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Autologous huMNC2-CAR44 or huMNC2-CAR22 T Cells for Breast Cancer Targeting Cleaved Form of MUC1 (MUC1*)

Primary Purpose

Metastatic Breast Cancer

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
huMNC2-CAR44 CAR T cells or huMNC2-CAR22 CAR T cells
huMNC2-CAR44 CAR T cells or huMNC2-CAR22 CAR T cells @ RP2D
Sponsored by
Minerva Biotechnologies Corporation
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Metastatic Breast Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Confirmation of diagnosis of breast cancer by internal pathology review of initial or subsequent biopsy or other pathologic material at FHCRC/SCCA. ER, PR, and HER2 status known and documented per ASCO/CAP guidelines.
  2. Patients must have received standard metastatic systemic therapy per NCCN guidelines or institutional practice which are known to confer benefit. No maximum on number of prior systemic treatment regimens.

    1. Patients with hormone receptor positive disease must have received at least 3 prior endocrine therapies and at least 2 prior lines of chemotherapy in the metastatic setting.
    2. Patients with HER2 positive breast cancer must have received at least 3 prior HER2-directed therapies (trastuzumab, pertuzumab, TDM-1 or others) in the metastatic setting.
    3. Patients with triple negative disease must have received at least 2 prior lines of chemotherapy in the metastatic setting.
  3. MUC1* membrane expression ≥30% by immunohistochemistry on a tumor specimen obtained at screening or previous tumor specimen.
  4. Patients must be 18 years of age or older, of any gender, race or ethnicity.
  5. Patients must be capable of understanding and providing a written informed consent.
  6. Patients must have a Karnofsky performance status of ≥ 60%.
  7. Patients must have measurable disease by at least one of the criteria below:

    1. Extra skeletal disease that can be accurately measured by CT or MRI per RECIST 1.1,
    2. Skeletal or bone-only metastases measurable by FDG PET imaging
  8. Negative serum pregnancy test within 14 days before leukapheresis and within 28 days before lymphodepleting chemotherapy for women of childbearing potential, defined as those who have not been surgically sterilized or who have not been free of menses for at least 1 year.
  9. Fertile male and female patients must be willing to use an effective contraceptive method before, during, and for at least 4 months after the huMNC2-CAR44 T cell infusion.

Exclusion Criteria:

  1. Patients requiring ongoing daily corticosteroid therapy at a dose of >15 mg of prednisone per day (or equivalent). Pulsed corticosteroid use for disease control is acceptable.
  2. Active autoimmune disease requiring immunosuppressive therapy is excluded unless discussed with the PI.
  3. Major organ dysfunction defined as:

    1. Serum creatinine > 2 mg/dL
    2. Bilirubin ≥ 1.5 mg/dL with the following exception: Patients with known Gilbert disease, serum bilirubin > 3 mg/dL
    3. AST or ALT ≥ 2.5 x upper institutional limit of normal with the following exception: Patients with known hepatic metastases, AST or ALT > 3 x upper institutional limit of normal
    4. Patients with clinically significant pulmonary dysfunction, as determined by medical history and physical exam should undergo pulmonary function testing. Those with an FEV1 of < 50 % of predicted or DLCO (corrected) < 40% will be excluded.
    5. Significant cardiovascular abnormalities as defined by any one of the following:

    i. NYHA class III or IV congestive heart failure, ii. clinically significant hypotension, iii. uncontrolled symptomatic coronary artery disease, or iv. a documented ejection fraction of <45%. Any patient with an EF of 45-49% must receive clearance by a cardiologist to be eligible for the trial.

  4. ANC <1000/mm3.
  5. Hemoglobin <9 mg/dl (transfusion permitted to achieve this).
  6. Platelet count <75,000/mm3.
  7. Treatment with investigational agent(s) within 30 days of planned lymphodepletion.
  8. HIV seropositive.
  9. Uncontrolled active infection.
  10. Anticipated survival of <3 months.
  11. Breast-feeding women.
  12. Patients who have a contraindication to cyclophosphamide chemotherapy.
  13. Known second malignancy that is progressing or requires active treatment.
  14. Untreated CNS metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate with documented stable disease as defined by no evidence of progression by imaging or symptoms for at least 4 weeks prior to enrollment.
  15. Have psychiatric illness, social situation, or other medical condition that would preclude informed consent to limit compliance with study requirements, as determined by the investigator.

Sites / Locations

  • City of Hope Medical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Dose Escalation

Luminal

HER2+

Triple Negative

Arm Description

Dose escalation or de-escalation is tested in cohorts of 3 patients each using standard "3+3" dose-finding.

Dose Expansion - 15 patients will be enrolled with luminal (hormone receptor positive, HER2 negative) metastatic breast cancer.

Dose Expansion - 15 patients will be enrolled with HER2+ metastatic breast cancer.

Dose Expansion - 15 patients will be enrolled with triple negative metastatic breast cancer.

Outcomes

Primary Outcome Measures

Incidence of Adverse Events
To determine the safety and maximally tolerated cell dose (MTD) and recommended phase 2 cell dose (RP2D) of ex vivo expanded autologous huMNC2-CAR44 T cells or huMNC2-CAR22 CAR T cells for patients with advanced MUC1* positive breast cancer using CTCAE version 5.0 and Lee criteria.

Secondary Outcome Measures

In vivo persistence
Determine duration of in vivo persistence and phenotype of adoptively transferred huMNC2-CAR44 T cells or huMNC2-CAR22 CAR T cells.
Preliminary Antitumor Activity
Preliminary antitumor activity of the adoptive transfer of huMNC2-CAR44 T cells or huMNC2-CAR22 CAR T cells in all patients with measurable tumor prior to T cell transfer by RECIST 1.1
Antitumor Activity
Determine antitumor activity at MTD/RP2D of huMNC2-CAR44 T cells or huMNC2-CAR22 CAR T cells in patients with luminal breast cancer (hormone receptor positive, HER2 negative), HER2 positive breast cancer, and triple negative breast cancer (hormone receptor and HER2 negative) by RECIST 1.1 in expansion cohorts.

Full Information

First Posted
July 12, 2019
Last Updated
June 15, 2023
Sponsor
Minerva Biotechnologies Corporation
Collaborators
City of Hope Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT04020575
Brief Title
Autologous huMNC2-CAR44 or huMNC2-CAR22 T Cells for Breast Cancer Targeting Cleaved Form of MUC1 (MUC1*)
Official Title
Adoptive Immunotherapy for Advanced MUC1* Positive Breast Cancer With Autologous T Cells Engineered to Express a Chimeric Antigen Receptor, huMNC2-CAR44 or huMNC2-CAR22, Specific for a Cleaved Form of MUC1 (MUC1*)
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 15, 2020 (Actual)
Primary Completion Date
January 2025 (Anticipated)
Study Completion Date
January 15, 2035 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Minerva Biotechnologies Corporation
Collaborators
City of Hope Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

Brief Summary
Phase I/II study of adoptive immunotherapy for advanced MUC1* positive breast cancer with autologous T cells engineered to express either a chimeric antigen receptor, huMNC2-CAR44 or huMNC2-CAR22, which are specific for a cleaved form of MUC1 (MUC1*).
Detailed Description
Recent trials have demonstrated that chimeric antigen receptor (CAR)-modified T cells (CAR-T cells) specific for the CD19 molecule can mediate marked tumor regression in a subset of patients with advanced acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL). It would be ideal to extend CAR-T cell therapy to common epithelial cancers. However, this poses several challenges, including the identification of molecules expressed on tumor cells that can be targeted safely with CAR-T cells. Minerva Biotechnologies has developed a CAR T product (huMNC2-CAR44 or huMNC2-CAR22) that targets the extra cellular domain of the cleaved form of MUC1 (called MUC1*), which is the form of MUC1 that functions as a growth factor receptor and is present on large percentage of solid tumors, including breast tumors. The antibody targeting head of huMNC2-CAR44 or huMNC2-CAR22 specifically recognizes a cancerous form of MUC1* and does not bind to another form of cleaved MUC1 that is present on some normal tissues that also have a rapid turnover. To be clear, patients will receive either huMNC2-CAR44 or huMNC2-CAR22, but not a combined product. The huMNC2-CAR44 product consists of autologous T cells that are isolated from cancer patients, transduced with a proprietary lentiviral vector backbone manufactured under cGMP and containing sequences for a human CD8 alpha leader sequence, humanized MNC2-scFv (MUC1* targeting head), portions of human CD8 hinge and transmembrane domains, and human 4-1BB and human CD3-zeta costimulatory domains. The huMNC2-CAR44 transduced T cells are antigen-stimulated in vitro, with a synthetic MUC1* extracellular domain peptide. The CAR T cells are then ready for administration to the patient. Alternatively, the CAR T cells can be cryopreserved, then administered to the patient after thaw at bedside. The huMNC2-CAR22 product is comprised of a CD8-α leader sequence, the huMNC2 scFv, a CD28 hinge and transmembrane region, followed by a CD28 co-stimulatory domain and a CD3-ζ signaling domain bearing two Tyrosine to Phenylalanine mutations in each of ITAMs 2 and 3 to minimize CAR T cell exhaustion and increase in vivo persistence. The huMNC2-CAR22 transduced T cells are not antigen-stimulated. The CAR T cells can be cryopreserved, then administered to the patient after thaw at bedside. The investigators propose to evaluate the safety and preliminary anti-tumor activity of adoptively transferred autologous T cells genetically modified to express a CAR that targets MUC1*, huMNC2-CAR44 or huMNC2-CAR22, in Phase I/II clinical trials in patients with metastatic MUC1* positive breast cancers.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metastatic Breast Cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
69 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Dose Escalation
Arm Type
Experimental
Arm Description
Dose escalation or de-escalation is tested in cohorts of 3 patients each using standard "3+3" dose-finding.
Arm Title
Luminal
Arm Type
Experimental
Arm Description
Dose Expansion - 15 patients will be enrolled with luminal (hormone receptor positive, HER2 negative) metastatic breast cancer.
Arm Title
HER2+
Arm Type
Experimental
Arm Description
Dose Expansion - 15 patients will be enrolled with HER2+ metastatic breast cancer.
Arm Title
Triple Negative
Arm Type
Experimental
Arm Description
Dose Expansion - 15 patients will be enrolled with triple negative metastatic breast cancer.
Intervention Type
Biological
Intervention Name(s)
huMNC2-CAR44 CAR T cells or huMNC2-CAR22 CAR T cells
Intervention Description
huMNC2-CAR44 T cells or huMNC2-CAR22 CAR T cells are an autologous T cell product transduced with a proprietary lentiviral vector backbone coding for humanized MNC2-scFv (the targeting head).
Intervention Type
Biological
Intervention Name(s)
huMNC2-CAR44 CAR T cells or huMNC2-CAR22 CAR T cells @ RP2D
Intervention Description
huMNC2-CAR44 T cells or huMNC2-CAR22 CAR T cells are an autologous T cell product transduced with a proprietary lentiviral vector backbone coding for humanized MNC2-scFv (the targeting head) @ RP2D
Primary Outcome Measure Information:
Title
Incidence of Adverse Events
Description
To determine the safety and maximally tolerated cell dose (MTD) and recommended phase 2 cell dose (RP2D) of ex vivo expanded autologous huMNC2-CAR44 T cells or huMNC2-CAR22 CAR T cells for patients with advanced MUC1* positive breast cancer using CTCAE version 5.0 and Lee criteria.
Time Frame
Within 35 days after T cell infusion
Secondary Outcome Measure Information:
Title
In vivo persistence
Description
Determine duration of in vivo persistence and phenotype of adoptively transferred huMNC2-CAR44 T cells or huMNC2-CAR22 CAR T cells.
Time Frame
Up to 365 days after the T cell infusion
Title
Preliminary Antitumor Activity
Description
Preliminary antitumor activity of the adoptive transfer of huMNC2-CAR44 T cells or huMNC2-CAR22 CAR T cells in all patients with measurable tumor prior to T cell transfer by RECIST 1.1
Time Frame
Up to 15 years
Title
Antitumor Activity
Description
Determine antitumor activity at MTD/RP2D of huMNC2-CAR44 T cells or huMNC2-CAR22 CAR T cells in patients with luminal breast cancer (hormone receptor positive, HER2 negative), HER2 positive breast cancer, and triple negative breast cancer (hormone receptor and HER2 negative) by RECIST 1.1 in expansion cohorts.
Time Frame
Up to 15 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Please note that results of tests and/or procedures conducted as per standard of care purposes may be used for research purposes if conducted within the protocol-defined window prior to screening/leukapheresis and/or T-Cell Therapy. Inclusion Criteria: Confirmation of diagnosis of breast cancer by pathology review of initial or subsequent biopsy or other pathologic material at the City of Hope Pathology department. ER, PR, and HER2 status known and documented per ASCO/CAP guidelines. For dose expansion cohorts, tumors with ER and/or PR ≥1% will be considered hormone receptor positive. Tumors with ER and PR <1% will be considered hormone receptor negative. HER2 status will be determined by IHC or FISH per ASCO/CAP guidelines. Patients will be allocated to expansion cohorts according to guidelines in table below. Dose expansion cohorts Expansion Cohort Hormone Receptor status HER2 status Luminal ER and/or PR >/=1% positive Negative by IHC or FISH HER2 positive Any ER or PR status Positive by IHC or FISH Triple Negative ER and PR <1% Negative by IHC or FISH Patients must have received standard metastatic systemic therapy per NCCN guidelines or institutional practice which are known to confer benefit. No maximum on number of prior systemic treatment regimens. Patients with hormone receptor positive disease must have received at least 3 prior endocrine therapies and at least 2 prior lines of chemotherapy in the metastatic setting. Patients with HER2 positive breast cancer must have received at least 3 prior HER2- directed therapies (trastuzumab, pertuzumab, TDM-1 or others) in the metastatic setting. Patients with triple negative disease must have received at least 2 prior lines of chemotherapy in the metastatic setting. MUC1* membrane expression ≥30% by immunohistochemistry on a tumor specimen obtained at screening or previous tumor specimen that is less than 6-months old (see Appendix I for examples of MUC1* expression patterns). Patients must be 18 years of age or older, of any gender, race or ethnicity. Patients must be capable of understanding and providing a written informed consent. Patients must have a Karnofsky performance status of ≥60%. Patients must have measurable disease by at least one of the criteria below: Extra skeletal disease that can be accurately measured by CT or MRI per RECIST 1.1, Skeletal or bone-only metastases measurable by FDG PET imaging. Negative serum pregnancy test within 14 days of planned leukapheresis and within 28 days of lymphodepleting chemotherapy for women of childbearing potential, defined as those who have not been surgically sterilized or who have not been free of menses for at least 1 year. Fertile male and female patients must be willing to use an effective contraceptive method before, during, and for at least 4 months after the huMNC2-CAR T cell infusion. Exclusion Criteria: Patients requiring ongoing daily corticosteroid therapy at a dose of >15 mg of prednisone per day (or equivalent). Pulsed corticosteroid use for disease control is acceptable. Active autoimmune disease requiring immunosuppressive therapy is excluded unless discussed with the PI. Major organ dysfunction defined as: Serum creatinine > 2 mg/dL Bilirubin ≥ 1.5 mg/dL with the following exception: Patients with known Gilbert disease, serum bilirubin > 3 mg/dL AST or ALT ≥ 2.5 x upper institutional limit of normal with the following exception: Patients with known hepatic metastases, AST or ALT > 3x upper institutional limit of normal Patients with clinically significant pulmonary dysfunction, as determined by medical history and physical exam should undergo pulmonary function testing. Those with an FEV1 of < 50 % of predicted or DLCO (corrected) < 40% will be excluded. Significant cardiovascular abnormalities as defined by any one of the following: i. NYHA class III or IV congestive heart failure, ii. clinically significant hypotension, iii. uncontrolled symptomatic coronary artery disease, or iv. a documented ejection fraction of <45%. Any patient with an EF of 45-49% must receive clearance by a cardiologist to be eligible for the trial. ANC <1000/mm^3. Hemoglobin <9 mg/dl (transfusion permitted to achieve this). Platelet count <75,000/mm^3. Treatment with investigational agent(s) within 30 days of planned lymphodepletion. HIV seropositive. Uncontrolled active infection. Anticipated survival of <3 months. Breast-feeding women. Patients who have a contraindication to cyclophosphamide chemotherapy. Known second malignancy that is progressing or requires active treatment. Untreated CNS metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate with documented stable disease as defined by no evidence of progression by imaging or symptoms for at least 4 weeks prior to enrollment. Have psychiatric illness, social situation, or other medical condition that would preclude informed consent to limit compliance with study requirements, as determined by the investigator.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Joanne Mortimer, MD
Phone
1-800-826-4673
Email
Minerva18625@coh.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Joanne Mortimer, MD
Organizational Affiliation
City of Hope Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
City of Hope Medical Center
City
Duarte
State/Province
California
ZIP/Postal Code
91010-3000
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Joanne Mortimer, MD
Phone
800-826-4673
First Name & Middle Initial & Last Name & Degree
Joanne Mortimer, MD

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Autologous huMNC2-CAR44 or huMNC2-CAR22 T Cells for Breast Cancer Targeting Cleaved Form of MUC1 (MUC1*)

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