A Study of CART-TnMUC1 in Patients With TnMUC1-Positive Advanced Cancers

Multiple Myeloma Clinical Trial

Official title:

A Phase 1 Open-Label, Multi-Center First in Human Study of TnMUC1-Targeted Genetically-Modified Chimeric Antigen Receptor T Cells in Patients With Advanced TnMUC1-Positive Solid Tumors and Multiple Myeloma

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04025216
• Other study ID #: CART-TnMUC1-01
• Status: Terminated
• Phase: Phase 1
• Start date: October 10, 2019
• Est. completion date: December 2, 2022

Study information

• Verified date: April 2023
• Source: Gilead Sciences
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Multi-center, open-label, first in human Phase 1 study of the safety, tolerability, feasibility, and preliminary efficacy of the administration of genetically modified autologous T cells (CART-TnMUC1 cells) engineered to express a chimeric antigen receptor (CAR) capable of recognizing the tumor antigen, TnMUC1 and activating the T cell (CART- TnMUC1 cells).

Description:

The Dose Escalation phase of the study is designed to identify the dose and regimen of CART-TnMUC1 cells that can be safely administered intravenously following the lymphodepletion (LD) regimen to patients with (1) advanced TnMUC1+ solid tumors (triple negative breast cancer, epithelial ovarian cancer, pancreatic cancer, and non-small cell lung cancer) and (2) advanced TnMUC1+ multiple myeloma in a parallel two-arm dose escalation study. The Dose Escalation phase is anticipated to enroll approximately 40 patients.

The Expansion phase of the study is designed to assess the preliminary efficacy of CART-TnMUC1 cells administered intravenously to patients with TnMUC1+ solid tumors. The Expansion phase is anticipated to enroll approximately 72 patients (18 patients per each tumor indication).

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 16
• Est. completion date: December 2, 2022
• Est. primary completion date: December 2, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Key Inclusion Criteria:

• Confirmed diagnosis of metastatic treatment-resistant ovarian cancer (including cancers of the fallopian tube), pancreatic adenocarcinoma, hormone receptor (HR)-negative and HER2-negative (triple negative) breast cancer (TNBC) or non-small cell lung cancer (NSCLC), or relapsed/refractory multiple myeloma

• Eastern Cooperative Oncology Group (ECOG) score of 0 or 1

• Prior therapies as defined by tumor type:

• Multiple myeloma: relapsed or refractory disease previously treated with or intolerant to at least three different lines of therapy that contained at least one of the following drug classes: proteasome inhibitor, an immune modulatory drug, alkylators, CD38 monoclonal antibody and glucocorticoids. Patients must be at least 90 days since autologous stem cell transplant

• NSCLC: i.) Patients without driver mutations must have received standard therapy, including both checkpoint inhibition and platinum-based chemotherapy or be intolerant of these standard therapies ii.) Patients with driver mutations must have received or be intolerant to prior targeted therapy directed at the specific identified mutations in addition to the standard chemotherapy classes

• Pancreatic adenocarcinoma: disease progression following at least one standard of care systemic chemotherapy for metastatic or unresectable disease or be intolerant of these standard therapies

• TNBC: ER and/or PR < or =10%, HER2 negative and experienced disease progression following at least one prior systemic anti-cancer therapy regimen as part of their treatment for management of metastatic breast cancer or be intolerant to these standard therapies

• Ovarian: platinum-resistant (progression of disease by either CA-125, clinical or radiographic assessment within 6 months of last platinum-based chemotherapy ) and must have received at least two prior lines of therapy for metastatic ovarian cancer, including at least one prior line of therapy including a platinum-containing regimen or be intolerant of these standard therapies

• Evaluable disease as defined by tumor type

• TnMUC1+ disease, determined by centrally tested TnMUC1 expression in a prior or archival tumor biopsy

• Toxicities from any previous therapy must have recovered to Grade 1 or baseline

• Estimated estimated glomerular filtration rate = 60 m/min by Modification of Diet in Renal Disease criteria

• Aspartate aminotransferase (AST) or alanine aminotransferase (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

• Serum total bilirubin < 1.5 mg/dL with the following exception: patients with known Gilbert's disease, serum total bilirubin < 3 mg/dL

• Serum albumin = 3.0 g/dL (solid tumor patients in Arm 1 and Phase 1a only, not applicable to patients with multiple myeloma)

• Left ventricular ejection fraction (LVEF) = 50%. LVEF assessment must have been performed within 6 months of treatment start

• Hemoglobin = 8 g/dL

• Absolute neutrophil count = 1000/µL

• Platelet count = 75,000/µL (for Multiple Myeloma patients with bone marrow plasma cells = 50% of cellularity: = 30,000/µL)

• Patients of reproductive potential agree to use approved contraceptive methods per protocol

Key Exclusion Criteria:

• Active invasive cancer other than the proposed cancers included in the study

• Current treatment with systemic high-dose corticosteroids (defined as a dose greater than the equivalent of prednisone 10 mg/day)

• Active autoimmune disease (including connective tissue disease, uveitis, sarcoidosis, inflammatory bowel disease or multiple sclerosis) or have a history of severe autoimmune disease requiring prolonged immunosuppressive therapy (any immunosuppressive therapy should have been stopped within 6 weeks prior to screening visit)

• Current human immunodeficiency virus (HIV), hepatitis C virus (HCV), hepatitis B virus (HBV) infections

• Other active or uncontrolled medical or psychiatric condition that would preclude participation in the opinion of the Sponsor or Principal Investigator

• Prior allogeneic stem cell transplant

• Active and untreated central nervous system (CNS) malignancy

• History of severe infusion reaction to monoclonal antibodies or biological therapies, or to study product excipients that would preclude the patient safely receiving CART-TnMUC1 cells

• Active or recent (within the past 6 months prior to apheresis) cardiovascular disease, defined as (1) New York Heart Association (NYHA) Class III or IV heart failure, (2) unstable angina or (3) a history of recent (within 6 months) myocardial infarction or sustained (> 30 second) ventricular tachyarrhythmias, or (4) cerebrovascular accident

• Have inadequate venous access for or contraindications for the apheresis procedure

• Pregnant or breastfeeding women

Related Conditions & MeSH terms

• Fallopian Tube Cancer
• Fallopian Tube Neoplasms
• Multiple Myeloma
• Neoplasms, Plasma Cell
• Non-Small Cell Lung Cancer
• Ovarian Cancer
• Pancreatic Ductal Adenocarcinoma
• Triple Negative Breast Cancer
• Triple Negative Breast Neoplasms

Intervention

Biological:
• CART-TnMUC1
Single intravenous administration of genetically modified autologous T cells engineered to express a TnMUC1-Targeted Genetically-Modified Chimeric Antigen (CAR)

Drug:
• Cyclophosphamide
Patients will receive cyclophosphamide and fludarabine lymphodepletion chemotherapy followed by the investigational product, CART-TnMUC1
• Fludarabine
Patients will receive cyclophosphamide and fludarabine lymphodepletion chemotherapy followed by the investigational product, CART-TnMUC1

Locations

Country	Name	City	State
United States	University of Chicago Medical Center	Chicago	Illinois
United States	The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	The Angeles Clinic and Research Institute	Los Angeles	California
United States	Sarah Cannon Research Institute	Nashville	Tennessee
United States	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Mayo Clinic of Arizona	Phoenix	Arizona
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	University of Washington Medical Center	Seattle	Washington
United States	Moffitt Cancer Center	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Kite, A Gilead Company

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dose Escalation: Dose Identification of CART-TnMUC1	Incidence of Dose Limiting Toxicity (DLT) in solid tumors and multiple myeloma	Up to 2 years
Primary	Cohort Expansion: Objective Response in solid tumors	Proportion of patients having a confirmed Complete Response (CR) or Partial Response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1	Up to 2 years
Secondary	Safety of CART-TnMUC1 in solid tumors and multiple myeloma	Percentage of patients experiencing adverse events (AEs), including serious and severe AEs overall, by dose level, and by severity Grade	Up to 2 years
Secondary	Tolerability of CART-TnMUC1 in solid tumors and multiple myeloma	Frequency of treatment emergent AEs, frequency of clinical changes from baseline in vital signs, changes in electrocardiogram, and hematology and chemistry laboratory shifts from baseline	Up to 2 years
Secondary	Feasibility of CART-TnMUC1 in solid tumors and multiple myeloma	Proportion of enrolled patients who did not receive CART-TnMUC1 cells	Up to 2 years
Secondary	Preliminary anti-tumor efficacy of CART as assessed by Overall Survival (OS) in solid tumors and multiple myeloma	OS as defined by the interval between CART-TnMUC1 cell infusion and date of death by any cause	Up to 2 years
Secondary	Preliminary anti-tumor efficacy of CART as assessed by Progression Free Survival (PFS) in solid tumors	PFS as defined by the interval between CART-TnMUC1 cell infusion and date of disease progression by RECIST v1.1 or death in solid tumors and by International Myeloma Working Group (IMWG) criteria in multiple myeloma	Up to 2 years
Secondary	Preliminary anti-tumor efficacy of CART as assessed by Objective Response Rate (ORR) in solid tumors and multiple myeloma	Proportion of patients having a confirmed CR or PR per RECIST v1.1 in solid tumors and IMWG criteria (PR, Very Good PR, CR, Stringent CR) in multiple myeloma	Up to 2 years
Secondary	Preliminary anti-tumor efficacy of CART as assessed by Clinical Benefit Rate in solid tumors	Proportion of patients having a confirmed CR, PR, or Stable Disease (SD) per RECIST v1.1	Up to 2 years
Secondary	Preliminary anti-tumor efficacy of CART as assessed by Duration of Response (DOR) in solid tumors and multiple myeloma	DOR as defined by the interval of first documented response until first documented disease progression or death in solid tumors and multiple myeloma	Up to 2 years
Secondary	Preliminary anti-tumor efficacy of CART as assessed by Time to Response (TTR) in solid tumors and multiple myeloma	Time to Response as defined by the interval between CART-TnMUC1 cell infusion and first documented CR or PR per RECIST v1.1 in solid tumors and IMWG criteria in multiple myeloma	Up to 2 years
Secondary	Preliminary anti-tumor efficacy of CART as assessed by Time to Progression (TTP) in multiple myeloma	Time to Progression as defined by the interval between CART-TnMUC1 cell infusion and first documented progression or death due to disease per RECIST v1.1 in solid tumors and IMWG criteria in multiple myeloma	Up to 2 years
Secondary	Preliminary anti-tumor efficacy of CART as assessed by Minimal Residual Disease (MRD) in multiple myeloma	Defined by MRD-negative rate per IMWG criteria	Up to 2 years
Secondary	Peripheral expansion and persistence of CART-TnMUC1 cells in solid tumors and multiple myeloma	Defined as quantitative polymerase chain reaction (qPCR) documenting loss of CART cells	Up to 15 years