A Study of Allogenic Natural Killer Cells in Combination With Trastuzumab and Pertuzumab in Adult Patients With Refractory Metastatic Her2 Positive Breast Cancer. NK-ACT-BC_2020

Summary

Breast cancer is the second most common invasive malignancy and the leading cause of cancer-related mortality in women. Overexpression of human epidermal growth factor receptor 2 (HER2) is observed in approximately 20% of breast cancers.

Trastuzumab provided patients with HER2 overexpressing breast cancer a better outcome than chemotherapy alone. Trastuzumab and pertuzumab exert part of their activity based on antibody-dependent cell-mediated cytotoxicity (ADCC), mediated by natural killer (NK) cells.

Trastuzumab (Herceptin®) is a recombinant DNA-derived humanized monoclonal antibody that selectively binds with high affinity to the extracellular domain of the human epidermal growth factor receptor 2 (HER2). Inhibits the proliferation of human tumor cells that overexpress HER2 and to mediate antibody-dependent cellular cytotoxicity (ADCC).

Pertuzumab (Perjeta®) is a fully humanized monoclonal antibody and, like trastuzumab, is directed against the extracellular domain of HER2. It differs from trastuzumab because they bind to different domains. Due to their distinct mechanisms of action, the combination of pertuzumab and trastuzumab, is hypothesized to have complementary roles in treating HER2-overexpressing diseases.

Natural killer cells are lymphocytes arising from CD34+ hematopoietic progenitor cells in the bone marrow. NK cells are identified as CD3-, CD56+ lymphocytes. These cells were identified on the basis of their ability to lyse tumor cells without prior sensitization. NK function is also regulated by cytokines such as IL-2, IL-15, IL-12 and IL-18.

Our hypothesis is that the effect of trastuzumab and pertuzumab can be improved by regulating the efficiency of the ADCC activity through the infusion of ex-vivo activated allogenic NK cells.

Objetives:

Primary: To assess the safety and the tolerability of NK-ACT and trastuzumab/pertuzumab when used in combination.

Secondary: To evaluate the initial clinical activity of NK-ACT concomitant with trastuzumab/pertuzumab.

Exploratory Objectives: In vivo human NK cell biology:

* To describe the mechanisms of action of the combination of ICTP and rastuzumab/pertuzumab.
* To assess the biomarkers that might act as indicators of the immunemodulatory effect and anti-tumor activity of the combination.

Conditions

• Breast Neoplasms

Interventions

DRUG

Cyclophosphamide

Cyclophosphamide at a single dose of 600mg/m2 IV between days -5 and -3 before NK cell infusion for preconditioning the tumoral microenvironment by reducing the levels of lymphocyte T regulators (Tregs FOXP3+, CD3+, CD4+, CD25+).

DRUG

Trastuzumab

Trastuzumab at a dose of 8mg/kg IV for the loading dose on Day 1, and 6mg/kg IV for the maintenance dose every 3 weeks (Q3W).

DRUG

Pertuzumab

Pertuzumab at a dose of 840mg IV for the loading dose on Day 1, and 420 mg IV for the maintenance dose every 3 weeks (Q3W).

BIOLOGICAL

NK cells

NK product is a cellular investigational product comprising a live cell suspension of allogenic NK cells derived from a compatible donor that will be infused on Day 2.

DRUG

Interleukin-2

IL-2 (Proleukin) will be administered on Day 2 (within 24h after NK infusion), 4 and 6 as a subcutaneous dose of 5x105 UI/m2, following the label instructions.

Sponsors & Collaborators

• Clinica Universidad de Navarra, Universidad de Navarra

  collaborator OTHER

• Puerta de Hierro University Hospital

  collaborator OTHER

• Hospital del Mar

  collaborator OTHER

• Banc de Sang i Teixits

  collaborator OTHER

• Vall d'Hebron Institute of Oncology

  lead OTHER

Principal Investigators

• Elena Garralda, MD · Vall d'Hebron Institute of Oncology

• Ignacio Melero, MD · Clinica Universidad de Navarra

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Sex

FEMALE

Healthy Volunteers

No

Timeline & Regulatory

Start

2022-05-11

Primary Completion

2024-07-11

Completion

2024-07-11

Countries

• Spain

Study Locations