ULTIMATE (BIG 16-01)

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An open-label, multicentre, international 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.

ClinicalTrials.gov identifier: NCT02997995

ULTIMATE is an international phase II clinical trial set up to evaluate the safety and efficacy of an immunotherapy treatment with durvalumab when given before surgery (i.e. neoadjuvant treatment) and in combination with the standard endocrine therapy (exemestane). Durvalumab is expected to activate the immune system (specifically white cells called the T lymphocytes) to reinforce the pre-surgical anti-tumour treatment.

This trial is being conducted in postmenopausal women with oestrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer whose recommended treatment includes an endocrine therapy prior to surgery.

Breast cancer patients whose tumours exceed 2 cm are candidates to receive neoadjuvant therapy, i.e. treatment given before breast surgery to reduce the tumour size.

International guidelines recommend the use of neoadjuvant endocrine therapy as an option in postmenopausal women presenting a ER+/HER2- breast cancer.

Cytotoxic T lymphocytes (also called CD8+ T cells) are a type of white cells that, once activated, may help fight cancer. The role of the drug durvalumab is to activate the CD8+ T cells.

The main objective of ULTIMATE is to evaluate whether adding durvalumab to standard endocrine therapy given before surgery will help boost the immune system and reinforce the anti-tumour treatment.

Since it is known that ER+ breast cancers present very few T lymphocytes within the tumour, the ULTIMATE trial consists of two treatment phases:

1. an initial phase to attract CD8+ T lymphocytes within the tumour

2. a second phase to activate these CD8+ T lymphocytes against the tumour

Part 1: lymphocyte attraction

Patients will receive an immune-attractant treatment concomitantly with the standard endocrine therapy (exemestane) for six weeks to boost the accumulation of T lymphocytes within the tumour.

After about three weeks of treatment, a tumour biopsy will be done to analyse the rate of CD8+ T lymphocytes accumulated in the tumour. If the rate of CD8+ cells in the tumour is high enough (>10%), patients will be included in the second part of the trial (patients who do not present a sufficient rate of CD8+ T cells will be offered the most suitable standard anticancer treatment by their doctor).

Part 2: lymphocyte activation (anti-PD1 treatment)

Patients eligible for the second part of the study will receive durvalumab in combination with the standard endocrine treatment (exemestane) until surgery (for approximately 6 months).The aim is to activate the immune cells (with the durvalumab) and contribute to the reduction of the tumour size before surgery. This is important because a smaller tumour is removed more easily and has a better prognosis

Patients with ER+ / HER2- operable breast cancer who are eligible to receive a neoadjuvant endocrine therapy.

- up to 240 patients will be involved in the first part of the study (with immune-attractants)

- up to 56 patients will be eligible for the second part of the study (treatment with durvalumab)

This study is conducted and sponsored by UNICANCER (France) in collaboration with the Breast International Group (BIG).

Recruitment started in 2017.

The study is currently open in France, Spain and Sweden.

Not yet applicable.

ULTIMATE is made possible by a grant and drugs provided by AstraZeneca. It is conducted according to BIG’s Principles of Research Conduct.