A Phase Ib Study With a Safety lead-in Cohort and Expansion Phase, of the Safety, Tolerability, Biological Effect, and Efficacy of Allogenic Natural Killer Cells in Combination With Trastuzumab and Pertuzumab in Adult Patients With Refractory Metast

• Status: Recruiting
• Trial end date: 2025-04-11

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.

• Phase: Phase 1

Details

• Lead Sponsor: Vall d'Hebron Institute of Oncology
• Collaborators: Banc de Sang i Teixits; Clinica Universidad de Navarra, Universidad de Navarra; Hospital del Mar; Puerta de Hierro University Hospital
• Treatments: Cyclophosphamide; Interleukin-2; Pertuzumab; Trastuzumab