A Phase II Trial Testing Durvalumab Combined With Endocrine Therapy in Patients With ER+/Her2- Breast Cancer Eligible for Neoadjuvant Endocrine Therapy And Who Present CD8+ T Cell Infiltration After 4-6 Weeks Exposure to Immune-Attractant
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- UNICANCER
- 入组人数
- 61
- 试验地点
- 29
- 主要终点
- pathological Complete Response
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •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
- •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
- •cT2-T4, any N; cT2 are eligible only if the clinical tumor size is >3 cm
- •Non metastatic, M0 (according to clinical staging)
- •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%
- •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
- •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)
- •Available tumor samples from baseline biopsy
- •World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at enrolment
- •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)
- •Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures
- •Written informed consent obtained prior to performing any protocol-related procedures, including screening evaluations
排除标准
- •Inflammatory breast cancer
- •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
- •Any concurrent chemotherapy, investigational product (IP), biologic therapy for cancer treatment
- •Previous Radiotherapy treatment to more than 30% of the bone marrow;
- •Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose
- •History of allogenic organ transplantation
- •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
- •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
- •Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms
- •History of active primary immunodeficiency
- •Known history of active tuberculosis
- •Active infection including hepatitis B, hepatitis C, or human immunodeficiency virus (HIV)
- •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)
- •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
- •Known allergy or hypersensitivity to any medicinal product used in the trial or any excipient
研究组 & 干预措施
Immune-attractant/lymphocyte activation
After the screening phase, the patient will receive immune-attractant combined with exemestane for six weeks. 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 i.e. lymphocyte activation. In this second part, patients will receive durvalumab 1500 mg Q4W (equivalent to 20 mg/kg Q4W) IV, combined with exemestane (25 mg daily), for six months. The pathological response will be checked by surgery.
干预措施: Immune-attractant (Drug)
Immune-attractant/lymphocyte activation
After the screening phase, the patient will receive immune-attractant combined with exemestane for six weeks. 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 i.e. lymphocyte activation. In this second part, patients will receive durvalumab 1500 mg Q4W (equivalent to 20 mg/kg Q4W) IV, combined with exemestane (25 mg daily), for six months. The pathological response will be checked by surgery.
干预措施: Durvalumab (Drug)
Immune-attractant/lymphocyte activation
After the screening phase, the patient will receive immune-attractant combined with exemestane for six weeks. 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 i.e. lymphocyte activation. In this second part, patients will receive durvalumab 1500 mg Q4W (equivalent to 20 mg/kg Q4W) IV, combined with exemestane (25 mg daily), for six months. The pathological response will be checked by surgery.
干预措施: Biopsy (Procedure)
结局指标
主要结局
pathological Complete Response
时间窗: at time of surgery
Response at surgery
次要结局
- Assessment of Ki67(at surgery)
- Predictive value of PDL1 expression for the efficacy of Durvalumab(on baseline biopsy and biopsy at 3 weeks)
- Clinical response(after 6 months of Durvalumab)
- Toxicities(1 year and 8 months)
- Predictive value of Mutational load for efficacy of Durvalumab(on baseline biopsy and blood samples)
- Number of CD8+ T cell(at biopsy (3 weeks))