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ADDC-R - Epo-R T Cells With Trastuzumab in HER2+ Advanced Breast Cancer and Other Solid Tumors

Primary Purpose

HER2+ Advanced Breast Cancer, Other Solid Tumors

Status
Not yet recruiting
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
ADCC-R-Epo-R T-cells + Trastuzumab
Erythropoietin beta
Fludarabine and Cyclophosphosphamide
Sponsored by
National University Hospital, Singapore
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for HER2+ Advanced Breast Cancer

Eligibility Criteria

21 Years - 99 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Patients may be included in the study only if they meet all of the following criteria: Age ≥ 21 years. Histologically confirmed diagnosis of HER2-positive cancer defined by immunohistochemistry (IHC) to be HER2 IHC3+ or HER2 IHC2+ and FISH positive. If immunohistochemistry is not available, FISH method is acceptable. The HER2 positivities by FISH is determined as FISH amplification ratio positive by institutional guidelines. Tumor subtype for each phase include : Phase I: HER2-positive breast or gastric cancer or other treatment-refractory HER2-positive solid tumors Phase II : HER2-positive breast carcinoma Eastern Cooperative Oncology Group (ECOG) performance status 0-1. Has measurable or evaluable disease based on RECIST 1.1 criteria Estimated life expectancy of at least 12 weeks. Prior lines of therapy: HER2-positive breast cancer - patient must have failed at least two lines of anti-HER2 based therapy for advanced/metastatic cancer. Patients with documented relapse while receiving or within 6 months of completion of adjuvant or neoadjuvant trastuzumab for HER2-positive breast cancer will be considered as 1 prior line of therapy. HER2-positive gastric cancer - patient must have failed at least one line of anti-HER2 based therapy. Other refractory HER2-positive solid tumors (non-breast, non-gastric) - have no standard therapies or have failed or unable to tolerate standard therapies Has recovered from acute toxicities from prior anti-cancer therapies Left ventricular ejection fraction ≥50% Adequate organ function including the following: o Bone marrow: Absolute neutrophil (segmented and bands) count (ANC) ≥ 1.5 x 109/L Platelets ≥ 100 x 109/L Haemoglobin ≥ 8 x 109/L o Hepatic: Bilirubin ≤ 1.5 x upper limit of normal (ULN), ALT or AST≤ 2.5x ULN, (or ≤5 X with liver metastases) o Renal: Creatinine ≤ 1.5x ULN Signed informed consent from patient or legal representative. Able to comply with study-related procedures. Specific to cohorts 3, 4 and 5 : Patients who have a history of VTE are eligible if as long as they are receiving therapeutic/prophylactic doses of anticoagulation. Exclusion Criteria: Patients will be excluded from the study for any of the following reasons: Treatment within the last 30 days with any investigational drug. Concurrent administration of any other tumour therapy, including cytotoxic chemotherapy, hormonal therapy, and immunotherapy. Major surgery within 28 days of study drug administration. Active infection that in the opinion of the investigator would compromise the patient's ability to tolerate therapy. Pregnancy. Breast feeding. Serious concomitant disorders that would compromise the safety of the patient or compromise the patient's ability to complete the study, at the discretion of the investigator. Active bleeding disorder or bleeding site. Non-healing wound. Poorly controlled diabetes mellitus. Second primary malignancy that is clinically detectable at the time of consideration for study enrolment. Symptomatic brain metastasis. History of significant neurological or mental disorder, including seizures or dementia, History of autoimmune disease or use of gamma immunoglobulin Unable to comply with study procedures

Sites / Locations

    Arms of the Study

    Arm 1

    Arm Type

    Experimental

    Arm Label

    ADCC-R-Epo-R T-cells

    Arm Description

    Eligible patients will undergo apheresis prior to cycle 1 therapy. Treatment comprises of trastuzumab followed by ADCC-R-Epo-R T-cells in cycle 1. Subcutaneous Erythropoetin beta (SC Epo) will be administered during cycle 1 in dose levels 3, 4, and 5. Lymphodepletion will be carried out in dose level 5, with fludarabine and cyclophosphamide. During Cycle 2 onwards till disease progression, patients will receive IV or SC trastuzumab only, every 3 weeks.

    Outcomes

    Primary Outcome Measures

    Time to treatment failure
    defined as the time from the date of study enrolment to the date of the first of the following events: early discontinuation of study therapy, progressive disease, or death due to any cause. Time to treatment failure will be censored at the date of the last follow-up visit for patients who did not discontinue early, who are still alive, and who have not progressed.
    Progression-free survival
    is defined as the time from the date of study enrolment to the first date of documented disease progression. Progression-free survival will be censored at the date of death for patients who have not had documented disease progression. For patients who are still alive at the time of analysis and who have not had documented disease progression, progression-free survival will be censored at the date of the last follow-up visit.
    Duration of tumour response
    Among tumor responders, the duration of tumor response is measured from the date of enrolment until the first date of documented disease progression or death due to any cause, whichever occurs first. Duration of tumor response will be censored at the date of the last follow-up visit for tumor responders who are still alive and who have not progressed.

    Secondary Outcome Measures

    Full Information

    First Posted
    August 31, 2023
    Last Updated
    September 26, 2023
    Sponsor
    National University Hospital, Singapore
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    1. Study Identification

    Unique Protocol Identification Number
    NCT06027983
    Brief Title
    ADDC-R - Epo-R T Cells With Trastuzumab in HER2+ Advanced Breast Cancer and Other Solid Tumors
    Official Title
    Phase IB Followed by Phase II Study of Trastuzumab Combined With Autologous T Cells Expressing an Antibody-dependent Cell Cytotoxicity Receptor (ADCC-R) and an Erythropoietin Receptor (Epo-R) in HER2+ Advanced Breast Cancer and Other Solid Tumors
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    June 2023
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    November 1, 2023 (Anticipated)
    Primary Completion Date
    December 31, 2025 (Anticipated)
    Study Completion Date
    December 31, 2027 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    National University Hospital, Singapore

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Product Manufactured in and Exported from the U.S.
    No
    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    This phase Ib study aims to assess the safety and feasibility of combination of ADCC-R-Epo-R T cells with trastuzumab in patients with HER2+ solid tumors, with further expansion of study population in HER2+ metastatic breast cancer once safety has been established.
    Detailed Description
    Hypothesis Investigator hypothesize that trastuzumab-mediated ADCC will be augmented by the infusion of autologous ADCC-R-Epo-R T-cells. Investigator further hypothesize that infused ADCC-R Epo-R T-cells can expand in vivo in the absence of prior lymphodepletion, supported by either endogenous levels of Epo or exogenous Epo administration. Primary Objectives To determine the safety of autologous ADCC-R-Epo-R T-cells in patients with HER2+ advanced solid tumors To determine the clinical benefit rate (CBR) of autologous ADCC-R-Epo-R T-cells in patients with HER2+ advanced breast cancer Secondary Objectives To determine the expansion and persistence of autologous ADCC-R-Epo-R T-cells after a single infusion in patients with advanced solid tumors To determine anti-tumor efficacy in terms of objective response rate (ORR) and progression-free survival (PFS) of autologous ADCC-R-Epo-R T-cells in patients with HER2+ advanced breast cancer Exploratory Objectives To determine if endogenous levels of Epo can stimulate and support the expansion of ADCC-R-Epo-R T-cells in vivo To investigate if exogenous administration of Epo can support the persistence of ADCC-R-Epo-R T-cells in vivo when endogenous Epo is not sufficient To study the presence of ADCC-R-Epo-R T-cells in tumors and tumor microenvironment using serial tumor biopsies

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    HER2+ Advanced Breast Cancer, Other Solid Tumors

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 1, Phase 2
    Interventional Study Model
    Sequential Assignment
    Model Description
    This is a single arm, open-label, phase Ib safety lead in, followed by phase II study. The phase Ib segment will be carried out in a standard 3+3 dose escalation design. In the phase II, dose expansion will be carried out to a total of 10 patients at recommended phase II dose in both phase Ib and II. Phase Ib: Patients with advanced solid tumors will be enrolled in a 3+3 dose escalation fashion, with projected enrolment of between 6-30 patients to determine RP2D. Once the RP2D is confirmed, the study will proceed to phase II. Phase II: Up to a total of 10 patients with HER2+ advanced breast cancer will be enrolled. For patients who are in Dose level 3 - 5 will require additional Trastuzumab,erythropoietin beta and Lymphodepletion.
    Masking
    None (Open Label)
    Allocation
    N/A
    Enrollment
    36 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    ADCC-R-Epo-R T-cells
    Arm Type
    Experimental
    Arm Description
    Eligible patients will undergo apheresis prior to cycle 1 therapy. Treatment comprises of trastuzumab followed by ADCC-R-Epo-R T-cells in cycle 1. Subcutaneous Erythropoetin beta (SC Epo) will be administered during cycle 1 in dose levels 3, 4, and 5. Lymphodepletion will be carried out in dose level 5, with fludarabine and cyclophosphamide. During Cycle 2 onwards till disease progression, patients will receive IV or SC trastuzumab only, every 3 weeks.
    Intervention Type
    Drug
    Intervention Name(s)
    ADCC-R-Epo-R T-cells + Trastuzumab
    Intervention Description
    ADCC-R-Epo-R T-cells will be administered by infusion. Trastuzumab will be administered intravenously.
    Intervention Type
    Drug
    Intervention Name(s)
    Erythropoietin beta
    Intervention Description
    Administered as Subcutaneously
    Intervention Type
    Drug
    Intervention Name(s)
    Fludarabine and Cyclophosphosphamide
    Other Intervention Name(s)
    Lymphodepletion
    Intervention Description
    3-day chemotherapy regimen of fludarabine and cyclophosphamide for lymphodepletion
    Primary Outcome Measure Information:
    Title
    Time to treatment failure
    Description
    defined as the time from the date of study enrolment to the date of the first of the following events: early discontinuation of study therapy, progressive disease, or death due to any cause. Time to treatment failure will be censored at the date of the last follow-up visit for patients who did not discontinue early, who are still alive, and who have not progressed.
    Time Frame
    3 years
    Title
    Progression-free survival
    Description
    is defined as the time from the date of study enrolment to the first date of documented disease progression. Progression-free survival will be censored at the date of death for patients who have not had documented disease progression. For patients who are still alive at the time of analysis and who have not had documented disease progression, progression-free survival will be censored at the date of the last follow-up visit.
    Time Frame
    3 Years
    Title
    Duration of tumour response
    Description
    Among tumor responders, the duration of tumor response is measured from the date of enrolment until the first date of documented disease progression or death due to any cause, whichever occurs first. Duration of tumor response will be censored at the date of the last follow-up visit for tumor responders who are still alive and who have not progressed.
    Time Frame
    3 Years

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    21 Years
    Maximum Age & Unit of Time
    99 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Patients may be included in the study only if they meet all of the following criteria: Age ≥ 21 years. Histologically confirmed diagnosis of HER2-positive cancer defined by immunohistochemistry (IHC) to be HER2 IHC3+ or HER2 IHC2+ and FISH positive. If immunohistochemistry is not available, FISH method is acceptable. The HER2 positivities by FISH is determined as FISH amplification ratio positive by institutional guidelines. Tumor subtype for each phase include : Phase I: HER2-positive breast or gastric cancer or other treatment-refractory HER2-positive solid tumors Phase II : HER2-positive breast carcinoma Eastern Cooperative Oncology Group (ECOG) performance status 0-1. Has measurable or evaluable disease based on RECIST 1.1 criteria Estimated life expectancy of at least 12 weeks. Prior lines of therapy: HER2-positive breast cancer - patient must have failed at least two lines of anti-HER2 based therapy for advanced/metastatic cancer. Patients with documented relapse while receiving or within 6 months of completion of adjuvant or neoadjuvant trastuzumab for HER2-positive breast cancer will be considered as 1 prior line of therapy. HER2-positive gastric cancer - patient must have failed at least one line of anti-HER2 based therapy. Other refractory HER2-positive solid tumors (non-breast, non-gastric) - have no standard therapies or have failed or unable to tolerate standard therapies Has recovered from acute toxicities from prior anti-cancer therapies Left ventricular ejection fraction ≥50% Adequate organ function including the following: o Bone marrow: Absolute neutrophil (segmented and bands) count (ANC) ≥ 1.5 x 109/L Platelets ≥ 100 x 109/L Haemoglobin ≥ 8 x 109/L o Hepatic: Bilirubin ≤ 1.5 x upper limit of normal (ULN), ALT or AST≤ 2.5x ULN, (or ≤5 X with liver metastases) o Renal: Creatinine ≤ 1.5x ULN Signed informed consent from patient or legal representative. Able to comply with study-related procedures. Specific to cohorts 3, 4 and 5 : Patients who have a history of VTE are eligible if as long as they are receiving therapeutic/prophylactic doses of anticoagulation. Exclusion Criteria: Patients will be excluded from the study for any of the following reasons: Treatment within the last 30 days with any investigational drug. Concurrent administration of any other tumour therapy, including cytotoxic chemotherapy, hormonal therapy, and immunotherapy. Major surgery within 28 days of study drug administration. Active infection that in the opinion of the investigator would compromise the patient's ability to tolerate therapy. Pregnancy. Breast feeding. Serious concomitant disorders that would compromise the safety of the patient or compromise the patient's ability to complete the study, at the discretion of the investigator. Active bleeding disorder or bleeding site. Non-healing wound. Poorly controlled diabetes mellitus. Second primary malignancy that is clinically detectable at the time of consideration for study enrolment. Symptomatic brain metastasis. History of significant neurological or mental disorder, including seizures or dementia, History of autoimmune disease or use of gamma immunoglobulin Unable to comply with study procedures
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Soo Chin Lee
    Phone
    +65 6908 2222
    Email
    soo_chin_lee@nuhs.edu.sg
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Soo Chin Lee
    Organizational Affiliation
    National University Hospital, Singapore
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Plan to Share IPD
    No
    Citations:
    PubMed Identifier
    32522887
    Citation
    Lee SC, Shimasaki N, Lim JSJ, Wong A, Yadav K, Yong WP, Tan LK, Koh LP, Poon MLM, Tan SH, Ow SGW, Bharwani L, Yap YS, Foo MZQ, Coustan-Smith E, Sundar R, Tan HL, Chong WQ, Kumarakulasinghe NB, Lieow JLM, Koe PJX, Goh BC, Campana D. Phase I Trial of Expanded, Activated Autologous NK-cell Infusions with Trastuzumab in Patients with HER2-positive Cancers. Clin Cancer Res. 2020 Sep 1;26(17):4494-4502. doi: 10.1158/1078-0432.CCR-20-0768. Epub 2020 Jun 10.
    Results Reference
    result
    PubMed Identifier
    24197131
    Citation
    Kudo K, Imai C, Lorenzini P, Kamiya T, Kono K, Davidoff AM, Chng WJ, Campana D. T lymphocytes expressing a CD16 signaling receptor exert antibody-dependent cancer cell killing. Cancer Res. 2014 Jan 1;74(1):93-103. doi: 10.1158/0008-5472.CAN-13-1365. Epub 2013 Nov 6.
    Results Reference
    result
    PubMed Identifier
    31697835
    Citation
    Vinanica N, Yong A, Wong D, Png YT, Seow SV, Imamura M, Campana D. Specific stimulation of T lymphocytes with erythropoietin for adoptive immunotherapy. Blood. 2020 Feb 27;135(9):668-679. doi: 10.1182/blood.2019001645.
    Results Reference
    result

    Learn more about this trial

    ADDC-R - Epo-R T Cells With Trastuzumab in HER2+ Advanced Breast Cancer and Other Solid Tumors

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