Study assessing the efficacy and safety of durvalumab plus olaparib plus fulvestrant in selected metastatic or locally advanced ER-positive, HER2-negative breast cancer patients

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Unicancer

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

27 Aug 2019 → ongoing

Decision date (initial)

2024-10-21

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Astra Zeneca France

External identifiers

EU CT number

2024-516847-23-00

EudraCT number

2018-003832-57

ClinicalTrials.gov

NCT04053322

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To evaluate the efficacy of the combination of olaparib, durvalumab, and fulvestrant for the treatment of patients with ER-positive, HER2-negative, locally advanced or metastatic breast cancer with BRCA gene alterations or alterations of genes involved in HRR or MSI status, in terms of the progression-free survival rate (PFSR) at 24 weeks

Secondary objectives 11

1. Safety objective in overall and germline BRCA mutated populations : To determine the safety of the combination of olaparib, durvalumab, and fulvestrant
2. Efficacy objective in the overall study population : To determine the efficacy in term of overall survival (OS).
3. Efficacy objective in the overall study population: To determine the efficacy in term of objective response rate (ORR)
4. Efficacy objective in the overall study population: To determine the efficacy in term of duration of response (DoR).
5. Efficacy objective in the overall study population: To determine the efficacy in term of progression-free survival (PFS).
6. Efficacy objective in the germline BRCA mutated population: To determine the efficacy in term of OS
7. Efficacy objective in the germline BRCA mutated population: To evaluate the efficacy in term of PFSR at 24 weeks
8. Efficacy objective in the germline BRCA mutated population: To evaluate the efficacy in term of ORR
9. Efficacy objective in the germline BRCA mutated population: To evaluate the efficacy in term of DoR
10. Efficacy objective in the germline BRCA mutated population: To evaluate the efficacy in term of PFS.
11. Exploratory analysis to evaluate efficacy and safety of the combination will be performed in patients: 1. Previously treated with CDK4/6 inhibitors. 2. With different PD-L1 expression status.

Conditions and MedDRA coding

ER-positive and HER2-negative metastatic or locally advanced breast cancer with either a germline or somatic BRCA mutation, or a deleterious alteration of other genes involved in homologous recombination repair (HRR) or in MSI status.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Histologically confirmed ER-positive (≥10%), HER2-negative (0, 1+, 2+, and no HER2 gene amplification by ISH), metastatic or locally advanced breast cancer that is not amenable to resection or radiation with curative intent
2. Patients aged ≥18 years old (post-menopausal or pre/per-menopausal women and men).
3. Documented personal germline alteration in BRCA1 or BRCA2 that is predicted to be deleterious. Testing may be performed at any time prior to inclusion. OR Documented deleterious germline or somatic alterations implicated in the HRR pathway (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCA, FAND2, FANCL, MRE11A, NBN, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D and RAD54L) or in MSI status. Testing may be performed at any time prior to inclusion. Local NGS can be used but reports will have to be sent to central NGS platforms for validation. A tumor biopsy sample must be available: if obtaining an adequate metastatic tumor biopsy is impossible (including bone metastasis), analyses will be done on a biopsy from the primary breast tumor
4. Patients with a life expectancy ≥16 weeks
5. ECOG performance status 0-1.
6. At least one evaluable lesion, either measurable or non-measurable that can be accurately assessed at baseline by CT-scan or MRI by RECIST v1.1
7. In the metastatic setting: patients must have received 1 line of endocrine therapy with CDK4/6 inhibitor and could have received 1 line of chemotherapy. Note 1: Patient may have received tamoxifen in first intent (the patient will have received a maximum of 2 lines of ET) Note 2: Fulvestrant and mTOR inhibitor are not allowed
8. Within 28 days prior to administration of study treatment, patients must have adequate organ and bone marrow functions:  Hemoglobin ≥10 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).  AST/ALT ≤2.5 x institutional ULN unless liver metastases are present in which case AST/ALT levels must be ≤5 x ULN.  Estimated creatinine clearance ≥ 51 mL/min according to the Cockcroft-Gault equation or based on a 24-hour urine test.
9. Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on day 1.
10. Woman of childbearing potential patients must agree to use adequate contraception for the duration of trial participation and up to 6 months after the last dose of olaparib. Male patients must use a condom during treatment and for 6 months after the last dose of olaparib when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception.
11. Patients having provided written informed consent prior to any study-related procedures
12. Patient is willing and able to comply with the protocol for the duration of the study
13. Patients must have national social insurance coverage (applicable only in France)

Exclusion criteria 26

1. Patients without olaparib targetable genomic anomaly identified during the screening phase.
2. Gene variants (class 1, 2, and 3) of unknown significant prognostic for olaparib sensitivity.
3. Patients with history of other malignancy except non-melanoma skin cancer, in-situ cancer of the cervix, or solid tumors including lymphomas (without bone marrow involvement) curatively treated and with no evidence of disease for ≥5 years prior to study entry
4. Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of myelodysplastic syndrome/acute myeloid leukemia
5. Patients with symptomatic uncontrolled brain metastases. In addition, treatment of the central nervous system disease must have finished (whole brain radiation, radiosurgery) at least 2 weeks before Cycle 1 Day 1. Patients must not require >10 mg of prednisone per day or an equivalent dose of other corticosteroids
6. Prior treatment with a PARP inhibitor (including olaparib) and/or PD-1 or PD-L1 inhibitor (including durvalumab).
7. Patients having received anticancer chemotherapy or any other investigational therapy within 3 weeks prior of the study. Endocrine therapy must have been discontinued 7 or more days before Cycle 1 Day 1 and CDK4/6 inhibitor must have been discontinued 14 or more days before Cycle 1 Day 1. Palliative radiotherapy must have been completed 14 or more days before Cycle 1 Day 1. Biphosphonates and denosumab are allowed.
8. Major surgery within 2 weeks prior to registration. Patients must have recovered from earlier major surgery before registration.
9. Persistent toxicities (NCI-CTCAE grade ≥2) caused by previous cancer therapy, excluding alopecia and peripheral neuropathy (grade ≤2).
10. Patients with known history of bleeding diathesis or hemorrhage.
11. 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 HBV surface antigen [HBsAg] result), hepatitis C (HCV), or human immunodeficiency virus (positive HIV 1/2 antibodies). 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 HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
12. Patients considered at poor medical condition due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection, symptomaticcongestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, and active bleeding diatheses. 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.
13. Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (eg. unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation >470 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome
14. Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab, with the exceptions of intranasal or inhaled corticosteroids or systemic corticosteroids at physiological doses, not exceeding 10 mg/day of prednisone, or an equivalent corticosteroid.
15. Active or prior documented autoimmune disease within the past 2 years except for patients with vitiligo or psoriasis without systemic treatment during the past 2 years
16. Active or prior documented inflammatory bowel disease (Crohn’s disease, ulcerative colitis).
17. History of allogeneic organ transplant, including previous allogenic bone marrow transplant or double umbilical cord blood transplantation
18. Received live attenuated vaccination within 30 days prior to study entry
19. Patients unable to swallow orally administered medication, patients with gastrointestinal disorders likely to interfere with the absorption of olaparib, and patients with long-term oral anticoagulant therapy (excluding Warfarin).
20. Pregnant or breast feeding women
21. Known hypersensitivity to durvalumab, olaparib, and/or fulvestrant or any of the excipients of these products
22. Concomitant use of a known :  Strong or moderate CYP3A inhibitors. The required washout period prior to starting olaparib is 2 weeks.  Strong or moderate CYP3A inducers. The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents. Warning: For men and pre/per-menopausal women who will receive goserelin (Zoladex®) in combination with study drugs, the use of concomitant drugs which can prolong the QT interval or induce Torsades de pointes should be evaluated with caution
23. Whole blood transfusions in the 120 days prior to study enrolment (packed red blood cells and platelet transfusions are acceptable, if outside of 28 days prior to treatment).
24. Persons deprived of their liberty or under protective custody or guardianship
25. Patients enrolled in another therapeutic study within 30 days prior inclusion
26. Involvement in the planning and/or conduct of the study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The progression-free survival rate at 24 weeks defined as the percentage of patients alive without disease progression at 24 weeks after inclusion. PFSR will be evaluated by local investigator using Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST v1.1). The death of a patient for any cause within 24 weeks will be considered as failure.

Secondary endpoints 11

1. Safety endpoint in overall and germline BRCA mutated populations 1. The safety will be evaluated according to the NCI-CTCAE v5.0.
2. Efficacy endpoint in the overall study population 1. OS is defined as the interval between the date of inclusion and the date of death from any cause. A patient alive will be censored at the last date of follow-up.
3. The RECIST v1.1 will be used to determine: 2. The ORR defined as the percent of patients with a complete response (CR) or a partial response (PR).
4. 3. The DoR defined as the duration between the time measurement criteria are first met for CR or PR until the first date that recurrent disease is objectively documented
5. 4. PFS defined as the interval between the date of inclusion and the date of progression or death. A patient alive and without progression will be censored at the last date of follow-up.
6. Efficacy endpoint in the germline BRCA mutated population 1. OS is defined as the interval between the date of inclusion and the date of death from any cause. A patient alive at analysis will be censored at the last date of follow-up.
7. The RECIST v1.1 will be used to determine: 2. PFSR at 24 weeks defined as the percentage of patients without disease progression and who are alive at 24 weeks after inclusion. The death of a patient for any cause within 24 weeks will be considered as failure.
8. 3. The ORR defined as the number and the percent of patients with a CR or PR.
9. 4. The DoR defined as the duration between the time measurement criteria are first met for CR or PR until the first date that recurrent disease is objectively documented.
10. 5. PFS defined as the interval between the date of inclusion and the date of progression or death. A patient alive and without progression at analysis will be censored at the last date of follow-up.
11. Exploratory analysis to evaluate efficacy in terms of OS, PFS, ORR, and DoR and safety will be performed in patients: 1. Previously treated with CDK4/6 inhibitors. 2. With different PD-L1 expression status.

Investigational products

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

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Unicancer

Sponsor organisation

Unicancer

Address

101 Rue De Tolbiac

City

Paris

Postcode

75013

Country

France

Scientific contact point

Organisation

Unicancer

Contact name

Nourredine AIT RAHMOUNE

Public contact point

Organisation

Unicancer

Contact name

Nourredine AIT RAHMOUNE

Locations

3 EU/EEA countries · 42 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 34 files

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

Application history

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