Window-of-opportunity proof-of-concept, non-randomized, open-label phase II trial of Olaparib given alone (cohort A) or in combination with Durvalumab (cohort B) prior to primary debulking surgery in histologically proven high-grade epithelial ovarian cancer (EOC)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AGO Research GmbH

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Not possible to specify

Trial duration

5 May 2022 → ongoing

Decision date (initial)

2024-03-20

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Astra Zeneca GmbH

External identifiers

EU CT number

2024-511780-28-00

EudraCT number

2020-005101-12

ClinicalTrials.gov

NCT04644289

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Others

To proof the feasibility of a window-of-opportunity treatment with Olaparib alone in patients with newly diagnosed high-grade ovarian cancer planned for primary debulking surgery
To proof the feasibility of a window-of-opportunity treatment with Olaparib in combination with Durvalumab in patients with newly diagnosed high-grade ovarian cancer planned for primary debulking surgery

Secondary objectives 4

1. • To proof the safety of a window-of-opportunity treatment with Olaparib alone in pa-tients with newly diagnosed high-grade ovarian cancer planned for primary debulking surgery
2. • To proof the safety of a window-of-opportunity treatment with Olaparib in combina-tion with Durvalumab in patients with newly diagnosed high-grade ovarian cancer planned for primary debulking surgery
3. • To evaluate the utility of early ctDNA dynamics (cohort A + B) as clinically useful bi-omarker for response to therapy administered during a 3-4 weeks window-of-opportunity prior to interval debulking, based on tumor specific mutant ctDNA changes from baselines.
4. • ctDNA will be analyzed using 2 alternative platforms (1. ROCHE Diagnostics AVENIO ctDNA Analysis assay; 2. To be determined, depending on expected advances in technology)

Conditions and MedDRA coding

Patients with presumed and previously untreated advanced stage ovarian cancer planned to undergo laparoscopy for histologic diagnosis and treatment planning.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. 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
2. WoO pre-treatment (screening phase): 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
3. WoO pre-treatment (screening phase): 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
4. WoO pre-treatment (screening phase): Patients able and willing to provide formaldehyde-fixed paraffin embedded (FFPE) tissue samples from laparoscopy and primary debulking surgery
5. WoO pre-treatment (screening phase): Patients aged ≥18 years
6. WoO pre-treatment (screening phase): 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
7. WoO pre-treatment (screening phase): Provision of signed and dated, written ICF for the mandatory biomarker and genetic research as well as the clinical/therapeutic part of the study prior to any mandatory study specific procedures, sampling, and analyses
8. WoO pre-treatment (screening phase): Eastern cooperative oncology group (ECOG) performance status 0-1
9. WoO pre-treatment (screening phase): Patients must have a life expectancy ≥16 weeks
10. WoO pre-treatment (screening phase): Ability to take oral medication
11. WoO pre-treatment (screening phase): 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 negative urine or serum pregnancy test prior to treatment on day 1. Postmenopausal is defined as: - 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)
12. WoO pre-treatment (screening phase): Women of childbearing potential (WOCBP) and their partners, who are sexually active, must agree to the use of TWO highly effective forms of contraception in combination (as described in Appendix 5 of the CIP. 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 (as described in Appendix 5 of the CIP).
13. 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 BRCA mutation and any histologic type
14. WoO treatment phase: Planned primary debulking surgery after confirmation of diagnosis and disease evaluation during laparoscopy
15. WoO treatment phase: Body weight >30kg
16. WoO treatment phase: Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below: - Haemoglobin ≥10.0 g/dL with no blood transfusion in the past 28 days, - Absolute neutrophil count (ANC) ≥1.5×109/L, - Platelet count ≥100×109/L, - Total bilirubin ≤1.5 × institutional upper limit of normal (ULN), - Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) ≤2.5 × institutional upper limit of normal unless liver metastases are present in which case they must be ≤5×ULN. (Cave: patients with intrahepatic metastases affecting liver function test might not be candidates for primary debulking surgery), - Patients must have creatinine clearance estimated of ≥51 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test: Estimated creatinine clearance=((140-age [years])*weight (kg))/(serum creatinine (mg/dL)*72)(* 0,85)
17. WoO treatment phase: Patients must have successfully contributed blood and tissue samples as per requirements

Exclusion criteria 53

1. Medical conditions: Disease requiring urgent surgical intervention
2. Medical conditions: Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
3. Medical conditions: Evidence of significant uncontrolled concomitant disease that could affect compliance with the study protocol
4. Medical conditions: 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
5. Medical conditions: 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.
6. Medical conditions: 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).
7. Medical conditions: Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (eg., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation >500 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome.
8. Medical conditions: 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.
9. Medical conditions: Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of MDS/AML.
10. Medical conditions: 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
11. Prior / concomitant therapy: Prior antineoplastic therapy for ovarian, fallopian tube or primary peritoneal cancer
12. Medical conditions: 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.
13. Prior / concomitant therapy: Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment
14. Prior / concomitant therapy: 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
15. Prior / concomitant therapy: Patients planned for neoadjuvant chemotherapy or deemed unresectable at laparoscopy
16. Prior / concomitant therapy: Concomitant use of known strong 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.
17. Prior / concomitant therapy: 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
18. Prior / concomitant therapy: Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery
19. Prior / concomitant therapy: History of allogenic organ transplantation
20. Prior / concomitant therapy: Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT).
21. Prior / concomitant therapy: Patients with a known hypersensitivity to Olaparib or any of the excipients of the product.
22. Prior / concomitant therapy: Prior treatment with Olaparib or any other PARP inhibitor
23. Medical conditions: Evidence of central nervous system (CNS) or leptomeningeal metastases.
24. Prior / concomitant therapy: 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)
25. Other exclusions: Patients who are pregnant or breastfeeding 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).
26. Other exclusions: Involvement in the planning and/or conduct of the study
27. Other exclusions: Participation in another interventional clinical study with an investigational product during the last with the last 3 months.
28. Other exclusions: 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.
29. Other exclusions: Previous enrolment in the present study.
30. Other exclusions: Judgment 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.
31. Medical conditions: 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.
32. Medical conditions: 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.
33. Medical conditions: Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV).
34. Medical conditions: History of active primary immunodeficiency
35. Medical conditions: 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., a. Active HBV is defined by a known positive 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., b. Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA
36. Medical conditions: ECOG performance status (PS) ≥2 or general condition that might interfere with the compliance with the study protocol
37. 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 PK properties of an agent, a longer wash-out period will be required.
38. Additional Durvalumab-specific exclusion criteria for cohort B: 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 Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the coordinating investigator., b. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with Durvalumab may be included only after consultation with the coordinating investigator.
39. Additional Durvalumab-specific exclusion criteria for cohort B: Any concurrent chemotherapy, 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.
40. Additional Durvalumab-specific exclusion criteria for cohort B: Major surgical procedure (as defined by the investigator) within 28 days prior to the first dose of IMP. Note: local surgery of isolated lesions for palliative intent is acceptable.
41. Additional Durvalumab-specific exclusion criteria for cohort B: History of allogenic organ transplantation.
42. Additional Durvalumab-specific exclusion criteria for cohort B: 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: a. Patients with vitiligo or alopecia, b. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement, c. Any chronic skin condition that does not require systemic therapy, d. Patients without active disease in the last 5 years may be included but only after consultation with the study physician, e. Patients with celiac disease controlled by diet alone
43. Additional Durvalumab-specific exclusion criteria for cohort B: 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 AEs or compromise the ability of the patient to give written informed consent.
44. Additional Durvalumab-specific exclusion criteria for cohort B: History of another primary malignancy except for a. Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IMP and of low potential risk for recurrence, b. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease, c. Adequately treated carcinoma in situ without evidence of disease
45. Additional Durvalumab-specific exclusion criteria for cohort B: History of leptomeningeal carcinomatosis
46. Additional Durvalumab-specific exclusion criteria for cohort B: 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.
47. Additional Durvalumab-specific exclusion criteria for cohort B: 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)
48. Additional Durvalumab-specific exclusion criteria for cohort B: 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 (known positive 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-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.
49. Additional Durvalumab-specific exclusion criteria for cohort B: 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.
50. Additional Durvalumab-specific exclusion criteria for cohort B: Prior randomisation or treatment in a previous Durvalumab clinical study regardless of treatment arm assignment or other immunotherapies
51. Additional Durvalumab-specific exclusion criteria for cohort B: Patients who have received prior anti–PD-1, anti PD-L1 or anti CTLA-4: a. Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy., b. All Aes while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study., c. Must not have experienced a ≥grade 3 immune related AE or an immune related neurologic or ocular AE of any grade while receiving prior immunotherapy. NOTE: patients with endocrine AE of ≤grade 2 are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic., d. Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of >10 mg prednisone or equivalent per day.
52. Additional Durvalumab-specific exclusion criteria for cohort B: Patients planned for neoadjuvant chemotherapy (e.g. but not exclusively due to extend of disease spread or poor general condition etc.).
53. Additional Durvalumab-specific exclusion criteria for cohort B: (Sub)ileus or signs of malignant bowel obstruction.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Feasibility of WoO procedure defined as the successful completion of the WoO therapy: Relative dose intensity (RDI) of ≥80%. No treatment-related surgical delays. Adherence to therapeutic strategy. Lack of clinical progression prior to primary debulking surgery. No treatment-related toxicities of any grade that in the judgment of the investigator or surgeon significantly interfered with the subject’s optimal perioperative management

Secondary endpoints 4

1. Safety of the WoO procedure. Evaluated by the proportion of patients who experience any adverse event (CTCAE v5.0), of a grade ≥3.
2. Proportion of ctDNA mutation positive patients at baseline above a predefined a cut-off (copies/ml).
3. Circulating DNA ratio at day 21 (CDR21) defined as the ratio of mutation abundance at day 21 relative to baseline of the mutant ctDNA allele with the highest abundance (mutant copies/ml) at baseline.
4. Progression free survival (PFS). Defined as the time from registration into the trial (PIC2) until progression defined as progressive disease according to RECIST or GCIG criteria or death without progression or clinical deterioration of performance status with associated signs of disease (e.g. bowel obstruction and non-measurable disease).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 24

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AGO Research GmbH

Sponsor organisation

AGO Research GmbH

Address

Kaiser-Friedrich-Ring 71

City

Wiesbaden

Postcode

65185

Country

Germany

Scientific contact point

Organisation

AGO Research GmbH

Contact name

Study Office

Public contact point

Organisation

AGO Research GmbH

Contact name

Study Office

Third parties 3

Locations

1 EU/EEA country · 6 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 18 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications