Ignite Creation Date:
2024-05-06 @ 5:40 PM
Last Modification Date:
2024-10-26 @ 2:33 PM
Study NCT ID:
NCT05385705
Status:
RECRUITING
Last Update Posted:
2024-04-23
First Post:
2022-05-17
Brief Title:
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
Sponsor:
Vall dHebron Institute of Oncology
Organization:
Vall dHebron Institute of Oncology
Study Overview
Official Title:
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:
RECRUITING
Status Verified Date:
2024-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 trastuzumabpertuzumab when used in combination
Secondary To evaluate the initial clinical activity of NK-ACT concomitant with trastuzumabpertuzumab
Exploratory Objectives In vivo human NK cell biology
To describe the mechanisms of action of the combination of ICTP and rastuzumabpertuzumab
To assess the biomarkers that might act as indicators of the immunemodulatory effect and anti-tumor activity of the combination
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 trastuzumabpertuzumab when used in combination
Secondary To evaluate the initial clinical activity of NK-ACT concomitant with trastuzumabpertuzumab
Exploratory Objectives In vivo human NK cell biology
To describe the mechanisms of action of the combination of ICTP and rastuzumabpertuzumab
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 600mgm2 IV between days -5 and -3 before NK cell infusion
Trastuzumab at a dose of 8mgkg IV for the loading dose and 6mgkg 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 UIm2 on day 2 4 and 6 after NK infusion
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 600mgm2 IV between days -5 and -3 before NK cell infusion
Trastuzumab at a dose of 8mgkg IV for the loading dose and 6mgkg 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 UIm2 on day 2 4 and 6 after NK infusion
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None