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

• ClinicalTrials.gov Identifier: NCT04025216
• Recruitment Status: Terminated
• First Posted: July 18, 2019
• Last Update Posted: April 19, 2023
• Sponsor: Tmunity Therapeutics
• Information provided by (Responsible Party): Tmunity Therapeutics

Study Description

Brief 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).

Condition or disease	Intervention/treatment	Phase
Non-Small Cell Lung Cancer; Ovarian Cancer; Fallopian Tube Cancer; Triple Negative Breast Cancer; Multiple Myeloma; Pancreatic Ductal Adenocarcinoma	Biological: CART-TnMUC1; Drug: Cyclophosphamide; Drug: Fludarabine	Phase 1

Detailed 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).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 16 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Parallel arms with sequential dose escalation
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: October 10, 2019
• Actual Primary Completion Date: December 2, 2022
• Actual Study Completion Date: December 2, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Dose Escalation Arm1: Solid Tumors; Intravenous CART-TnMUC1 cells for patients with TnMUC1+ treatment-resistant ovarian cancer (including cancers of the fallopian tube), pancreatic ductal adenocarcinoma, hormone receptor (HR)-negative and human epidermal growth factor receptor 2 (HER2)-negative (triple negative) breast cancer and non-small cell lung cancer	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; Drug: Fludarabine; Patients will receive cyclophosphamide and fludarabine lymphodepletion chemotherapy followed by the investigational product, CART-TnMUC1
Experimental: Dose Escalation Arm 2: Multiple Myeloma; Intravenous CART-TnMUC1 cells for patients with TnMUC1+ relapsed/refractory multiple myeloma	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; Drug: Fludarabine; Patients will receive cyclophosphamide and fludarabine lymphodepletion chemotherapy followed by the investigational product, CART-TnMUC1

Outcome Measures

Primary Outcome Measures :

1. Dose Escalation: Dose Identification of CART-TnMUC1 [ Time Frame: Up to 2 years ]
   Incidence of Dose Limiting Toxicity (DLT) in solid tumors and multiple myeloma
2. Cohort Expansion: Objective Response in solid tumors [ Time Frame: Up to 2 years ]
   Proportion of patients having a confirmed Complete Response (CR) or Partial Response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

Secondary Outcome Measures :

1. Safety of CART-TnMUC1 in solid tumors and multiple myeloma [ Time Frame: Up to 2 years ]
   Percentage of patients experiencing adverse events (AEs), including serious and severe AEs overall, by dose level, and by severity Grade
2. Tolerability of CART-TnMUC1 in solid tumors and multiple myeloma [ Time Frame: Up to 2 years ]
   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
3. Feasibility of CART-TnMUC1 in solid tumors and multiple myeloma [ Time Frame: Up to 2 years ]
   Proportion of enrolled patients who did not receive CART-TnMUC1 cells
4. Preliminary anti-tumor efficacy of CART as assessed by Overall Survival (OS) in solid tumors and multiple myeloma [ Time Frame: Up to 2 years ]
   OS as defined by the interval between CART-TnMUC1 cell infusion and date of death by any cause
5. Preliminary anti-tumor efficacy of CART as assessed by Progression Free Survival (PFS) in solid tumors [ Time Frame: Up to 2 years ]
   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
6. Preliminary anti-tumor efficacy of CART as assessed by Objective Response Rate (ORR) in solid tumors and multiple myeloma [ Time Frame: Up to 2 years ]
   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
7. Preliminary anti-tumor efficacy of CART as assessed by Clinical Benefit Rate in solid tumors [ Time Frame: Up to 2 years ]
   Proportion of patients having a confirmed CR, PR, or Stable Disease (SD) per RECIST v1.1
8. Preliminary anti-tumor efficacy of CART as assessed by Duration of Response (DOR) in solid tumors and multiple myeloma [ Time Frame: Up to 2 years ]
   DOR as defined by the interval of first documented response until first documented disease progression or death in solid tumors and multiple myeloma
9. Preliminary anti-tumor efficacy of CART as assessed by Time to Response (TTR) in solid tumors and multiple myeloma [ Time Frame: Up to 2 years ]
   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
10. Preliminary anti-tumor efficacy of CART as assessed by Time to Progression (TTP) in multiple myeloma [ Time Frame: Up to 2 years ]
    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
11. Preliminary anti-tumor efficacy of CART as assessed by Minimal Residual Disease (MRD) in multiple myeloma [ Time Frame: Up to 2 years ]
    Defined by MRD-negative rate per IMWG criteria
12. Peripheral expansion and persistence of CART-TnMUC1 cells in solid tumors and multiple myeloma [ Time Frame: Up to 15 years ]
    Defined as quantitative polymerase chain reaction (qPCR) documenting loss of CART cells

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Arizona

Mayo Clinic of Arizona

Phoenix, Arizona, United States, 85054

United States, California

The Angeles Clinic and Research Institute

Los Angeles, California, United States, 90025

United States, Florida

Moffitt Cancer Center

Tampa, Florida, United States, 33637

United States, Illinois

University of Chicago Medical Center

Chicago, Illinois, United States, 60637

United States, Missouri

Washington University School of Medicine

Saint Louis, Missouri, United States, 63110

United States, Pennsylvania

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, United States, 15232

United States, Tennessee

Sarah Cannon Research Institute

Nashville, Tennessee, United States, 37203

United States, Texas

The University of Texas MD Anderson Cancer Center

Houston, Texas, United States, 77030

United States, Washington

University of Washington Medical Center

Seattle, Washington, United States, 98195

Sponsors and Collaborators

Tmunity Therapeutics

More Information

• Responsible Party: Tmunity Therapeutics
• ClinicalTrials.gov Identifier: NCT04025216
• Other Study ID Numbers: CART-TnMUC1-01
• First Posted: July 18, 2019
• Last Update Posted: April 19, 2023
• Last Verified: April 2023

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

Keywords provided by Tmunity Therapeutics:

Chimeric Antigen Receptor (CAR); T-cells; TnMUC1

Additional relevant MeSH terms:

Multiple Myeloma; Neoplasms, Plasma Cell; Triple Negative Breast Neoplasms; Fallopian Tube Neoplasms; Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Breast Neoplasms; Breast Diseases; Skin Diseases; Fallopian Tube Diseases; Cyclophosphamide