NCT05385705

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

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 Metastatic Her2 Positive Breast Cancer

• Status: Terminated
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 2 (actual)
• Sponsor: Vall d'Hebron Institute of Oncology · Academic / Other
• Sex: Female
• Age: 18 Years
• Healthy volunteers: Not accepted

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.

Detailed description

This is an open label, multi-center, proof of concept, phase Ib trial. A total of 6 patients will be included in the safety lead-in phase. If signs of both clinical and biological activity are seen, and no more than 1 TLT is observed in those first 6 patients, the study will expand with 14 additional patients (expansion phase). Enrollment - 24 months Duration - 35 months During the lead-in phase and the expansion phase, a staggered enrollment will be employed. In the lead-in phase, the subsequent patient will start the treatment after the TLT period completion (28 days) of the previously treated patient. In the expansion cohort, the patients will be dosed successively with a safety monitoring interval of at least 48 hours between the last subcutaneous administration of IL-2 in the previous patient and the first administration of intravenous cyclophosphamide (D-5) in the subsequent patient. Study treatment: Cyclophosphamide at a single dose of 600mg/m2 IV between days -5 and -3 before NK cell infusion. Trastuzumab at a dose of 8mg/kg IV for the loading dose, and 6mg/kg IV for the maintenance dose every 3 weeks (Q3W). Pertuzumab at a dose of 840mg IV for the loading dose, and 420 mg IV for the maintenance dose every 3 weeks (Q3W) NKs at a minimum dose of 5x107 NKc and at a maximum dose limit of 5x108 NKc. IL-2 at a dose of 5x105 UI/m2, on day 2, 4, and 6 after NK infusion.

Conditions

• Breast Neoplasms

Interventions

Type	Name	Description
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.

Timeline

• Start date: 2022-05-11
• Primary completion: 2024-07-11
• Completion: 2024-07-11
• First posted: 2022-05-23
• Last updated: 2025-09-22

Locations

2 sites across 1 country: Spain