Clinical Trials /

Durvalumab and Endocrine Therapy in ER+/Her2- Breast Cancer After CD8+ Infiltration Effective Immune-Attractant Exposure

NCT02997995

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Durvalumab and Endocrine Therapy in ER+/Her2- Breast Cancer After CD8+ Infiltration Effective Immune-Attractant Exposure
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: UC-0140/1606
  • SECONDARY ID: UCBG-105
  • SECONDARY ID: BIG 16-01
  • SECONDARY ID: 2016-000764-42
  • NCT ID: NCT02997995

Conditions

  • Breast Cancer
  • Estrogen Receptor Positive Tumor
  • Menopause
  • Hormone Antagonist

Interventions

DrugSynonymsArms
Immune-attractantTremelimumabImmune-attractant/lymphocyte activation
DurvalumabMEDI4736Immune-attractant/lymphocyte activation

Purpose

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.

Detailed Description

      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 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-weeks 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.
    

Trial Arms

NameTypeDescriptionInterventions
Immune-attractant/lymphocyte activationExperimentalAfter 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.
  • Immune-attractant
  • Durvalumab

Eligibility Criteria

        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 > 3cm

          4. Non metastatic, M0 (according to clinical staging);

          5. Luminal A patients ER-positive by 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 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; 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:pathological Complete Response
Time Frame:at time of surgery
Safety Issue:
Description:Response at surgery

Secondary Outcome Measures

Measure:Number of CD8+ T cell
Time Frame:at biopsy (3 weeks)
Safety Issue:
Description:exam at biopsy and comparison between biopsy and Baseline biopsy rates
Measure:Clinical response
Time Frame:after 6 months of Durvalumab
Safety Issue:
Description:Clinical exam
Measure:Assessment of Ki67
Time Frame:at surgery
Safety Issue:
Description:measure of Ki67
Measure:Toxicities
Time Frame:1 year and 8 months
Safety Issue:
Description:CTC AE v4.03
Measure:Predictive value of Mutational load for efficacy of Durvalumab
Time Frame:on baseline biopsy and blood samples
Safety Issue:
Description:exome sequencing on baseline samples
Measure:Predictive value of PDL1 expression for the efficacy of Durvalumab
Time Frame:on baseline biopsy and biopsy at 3 weeks
Safety Issue:
Description:correlate Immune infiltrate intensity with the proportion of tumor cells expressing PD-L1 by Ventana SP263 assay

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:UNICANCER

Trial Keywords

  • T2-T4 Breast cancer
  • Estrogen Receptor Positive Tumor
  • PD-1
  • Neoadjuvant
  • Immune-attractants
  • lymphocytes activation

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