
Resting electrocardiography (ECG) indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (eg., unstable ischemia, uncontrolled symptomatic arrhythmia, conges-tive heart failure, QTcF prolongation >500 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome.
Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
a. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with olaparib, durvalumab or the combination may be included only after consultation with the coordinating investigator.
Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML).
Brain metastases or spinal cord compression. Patients with suspected brain metastases at screening should have an MRI (preferred) or CT each preferably with IV contrast of the brain prior to study entry
Patients with symptomatic uncontrolled brain 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.
Evidence of central nervous system (CNS) or leptomeningeal metastases.
Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent.
Patients unable to swallow orally administered medication and patients with gastrointestinal disorders or any status that might interfere with resorption of the respective study drugs, e.g. parenteral nutrition, short bowel syndrome likely to interfere with absorption of the study medication.
Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV).
History of active primary immunodeficiency
Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B or hepatitis C.
ECOG performance status (PS) ≥2 or general condition that might interfere with the compliance with the study protocol
Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
Prior / concomitant therapy:
Prior antineoplastic therapy for ovarian, fallopian tube or primary peritoneal cancer
Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment
Any concurrent chemotherapy, investigational medicinal product (IMP), biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable
Patients planned for neoadjuvant chemotherapy or deemed unresectable at laparoscopy
Concomitant use of known strong cytochrome P450 3A (CYP3A) inhibitors (eg. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks.
Concomitant use of known strong (eg. 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
Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery
History of allogenic organ transplantation
Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT).
Patients with a known hypersensitivity to olaparib or any of the excipients of the product.
Prior treatment with olaparib or any other poly [ADP-ribose] polymerase (PARP) inhibitor
Whole blood transfusions in the last 120 days prior to entry to the study (packed red blood cells and platelet transfusions are acceptable, for timing refer to inclusion criteria no. 16)
Other exclusions:
Patients who are pregnant or breast-feeding or patients of reproductive potential who are not willing to employ effective birth control from screening to 6 months after the last dose of study drug(s).
Involvement in the planning and/or conduct of the study
Participation in another interventional clinical study with an investigational product during the last with the last 3 months.
Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
Previous enrolment in the present study.
Judgement by the investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements.
Additional Durvalumab-specific exclusion criteria for cohort B:
Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies) ≤28 days prior to the first dose of study drug. If sufficient wash-out time has not occurred due to the schedule or pharmacokinetic (PK) properties of an agent, a longer wash-out period will be required.
Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
Major surgical procedure (as defined by the investigator) within 28 days prior to the first dose of IP. Note: local surgery of isolated lesions for palliative intent is acceptable.
History of allogenic organ transplantation.
Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, sarcoidosis syndrome, or wegener syndrome [granulomatosis with polyangiitis, graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring (Adverse Events) AEs or compromise the ability of the patient to give written informed consent.
History of another primary malignancy except for
History of leptomeningeal carcinomatosis
Brain metastases or spinal cord compression. Patients with suspected brain metastases at screening should have an MRI (preferred) or CT each preferably with IV contrast of the brain prior to study entry.
Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart)
Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), hepatitis B (known positive hepatitis B virus (HBV) surface antigen (HBsAg) result), hepatitis C. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-hepatitis-B-core (HBc)] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:
Receipt of live attenuated vaccine within 30 days prior to the first dose of IMP. Note: patients, if enrolled, should not receive live vaccine whilst receiving IMP and up to 30 days after the last dose of IMP.
Prior randomisation or treatment in a previous durvalumab clinical study regardless of treatment arm assignment or other immunotherapies
Patients who have received prior anti-programmed cell death-protein 1(PD-1), anti PD-L1 or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4):
Patients planned for neoadjuvant chemotherapy (e.g. but not exclusively due to extend of disease spread or poor general condition etc.).
(sub)ileus or signs of malignant bowel obstruction.
Primary purpose
Allocation
Interventional model
Masking
60 participants in 2 patient groups
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Central trial contact
Jana Warby; Yvonne Treffner, Dr.
Data sourced from clinicaltrials.gov
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