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Trial record 1 of 1 for:    NCT02997995
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Durvalumab and Endocrine Therapy in ER+/Her2- Breast Cancer After CD8+ Infiltration Effective Immune-Attractant Exposure (ULTIMATE)

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ClinicalTrials.gov Identifier: NCT02997995
Recruitment Status : Active, not recruiting
First Posted : December 20, 2016
Last Update Posted : February 15, 2019
Sponsor:
Collaborator:
Breast International Group
Information provided by (Responsible Party):
UNICANCER

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Breast Cancer Estrogen Receptor Positive Tumor Menopause Hormone Antagonist Drug: Immune-attractant Drug: Durvalumab Procedure: Biopsy Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 240 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : February 15, 2017
Estimated Primary Completion Date : September 2019
Estimated Study Completion Date : September 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Durvalumab

Arm Intervention/treatment
Experimental: 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.
Drug: Immune-attractant
The first cohort patients will receive tremelimumab (3 mg/kg, single infusion) as immune-attractants combined with exemestane (25 mg daily).
Other Name: Tremelimumab

Drug: Durvalumab
Durvalumab (lymphocyte activation) will be administrated at a dose of 1500 mg Q4W (equivalent to 20 mg/kg Q4W) IV, combined with exemestane (25 mg daily), for six months
Other Name: MEDI4736

Procedure: Biopsy
After three weeks (+/- 3 days) of immune-attractants, a tumor biopsy will be done. Patients who present >10% CD8+ cells in the tumor after 3 weeks will receive the Durvalumab




Primary Outcome Measures :
  1. pathological Complete Response [ Time Frame: at time of surgery ]
    Response at surgery


Secondary Outcome Measures :
  1. Number of CD8+ T cell [ Time Frame: at biopsy (3 weeks) ]
    exam at biopsy and comparison between biopsy and Baseline biopsy rates

  2. Clinical response [ Time Frame: after 6 months of Durvalumab ]
    Clinical exam

  3. Assessment of Ki67 [ Time Frame: at surgery ]
    measure of Ki67

  4. Toxicities [ Time Frame: 1 year and 8 months ]
    Common terminology criteria for adverse events (CTC-AE) v4.03

  5. Predictive value of Mutational load for efficacy of Durvalumab [ Time Frame: on baseline biopsy and blood samples ]
    exome sequencing on baseline samples

  6. Predictive value of PDL1 expression for the efficacy of Durvalumab [ Time Frame: on baseline biopsy and biopsy at 3 weeks ]
    correlate Immune infiltrate intensity with the proportion of tumor cells expressing PD-L1 by Ventana SP263 assay



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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 >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 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 × 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.

    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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02997995


Locations
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France
Centre Hospitalier cote Basque
Bayonne, France, 64109
Institut Bergonié
Bordeaux, France, 33000
Centre François Baclesse
Caen, France
Centre Hospitalier de Cahors
Cahors, France, 46000
Centre Hôspitalier de Cholet
Cholet, France, 49300
Centre George François Leclerc
Dijon, France, 21000
Institut Daniel Hollard Groupe Hôspitalier
Grenoble, France, 38028
Centre Oscar Lambret
Lille, France, 59020
CHU Limoges
Limoges, France, 87042
Centre Hospitalier Bretagne Sud
Lorient, France, 56100
Centre Léon Bérard
Lyon, France, 69008
Institut Paoli Calmettes
Marseille, France, 13009
Institut Curie Site Paris
Paris, France, 75005
Hôpital Saint Louis APHP
Paris, France, 75010
Centre Hospitalier Perpignan
Perpignan, France, 66000
Institut Jean Godinot
Reims, France, 51726
Institut Curie Hôpital René Huguenin
Saint Cloud, France, 92210
Centre Paul Strauss
Strasbourg, France, 67065
Institut Claudius Regaud
Toulouse, France, 31059
CHU Bretonneau - Centre Henry Kaplan
Tours, France, 37044
Gustave Roussy
Villejuif, France, 94800
Spain
ICO Badalona
Badalona, Spain
Hospital Clinic Barcelona
Barcelona, Spain
HU Vall Hebron
Barcelona, Spain
HU Arnau de Vilanova
Lleida, Spain
CIO Clara Campal
Madrid, Spain
HU Ramon y Cajal
Madrid, Spain
Hospital Clínico Universitario de Valencia
Valencia, Spain
Sweden
Sahlgrenska University Hospital
Gothenburg, Sweden
Sponsors and Collaborators
UNICANCER
Breast International Group
Investigators
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Principal Investigator: Fabrice Andre, Prof Gustave ROUSSY

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Responsible Party: UNICANCER
ClinicalTrials.gov Identifier: NCT02997995     History of Changes
Other Study ID Numbers: UC-0140/1606
UCBG-105 ( Other Identifier: UNICANCER )
BIG 16-01 ( Other Identifier: BIG )
2016-000764-42 ( EudraCT Number )
First Posted: December 20, 2016    Key Record Dates
Last Update Posted: February 15, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by UNICANCER:
T2-T4 Breast cancer
Estrogen Receptor Positive Tumor
PD-1
Neoadjuvant
Immune-attractants
lymphocytes activation
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Durvalumab
Tremelimumab
Exemestane
Antibodies, Monoclonal
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists