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

• ClinicalTrials.gov Identifier: NCT04020575
• Recruitment Status: Recruiting
• First Posted: July 16, 2019
• Last Update Posted: December 23, 2021
• Sponsor: Minerva Biotechnologies Corporation
• Collaborator: City of Hope Medical Center
• Information provided by (Responsible Party): Minerva Biotechnologies Corporation

Study Description

Brief Summary:

Phase I study of adoptive immunotherapy for advanced MUC1* positive breast cancer with autologous T cells engineered to express a chimeric antigen receptor, huMNC2-CAR44 specific for a cleaved form of MUC1 (MUC1*)

Condition or disease	Intervention/treatment	Phase
Metastatic Breast Cancer	Biological: huMNC2-CAR44 CAR T cells; Biological: huMNC2-CAR44 CAR T cells @ RP2D	Phase 1

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 (huMNC2-CAR44) 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 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. 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. 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, in a phase I clinical trial in patients with metastatic MUC1* positive breast cancer.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 69 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Adoptive Immunotherapy for Advanced MUC1* Positive Breast Cancer With Autologous T Cells Engineered to Express a Chimeric Antigen Receptor, huMNC2-CAR44 Specific for a Cleaved Form of MUC1 (MUC1*)
• Actual Study Start Date: January 15, 2020
• Estimated Primary Completion Date: January 2023
• Estimated Study Completion Date: January 15, 2035

Arms and Interventions

Arm	Intervention/treatment
Experimental: Dose Escalation; Dose escalation or de-escalation is tested in cohorts of 3 patients each using standard "3+3" dose-finding.	Biological: huMNC2-CAR44 CAR T cells; huMNC2-CAR44 T cells are an autologous T cell product transduced with a proprietary lentiviral vector backbone coding for humanized MNC2-scFv (the targeting head).
Experimental: Luminal; Dose Expansion - 15 patients will be enrolled with luminal (hormone receptor positive, HER2 negative) metastatic breast cancer.	Biological: huMNC2-CAR44 CAR T cells @ RP2D; huMNC2-CAR44 T cells are an autologous T cell product transduced with a proprietary lentiviral vector backbone coding for humanized MNC2-scFv (the targeting head) @ RP2D
Experimental: HER2+; Dose Expansion - 15 patients will be enrolled with HER2+ metastatic breast cancer.	Biological: huMNC2-CAR44 CAR T cells @ RP2D; huMNC2-CAR44 T cells are an autologous T cell product transduced with a proprietary lentiviral vector backbone coding for humanized MNC2-scFv (the targeting head) @ RP2D
Experimental: Triple Negative; Dose Expansion - 15 patients will be enrolled with triple negative metastatic breast cancer.	Biological: huMNC2-CAR44 CAR T cells @ RP2D; huMNC2-CAR44 T cells are an autologous T cell product transduced with a proprietary lentiviral vector backbone coding for humanized MNC2-scFv (the targeting head) @ RP2D

Outcome Measures

Primary Outcome Measures :

1. Incidence of Adverse Events [ Time Frame: Within 35 days after T cell infusion ]
   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 for patients with advanced MUC1* positive breast cancer using CTCAE version 5.0 and Lee criteria.

Secondary Outcome Measures :

1. In vivo persistence [ Time Frame: Up to 365 days after the T cell infusion ]
   Determine duration of in vivo persistence and phenotype of adoptively transferred huMNC2-CAR44 T cells.
2. Preliminary Antitumor Activity [ Time Frame: Up to 15 years ]
   Preliminary antitumor activity of the adoptive transfer of huMNC2-CAR44 T cells in all patients with measurable tumor prior to T cell transfer by RECIST 1.1
3. Antitumor Activity [ Time Frame: Up to 15 years ]
   Determine antitumor activity at MTD/RP2D of huMNC2-CAR44 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Contacts

Contact: Yuan Yuan, MD PhD; 1-800-826-4673; Minerva18625@coh.org

Locations

United States, California

City of Hope Medical Center; Recruiting

Duarte, California, United States, 91010-3000

Contact: Yuan Yuan, MD PhD 800-826-4673

Principal Investigator: Yuan Yuan, MD PhD

Sponsors and Collaborators

Minerva Biotechnologies Corporation

City of Hope Medical Center

Investigators

• Principal Investigator: Yuan Yuan, MD PhD; City of Hope Medical Center

More Information

• Responsible Party: Minerva Biotechnologies Corporation
• ClinicalTrials.gov Identifier: NCT04020575
• Other Study ID Numbers: 10038
• First Posted: July 16, 2019
• Last Update Posted: December 23, 2021
• Last Verified: December 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases