Trial to Better Characterize the Status of HRD leading to a Benefit from Olaparib in Combination with Bevacizumab in Patients with Advanced Serous or Endometrioid Ovarian, Fallopian Tube, or Peritoneal Cancer. STROBE

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Vall D Hebron Institute Of Oncology

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

16 Feb 2024 → ongoing

Decision date (initial)

2024-11-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AstraZeneca Farmacéutica Spain

External identifiers

EU CT number

2024-517363-24-00

EudraCT number

2021-004455-17

ClinicalTrials.gov

NCT06377267

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Others, Safety, Therapy

To determine the concordance in HRD status identification between VHIO-CARD-300 test and SOPHiA DDM™ Dx HRD Solution.

Secondary objectives 4

1. To assess the accuracy in HRD status identification of the VHIO-CARD-300 test.
2. To determine the association between the selection of groups of the VHIO-CARD- 300 test (i.e., HRD positive and HRD negative) and efficacy outcomes.
3. To study efficacy outcomes in discrepant cases (i.e., HRD positive by VHIOCARD- 300 test but HRD negative by SOPHiA and HRD negative by VHIOCARD- 300 test but HRD positive by SOPHiA).
4. To evaluate the safety and tolerability of combining olaparib plus bevacizumab.

Conditions and MedDRA coding

Advanced FIGO Stage III‐IV High Grade Serous or Endometrioid Ovarian, Fallopian Tube, or Peritoneal Cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Females ≥18 years of age (at the time informed consent is obtained).
2. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form and in this protocol.
3. Provision of signed and dated, written informed consent form prior to any mandatory study specific procedures, sampling, and analyses.
4. Patient with newly diagnosed high- grade serous or endometrioid ovarian cancer, primary peritoneal cancer and/or fallopian-tube cancer at an advanced stage: FIGO stage III or IV of the 2014 FIGO classification (see Appendix A).
5. Patient who has completed prior to enrolment first line platinum-taxane chemotherapy: a. Platinum-taxane based regimen must have consisted of a minimum of 6 treatment cycles and a maximum of 8. However, if platinum-based therapy must be discontinued early as a result of non-haematological toxicity specifically related to the platinum regimen, (i.e., neurotoxicity, hypersensitivity etc.), the patient must have received a minimum of 4 cycles of the platinum regimen. b. Patient must have received prior to enrolment a minimum of 3 cycles of Bevacizumab in combination with the 3 last cycles of platinum-based chemotherapy. Only in case of interval debulking surgery, it is allowed to have received only 2 cycles of Bevacizumab in combination with the last 3 cycles of platinum-based chemotherapy. c. Patients must not have received an investigational agent during their first line course of chemotherapy.
6. Patient must be prior to enrolment without evidence of disease (NED) or in complete response (CR) or partial response (PR) from the first-line treatment. There should be no clinical evidence of disease progression (physical exam, imagery, CA-125) throughout her first-line treatment and prior to study enrolment. ‘Response’ is used throughout the protocol and refers to patients being, in the opinion of the Investigator, in clinical CR or PR on the post-treatment scan (at the end of platinum-based chemotherapy). Clinical CR is defined as no evidence of RECIST measurable or nonmeasurable disease on the post-treatment scan and a normal CA-125. PR is defined as ≥30% reduction in tumour volume demonstrated from the start to finish of chemotherapy OR no evidence of RECIST measurable disease on the post-treatment scan with a CA-125 which has not decreased to within the normal range.
7. Patient must be included at least 4 weeks and no more than 8 weeks after her last dose of chemotherapy (last dose is the day of the last infusion) and all major toxicities from the previous chemotherapy must have resolved to CTCAE grade 1 or better (except alopecia and peripheral neuropathy).
8. Formalin fixed, paraffin embedded (FFPE) tumour sample from the primary cancer must be available for central HRD testing and test result must be available before inclusion
9. Patients must have normal organ and bone marrow function measured within 7 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 x 109/L  Platelet count ≥ 100 x 109/L  Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present in which case they must be ≤ 5x ULN  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]) x weight (kg) (x F)a serum creatinine (mg/dL) x 72 a where F=0.85 for females  Urine dipstick for proteinuria <2+. Patients discovered to have 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate <1 g of protein in 24 hours or urine protein/creatinine (UPC) ratio ≤1.0
10. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 within 14 days before enrolment (see Appendix B).
11. Patients must have a life expectancy ≥ 16 weeks.
12. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients within 72 hours of receiving the first dose of study medication. Postmenopausal is defined as:  Amenorrhoeic 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)

Exclusion criteria 34

1. Epithelial ovarian cancer with histologies as clear cell, carcinosarcoma or undifferentiated cancer.
2. Non-epithelial origin of the ovary, the fallopian tube or the peritoneum (i.e., germ cell tumours).
3. Ovarian tumours of low malignant potential (e.g., borderline tumours) or mucinous carcinoma.
4. 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.
5. Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery.
6. Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment.
7. Any previous treatment with PARPi, including olaparib.
8. Prior history of hypertensive crisis (CTCAE grade 4) or hypertensive encephalopathy.
9. Clinically significant (e.g., active) cardiovascular disease, including: a. Myocardial infarction or unstable angina within ≤ 6 months of enrolment, b. New York Heart Association (NYHA) ≥ grade 2 congestive heart failure (CHF) (see Appendix C). c. Poorly controlled cardiac arrhythmia despite medication (patient with rate controlled atrial fibrillation are eligible), or any clinically significant abnormal finding on resting ECG, d. Peripheral vascular disease grade ≥ 3 (e.g., symptomatic and interfering with activities of daily living [ADL] requiring repair or revision).
10. Previous Cerebro-Vascular Accident (CVA), Transient Ischemic Attack (TIA) or Sub- Arachnoids Hemorrhage (SAH) within 6 months prior to enrolment.
11. History or evidence of haemorrhagic disorders within 6 months prior to enrolment.
12. History or clinical suspicion of brain metastases or spinal cord compression.
13. nt traumatic injury during 4 weeks prior to enrolment.
14. Non-healing wound, active ulcer, or bone fracture.
15. History of VEGF therapy related abdominal fistula or gastrointestinal perforation or active gastrointestinal bleeding within 6 months prior to the first study treatment.
16. Current, clinically relevant bowel obstruction, including sub-occlusive disease, related to underlying disease.
17. Patient with evidence of abdominal free air not explained by paracentesis or recent surgical procedure.
18. Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the Investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation >500 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome.
19. Persistent toxicities (> CTCAE grade 2) caused by previous cancer therapy, excluding alopecia.
20. Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features suggestive of MDS/AML.
21. 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.
22. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant 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.
23. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
24. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV).
25. Patients with known active hepatitis (i.e., Hepatitis B or C).  Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen (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.  Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
26. 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 study treatment is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
27. 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.
28. Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT).
29. Whole blood transfusions in the last 120 days prior to entry to the study (packed red blood cells and platelet transfusions are acceptable).
30. Patients with a known hypersensitivity to the study treatment (i.e., olaparib and bevacizumab) or any of the excipients of the products.
31. Involvement in the planning and/or conduct of the study.
32. Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements.
33. Previous enrolment in the present study.
34. Breastfeeding women.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Percentage of HR status agreement between VHIO-CARD-300 test and SOPHiA DDM™ Dx HRD Solution. The corresponding 95% confidence intervals (CI) will be reported.

Secondary endpoints 5

1. Sensitivity, specificity, predictive positive and negative value of the VHIO-CARD-300 test, using SOPHiA DDM™ Dx HRD Solution as a reference test.
2. Progression free survival (PFS) and overall survival (OS) will be analysed in HRD and HRP groups, as determined by the VHIOCARD- 300 test. PFS: time from the date of enrolment to the date of first documentation of disease progression or death due to any cause, whichever occurs first. OS: time from the date of enrolment to the date of death due to any cause. The progression of disease will be assessed by the Investigator according to the modified Response Evaluation Criteria in Solid Tumours (RECIST 1.1) will be used.
3. PFS and OS will be analysed in discrepant cases (i.e., HRD positive by VHIO-CARD- 300 test but HRD negative by SOPHiA DDM™ Dx HRD Solution and HRD negative by VHIO-CARD-300 test but HRD positive by SOPHiA DDM™ Dx HRD Solution).
4. Percentage of inconclusive results will be estimated for each test
5. Assessment of adverse events (AEs) graded by the National Cancer Institute (NCI) CTCAE v5.0, serious adverse events (SAEs), abnormal vital signs, abnormal ECG results, and evaluation of laboratory parameters.

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Vall D Hebron Institute Of Oncology

Sponsor organisation

Vall D Hebron Institute Of Oncology

Address

Calle Natzaret 115

City

Barcelona

Postcode

08035

Country

Spain

Scientific contact point

Organisation

Vall D Hebron Institute Of Oncology

Contact name

Head of Gynaecological Cancer Program

Public contact point

Organisation

Vall D Hebron Institute Of Oncology

Contact name

CRO Head

Third parties 4

Locations

1 EU/EEA country · 14 investigational sites

By country

Investigational sites

Country notifications

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 1 · Art. 52 CTR

Results and documents

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

Documents 8 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