E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with ER+ and HER2- primary non-metastatic breast cancer who are eligible to neoadjuvant endocrine therapy. |
|
E.1.1.1 | Medical condition in easily understood language |
Non-metastatic breast cancer |
|
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 | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10006187 |
E.1.2 | Term | Breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
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 assess the efficacy of durvalumab combined with exemestane in patients with CD8+ T cells on pathological response at surgery after a lymphocyte attraction phase. |
|
E.2.2 | Secondary objectives of the trial |
Efficacy Criteria : 1/ To evaluate the capacity of several “immune-attractants” approaches to increase CD8+ T cells in the tumor site and to determine the best “immune-attractant”. The ability to attract CD8+ T cells in the tumor will be assessed by comparing the rate of CD8+ T cells after part 1 treatment with rate of CD8+ T cells at baseline. 2/ To assess the efficacy of six months durvalumab + exemestane combination therapy in ER+/Her2- BC presenting CD8+ T cells after 4-6 weeks exposure to immune-attractants on secondary endpoints 3/ To evaluate whether durvalumab expands intratumor lymphocytes.
Safety : 4/ To assess the safety of each treatment (part 1 and part 2).
Molecular and Exploratory : 5/ To assess the predictive value of mutational load, PDL1 expression on the efficacy of durvalumab / endocrine therapy 6/ To identify predictive biomarkers as measured by mutation, expression and copy number data for the efficacy of durvalumab / endocrine therapy
|
7/ To explore the pCR after six months durvalumab + exemestane according to the lymphocyte attraction treatment 8/ To assess CD8+ cells in surgical specimens of non-pCR patients- 9/ To correlate Immune infiltrate intensity with the proportion of tumor cells expressing PD-L1. |
|
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 |
|
E.3 | Principal inclusion criteria |
1. Age ≥18 years post-menopausal according to the following criteria: Age > 60 years Bilateral ovariectomy Age ≤ 60, with an uterus and presenting an amenorrhea of more than 12 months Age ≤ 60, without an uterus and FSH > 20 IU/L 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 > 3cm 4. Non metastatic, M0 (according to clinical staging); 5. ER-positive by IHC according to local assessment; 6. Her2-negative by IHC (score 0 or 1+) and/or FISH/CISH negative according to local assessment; 7. CD8+ T Cell infiltration defined as >10% cells stained with anti-CD8 mAB 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 × the ULN. This will not apply to patients with confirmed Gilbert’s syndrome, who will be allowed in consultation with their physician. ALT and AST ≤2.5 × ULN; Calculated creatinine clearance >50 mL/min as determined by Cockcroft-Gault (using actual body weight) Males: Creatinine CL (mL/min) =Weight (kg) × (140 - Age) /(72 × serum creatinine (mg/dL)) Females: Creatinine CL (mL/min) =Weight (kg) × (140 - Age) × 0.85 / (72 × serum creatinine (mg/dL)) 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.
|
|
E.4 | Principal exclusion criteria |
1. 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;
2. Any concurrent chemotherapy, investigational product (IP), biologic therapy for cancer treatment;
3. Previous Radiotherapy treatment to more than 30% of the bone marrow;
4. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose;
5. History of allogenic organ transplantation;
6. 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;
7. 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;
8. Mean QT interval corrected for heart rate using Fridericia’s formula (QTcF) ≥470 ms;
9. History of active primary immunodeficiency;
10. Known history of active tuberculosis;
11. Active infection including hepatitis B, hepatitis C, or human immunodeficiency virus (HIV)
12. 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)
13. 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.
14. Known allergy or hypersensitivity to IP or any excipient |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Rate of pathological complete response on the surgical specimen. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
EFFICACY CRITERIA -Number of CD8+ T cells - Clinical response after 6 months therapy. Clinical response is determined by tumor assessments performed by palpation -Assessment of Ki67 on the surgical specimen according to the recommendations from the International Ki67 in Breast cancer Working Group. -Measurement of TILs according to the recommendations published by the international TILs working group 2014
SAFETY - According to the CTC-AE v4.03.
TRANSLATIONAL RESEARCH (EXPLORATORY ENDPOINTS): - Predictive value of Mutational load for the efficacy of durvalumab will be assessed by whole exome sequencing on baseline samples - Predictive value of PDL1 expression for the efficacy of durvalumab will be assessed both on baseline samples and at 3 weeks biopsy (Ventana SP263 assay) - Other biomarker research will be defined by the study steering committee at the end of the trial to ensure the optimal use of update technologies and hypotheses
|
|
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 | Yes |
E.6.13.1 | Other scope of the trial description |
identification of predictive biomarkers |
|
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 | No |
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 | No |
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.8.3 |
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 | 20 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |