This is an open-label, multicentric, international, phase II trial testing aromatase
inhibitors in combination with durvalumab in patients with CD8+ T cell infiltration (>10%
CD8+ T cells in the tumor). The trial includes two sequences: The first part of the treatment
will consist in 4-6 weeks treatment with immune-attractants; in the second part, CD8+
patients will receive 6 months of durvalumab combined with exemestane.
The study is conducted in 2 parts:
Part 1: lymphocyte attraction. After the screening phase, the patient will receive
immune-attractant combined with exemestane for six weeks.
As immune-attractants are added over the course of the study, they will appear as subsequent
appendices in the full protocol.
Up to 4 cohorts may be tested sequentially in this design until up to 240 evaluable patients
have been treated.
The first cohort of patients will receive tremelimumab (3 mg/kg, single infusion) combined
with exemestane (25 mg daily). In each cohort, an interim analysis will be performed after 30
patients in order to potentially stop the cohort (if less than 25% of patients present >10%
CD8+ cells in the tumor after 3 weeks). If all 4 cohorts are closed and the target number of
56 patients for part 2 has not been reached, additional patients will be recruited and
treated with the best performing immune-attractant treatment based on the part I results.
From the moment 56 patients are included in part 2, no more patients will be entered in part
1.
After three weeks (+/- 3 days), a tumor biopsy will be done. Patients who present >10% CD8+
cells in the tumor after 3 weeks and remain eligible will be included in the second part of
the trial (patients who do not present CD8+ T cells on the 3-week biopsy will be treated at
the investigator's choice).
Part 2: lymphocyte activation (anti-PD1 treatment) Four to six weeks after immune-attractant
start, patients having >10% CD8+ cells in the tumor will receive durvalumab 1500 mg Q4W
(equivalent to 20 mg/kg Q4W) IV, combined with exemestane (25 mg daily), for six months.
Part 2 will include two steps. In the first step, we will include 23 patients. If 2 or more
pathological complete responses are observed in these 23 patients, the part 2 will move to
step 2. 33 additional patients will be included in the step 2.
Inclusion Criteria:
1. Age ≥18 years post-menopausal according to one of the following criteria:
- Age >60 years
- Or Bilateral ovariectomy
- Or Age ≤60, with an uterus and presenting an amenorrhea of more than 12 months
and FSH and estradiol in the postmenopausal range
- Or Age ≤60, without an uterus and FSH and estradiol in the postmenopausal range
2. Histologically proven invasive breast cancer eligible to neoadjuvant endocrine therapy
according to multidisciplinary tumor board.
Note: Multicentric/multifocal tumors are allowed if all share the same characteristics
3. cT2-T4, any N; cT2 are eligible only if the clinical tumor size is >3 cm
4. Non metastatic, M0 (according to clinical staging)
5. Luminal A patients ER-positive by immunohistochemistry (IHC) according to the
following criteria (local assessment): Grade I or II AND ER-positive (≥60%) AND Ki67
<20%
6. Her2-negative by IHC (score 0 or 1+) and/or fluorescent in situ hybridization
(FISH)/chromogenic in situ hybridization (CISH) negative according to local assessment
7. CD8+ T Cell infiltration defined as >10% cells stained with anti-CD8 monoclonal
antibody by IHC at the 3-week biopsy (applicable for inclusion in part 2 only)
8. Available tumor samples from baseline biopsy
9. World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance
status of 0 or 1 at enrolment
10. Adequate organ and marrow function as defined below:
- Hemoglobin ≥9.0 g/dL
- Absolute neutrophil count ≥1.5 × 10⁹/L
- Platelet count ≥100 × 10⁹/L
- Serum bilirubin ≤1.5 × upper limit of normal (ULN). This will not apply to
patients with confirmed Gilbert's syndrome, who will be allowed in consultation
with their physician
- Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) ≤2.5 × ULN
- Adequate renal function as determined by CKD-EPI formula (using actual body
weight)
11. Willingness and ability to comply with scheduled visits, treatment plan, laboratory
tests, and other trial procedures
12. Written informed consent obtained prior to performing any protocol-related procedures,
including screening evaluations
Exclusion Criteria:
1. Inflammatory breast cancer
2. No prior exposure to immune-mediated therapy including, but not limited to, other
anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-programmed cell death ligand 2
(anti-PD-L2) antibodies, excluding therapeutic anticancer vaccines
3. Any concurrent chemotherapy, investigational product (IP), biologic therapy for cancer
treatment
4. Previous Radiotherapy treatment to more than 30% of the bone marrow;
5. Major surgical procedure (as defined by the Investigator) within 28 days prior to the
first dose
6. History of allogenic organ transplantation
7. Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis with the
exception of diverticulosis, celiac disease or other serious gastrointestinal chronic
conditions associated with diarrhea), systemic lupus erythematosus, Sarcoidosis
syndrome, or Wegener syndrome (granulomatosis with polyangiitis), Graves' disease,
rheumatoid arthritis, hypophysitis, uveitis, etc within the past 3 years prior to the
start of treatment. The following are exceptions to this criterion:
- Patients with vitiligo or alopecia
- Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone
replacement or psoriasis not requiring systemic treatment
8. Any condition that, in the opinion of the Investigator, would interfere with the
evaluation of investigational product or interpretation of patient safety or study
results, including ongoing or active infection, symptomatic congestive heart failure,
uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial
lung disease, or psychiatric illness/social situations that would limit compliance
with study requirement, substantially increase risk of incurring adverse events from
investigational products, or compromise the ability of the patient to give written
informed consent
9. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms
10. History of active primary immunodeficiency
11. Known history of active tuberculosis
12. Active infection including hepatitis B, hepatitis C, or human immunodeficiency virus
(HIV)
13. Current or prior use of immunosuppressive medication within 14 days before the first
dose. The following are exceptions to this criterion:
- Intranasal, inhaled, topical steroids, or local steroid injections (eg,
intra-articular injection)
- Systemic corticosteroids at physiologic doses not exceeding 10 mg/day of
prednisone or its equivalent
- Steroids as premedication for hypersensitivity reactions (eg, CT scan
premedication)
14. Receipt of live, attenuated vaccine within 30 days prior to the first dose of IP.
Note: Patients, if enrolled, should not receive live vaccine during the study and up
to 30 days after the last dose of IP
15. Known allergy or hypersensitivity to any medicinal product used in the trial or any
excipient
