| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| 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. |
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| E.1.1.1 | Medical condition in easily understood language |
| ER-positive and HER2-negative metastatic or locally advanced breast cancer |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10072740 |
| E.1.2 | Term | Locally advanced breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10070575 |
| E.1.2 | Term | Estrogen receptor positive breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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. |
|
| E.2.2 | Secondary objectives of the trial |
Safety objective in overall and germline BRCA mutated populations
1. To determine the safety of the combination of olaparib, durvalumab, and fulvestrant.
Efficacy objective in the overall study population
1. To determine the efficacy in term of overall survival (OS).
2. To determine the efficacy in term of objective response rate (ORR).
3. To determine the efficacy in term of duration of response (DoR).
4. To determine the efficacy in term of progression-free survival (PFS).
Efficacy objective in the germline BRCA mutated population
1. To determine the efficacy in term of OS.
2. To evaluate the efficacy in term of PFSR at 24 weeks.
3. To evaluate the efficacy in term of ORR.
4. To evaluate the efficacy in term of DoR.
5. To evaluate the efficacy in term of PFS.
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. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1. To investigate a diagnostic tool to predict response to the combination therapy.
2. To analyze the modulation of immune cell populations that might be predictive of tumor response to the combination therapy.
3. To assess pre/post treatment ctDNA mutational status |
|
| E.3 | Principal inclusion criteria |
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. 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 they 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). |
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| E.4 | Principal exclusion criteria |
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 disease, ... 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). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Safety endpoint in overall and germline BRCA mutated populations
1. Safety endpoint in overall and germline BRCA mutated populations will be evaluated according to the NCI-CTCAE v5.0.
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.
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).
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
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.
Efficacy endpoint in the germline BRCA mutated population will be evaluated in terms of OS, PFS, PFSR at 24 weeks, ORR and DoR.
Exploratory analysis to evaluate efficacy in terms of OS, PFS, ORR, and DoR and safety will be also performed in patients with: 1) prior CDK4/6 inhibitors ; 2) different PD-L1 expression status.
ANCILLARY ENDPOINT(S):
1. Investigation of the association of the RAD51 assay with alterations of BRCA1/2 and other HRR genes in one hand, and with clinical response in another hand.
2. Investigation of the correlation between biomarkers (biochemical, genomic) of the immune cell population and ORR that will be evaluated according the irRECIST criteria.
3 ctDNA sequencing will be performed on plasma samples to assess pre/post treatment ctDNA mutational status.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| a first step of safety run-in will be done in this study |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 55 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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