Phase I Study of Autologous huMNC2-CAR44 T Cells for Breast Cancer Targeting Cleaved Form of MUC1 (MUC1*)
- Confirmation of diagnosis of breast cancer by internal pathology review of initial or subsequent biopsy or other pathologic material at Fred Hutchinson Cancer Research Center (FHCRC)/Seattle Cancer Care Alliance (SCCA). Estrogen receptor (ER), progesterone receptor (PR), and HER2 status known and documented per American Society of Clinical Oncology (ASCO)/College of American Pathologists (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 fluorescence in situ hybridization (FISH) per ASCO/CAP guidelines. Patients will be allocated to expansion cohorts according to guidelines below: * Luminal: ER and/or PR >= 1% positive, HER2 negative by IHC or FISH * HER2 positive: Any ER or PR status, HER2 positive by IHC or FISH * Triple negative: ER and PR < 1%, HER2 negative by IHC or FISH.
- Patients must have received standard metastatic systemic therapy per National Comprehensive Cancer Network (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.
- Patients 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 computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1, * Skeletal or bone-only metastases measurable by fludeoxyglucose F-18 (FDG) positron emission tomography (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-CAR44 T cell infusion.
- 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 principal investigator (PI).
- Serum creatinine > 2 mg/dL.
- Bilirubin > 1.5 mg/dL with the following exception: Patients with known Gilbert disease, serum bilirubin > 3 mg/dL.
- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >= 2.5 x upper limit of institutional normal with the following exception: Patients with known hepatic metastases, AST or ALT > 3 x 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 forced expiratory volume in 1 second (FEV1) of < 50 % of predicted or diffusion capacity of the lung for carbon monoxide (DLCO) (corrected) < 40% will be excluded.
- Significant cardiovascular abnormalities as defined by any one of the following: * New York Heart Association (NYHA) class III or IV congestive heart failure, * Clinically significant hypotension, * Uncontrolled symptomatic coronary artery disease, or * A documented ejection fraction (EF) of < 45%. Any patient with an EF of 45-49% must receive clearance by a cardiologist to be eligible for the trial.
- Absolute neutrophil count (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.
- Human immunodeficiency virus (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 central nervous system (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.
I. To evaluate the safety and maximally tolerated 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 Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and Lee criteria.
I. To determine duration of in vivo persistence and phenotype of adoptively transferred huMNC2-CAR44 T cells.
II. To determine preliminary antitumor activity of the adoptive transfer of huMNC2-CAR44 T cells in all patients with measurable tumor prior to T cell transfer by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
III. To 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.
I. To determine trafficking of adoptively transferred huMNC2-CAR44 T cells to tumor sites and their effector function in vivo.
II. To evaluate the association between MUC1* tumor expression and huMNC2-CAR44 T cell persistence and anti-tumor response.
III. To evaluate changes in serum inflammatory cytokine levels in association with huMNC2-CAR44 T cell persistence and anti-tumor response.
IV. To evaluate the tumor immune microenvironment by multiplex immunohistochemistry (IHC) and Nanostring after huMNC2-CAR44 T cell therapy in patients with tumors accessible for pre and post treatment biopsy.
V. To evaluate changes in circulating tumor cells (CTCs) during huMNC2-CAR44 T cell therapy.
VI. To explore associations between pre-therapy CTCs, MUC1* expression on CTCs and huMNC2-CAR44 T cell persistence, toxicities and anti-tumor response.
OUTLINE: This is a dose escalation study of autologous huMNC2-CAR44 T cells.
Patients receive lymphodepleting chemotherapy consisting of cyclophosphamide intravenously (IV) on days 1-3 and fludarabine IV on days 1-3. Patients may receive a different lymphodepletion chemotherapy regimen at the principal investigator's discretion. Between 36 and 96 hours after completion of lymphodepleting chemotherapy, patients receive autologous huMNC2-CAR44 T cells IV over 20-30 minutes on day 0.
After completion of study treatment, patients are followed up every 30 days for 3 months, every 3 months up to 12 months, and then periodically for up to 15 years.
Trial Phase Phase I
Trial Type Treatment
Fred Hutch / University of Washington Cancer Consortium
Jennifer Marie Specht
- Primary ID RG1003846
- Secondary IDs NCI-2019-01491
- Clinicaltrials.gov ID NCT04020575