Clinical Trials /

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

NCT04020575

Description:

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*)

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Phase I Study of Autologous huMNC2-CAR44 T Cells for Breast Cancer Targeting Cleaved Form of MUC1 (MUC1*)
  • Official Title: 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*)

Clinical Trial IDs

  • ORG STUDY ID: 10038
  • NCT ID: NCT04020575

Conditions

  • Metastatic Breast Cancer

Interventions

DrugSynonymsArms
huMNC2-CAR44 CAR T cellsDose Escalation
huMNC2-CAR44 CAR T cells @ RP2DLuminal

Purpose

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*)

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.
    

Trial Arms

NameTypeDescriptionInterventions
Dose EscalationExperimentalDose escalation or de-escalation is tested in cohorts of 3 patients each using standard "3+3" dose-finding.
  • huMNC2-CAR44 CAR T cells
LuminalExperimentalDose Expansion - 15 patients will be enrolled with luminal (hormone receptor positive, HER2 negative) metastatic breast cancer.
  • huMNC2-CAR44 CAR T cells @ RP2D
HER2+ExperimentalDose Expansion - 15 patients will be enrolled with HER2+ metastatic breast cancer.
  • huMNC2-CAR44 CAR T cells @ RP2D
Triple NegativeExperimentalDose Expansion - 15 patients will be enrolled with triple negative metastatic breast cancer.
  • huMNC2-CAR44 CAR T cells @ RP2D

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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

Secondary Outcome Measures

Measure:In vivo persistence
Time Frame:Up to 365 days after the T cell infusion
Safety Issue:
Description:Determine duration of in vivo persistence and phenotype of adoptively transferred huMNC2-CAR44 T cells.
Measure:Preliminary Antitumor Activity
Time Frame:Up to 15 years
Safety Issue:
Description: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
Measure:Antitumor Activity
Time Frame:Up to 15 years
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Minerva Biotechnologies Corporation

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