DALY II USA/ MB-CART2019.1 for DLBCL

Central Nervous System Lymphoma Clinical Trial

Official title:

A Multi-center Single Arm Phase II Study to Evaluate the Safety and Efficacy of Genetically Engineered Autologous Cells Expressing Anti-CD20 and Anti-CD19 Specific Chimeric Antigen Receptor in Subjects With Relapsed and/or Refractory Diffuse Large B Cell Lymphoma

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04792489
• Other study ID #: M-2018-344
• Status: Recruiting
• Phase: Phase 2
• Start date: May 25, 2021
• Est. completion date: December 31, 2026

Study information

• Verified date: April 2024
• Source: Miltenyi Biomedicine GmbH
• Contact: Bryan Dumont
• Phone: 617-218-0044
• Email: clinicaltrials[@]miltenyi.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

DALY II USA is a phase II, multi-center, single arm study to evaluate the efficacy, safety, and pharmacokinetics of zamtocabtagene autoleucel (MB-CART2019.1) in patients with relapsed and/or refractory diffuse large B cell lymphoma (DLBCL) after receiving at least two lines of therapy.

Description:

A prospective, single arm, open label, multi-center, phase II study of autologous T cells engineered against both CD19 and CD20 antigens for subjects with relapsed or refractory DLBCL after receiving at least two lines of therapy. The investigational agent is the MB-CART2019.1 cells. After successful screening, subjects will undergo leukapheresis to collect product for manufacturing. In preparation for the fresh product infusion, subjects will undergo a lymphodepleting regimen with cyclophosphamide and fludarabine, or bendamustine. Cell infusion will be administered intravenously at a dose of 2.5 x 106 CAR+ cells/kg body weight. The study will start with enrollment of 3 subjects in the lead-in safety phase, and after safety is evaluated, the study will continue with enrollment of the remaining subjects. Subjects will be followed for up to 2 years, for efficacy and safety outcomes as well as health-related quality of life (HRQol). Additional long-term follow-up will be conducted for participants under a separate long-term follow-up protocol.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 110
• Est. completion date: December 31, 2026
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically confirmed DLBCL or associated subtype, defined by WHO 2016 classification:

• CNS Cohort only: B-cell primary or secondary central nervous system lymphoma (PCNSL or SCNSL)

• Relapsed or refractory disease after 2 or more lines of chemotherapy including rituximab and anthracycline and either having failed autologous stem cell transplant (ASCT), or ineligible, not intended for or not consenting to ASCT

• Chemotherapy-refractory disease is defined as persistent disease after last line of therapy or relapsed or persistent disease after prior ASCT for lymphoma

• Disease relapse in subjects without prior ASCT is defined as relapse of disease after the last dose of most recent therapy regimen

• CNS Cohort: Subjects with relapsed/refractory PCNSL that have failed (or unable to tolerate) first-line therapy.

• CNS Cohort: Subjects with SCNSL must have relapsed or refractory disease after having received at least 1 prior line of systemic therapy

• Age =18 years

• Eastern Cooperative Oncology Group (ECOG) performance status that is either 0 or 1 at screening. ECOG performance status of 2 at screen is allowed if the decrease in performance status is due to DLBCL

• Measurable disease according to Lugano 2014 criteria for assessing FDG-PET/CT in lymphoma (Cheson et al, 2014) for DLBCL and SCNSL while IPCG criteria for the primary PCNSL.

• Subject must have a tumor biopsy sample (at least 16 unstained slides of tissue or tissue block) from the most recent relapse available prior to MB-CART2019.1 infusion. If medically not feasible to obtain a biopsy from the most recent relapse and for cases when the amount of tissue is limited, the sponsor should be consulted, to confirm adequacy of the sample for study required analyses

• No clinical suspicion of central nervous system (CNS) lymphoma (not applicable to CNS cohort)

• If the subject has history of CNS disease (not applicable to CNS cohort), then he/she must have no signs or symptoms of CNS disease, have no active disease on magnetic resonance imaging (MRI), have no large cell lymphoma present in cerebral spinal fluid (CSF) on cytospin preparation and flow cytometry, regardless of the number of white blood cells (WBCs)

• If has history of cerebral vascular accident (CVA), the CVA event must be greater than 12 months prior to leukapheresis. Any neurological deficits must be stable.

• A creatinine clearance (as estimated by direct urine collection or Cockcroft-Gault Equation) > 45mL/min

• Cardiac ejection fraction (EF) = 45% as determined by an echocardiogram (ECHO) or Multigated Radionuclide Angiography (MUGA)

• Resting O2 saturation >90% on room air

• Serum alanine aminotransferase (ALT) / aspartate aminotransferase (AST) <5 times the Upper Limit of Normal (ULN) for age

• Total bilirubin <1.5 mg/dl, except in individuals with Gilbert's syndrome

• Absolute neutrophil count (ANC) > 1000/µL

• Absolute lymphocyte count > 100/µL

• Platelet count > 50,000/µL

• Estimated life expectancy of more than 3 months other than primary disease

Exclusion Criteria:

• Primary CNS lymphoma (not applicable to CNS cohort)

• Richter's transformed DLBCL arising from chronic lymphocytic leukemia (CLL)

• Unable to give informed consent

• Known history of infection with human immunodeficiency virus (HIV) or active hepatitis B (HBsAg positive). If there is a history of treated hepatitis B or hepatitis C, the viral load must be quantitative polymerase chain reaction (PCR) negative; antiviral prophylaxis is required if HBsAg negative and anti-HBc positive.

• Known history of infection with hepatitis C virus (anti-HCV positive) unless viral load is undetectable per quantitative PCR and/or nucleic acid testing.

• Seizure that is not effectively controlled pharmacologically.

• Known history of CVA within prior 12 months.

• Known history or presence of autoimmune CNS disease, such as multiple sclerosis, optic neuritis, or other immunologic or inflammatory disease

• Presence of CNS disorder that, in the judgment of the investigator, may impair the ability to evaluate neurotoxicity. For CNS Cohort: Bulky leptomeningeal disease and or CSF protein >100 mg/Dl. Recent (within 2 months) whole brain radiotherapy (WBRT)

• Active systemic fungal, viral, or bacterial infection

• Pregnant or breast-feeding woman

• Previous or concurrent malignancy with the following exceptions:

• Adequately treated basal cell or squamous cell carcinoma (adequate wound healing required prior to study entry)

• In situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 2 years prior to the study

• Adequately treated breast or prostate carcinoma on hormonal therapies such as Lupron or tamoxifen and in clinical remission of = 2 years

• A primary malignancy which has been completely resected / treated with curative intent and in complete remission of = 2 years

• Immunocompromised subjects e.g., due to current treatment of non-neurologic autoimmune disease (e.g., Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus).

• Medical condition requiring prolonged use of systemic corticosteroids equivalent to prednisone >10 mg/day

• History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 6 months of enrollment

• Concurrent radiotherapy (normal tissue sparing palliative radiotherapy allowed up to time of lymphodepletion). For systemic therapy, at least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed at the time of scheduled leukapheresis.

• Baseline dementia that would interfere with therapy or monitoring, determined using Immune Effector Cell-Associated Encephalopathy (ICE) Assessment at baseline

• History of severe immediate hypersensitivity reaction to any of the agents used in this study

• Refusal to participate in additional lentiviral gene therapy LTFU protocol

• Prior CAR-T therapy for any indication or systemic gene modifying therapy for DLBCL

• Prior allogeneic stem cell transplant for any indication

• Prior BITE antibodies for cancer therapy

• Prior T cell receptor-engineered T cell therapy

Related Conditions & MeSH terms

• Central Nervous System Lymphoma
• High Grade B-cell Lymphoma (HGBCL)
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Large B-Cell, Diffuse
• Primary Mediastinal B-cell Lymphoma (PMBCL)
• Refractory Diffuse Large B Cell Lymphoma (DLBCL)
• Transformed Lymphoma

Intervention

Biological:
• zamtocabtagene autoleucel (MB-CART2019.1)
Chimeric antigen receptor (CAR) T cell therapy

Drug:
• Cyclophosphamide
Lymphodepleting chemotherapy
• Fludarabine
Lymphodepleting chemotherapy
• Bendamustine
Lymphodepleting chemotherapy

Locations

Country	Name	City	State
United States	University of Michigan	Ann Arbor	Michigan
United States	Winship Cancer Institute of Emory University	Atlanta	Georgia
United States	Georgia Cancer Center at Augusta University	Augusta	Georgia
United States	University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center	Baltimore	Maryland
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Robert H Lurie Cancer Center	Chicago	Illinois
United States	The Ohio State University Wexner Medical Center James Cancer	Columbus	Ohio
United States	UT Southwestern Medical Center	Dallas	Texas
United States	Duke University Medical Center - Division of Hematologic Malignancies	Durham	North Carolina
United States	Banner MD Anderson Cancer Center	Gilbert	Arizona
United States	UC San Diego Health	La Jolla	California
United States	Baptist Health Miami Cancer Institute	Miami	Florida
United States	Froedtert Hospital and the Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Yale University	New Haven	Connecticut
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Mayo Clinic	Phoenix	Arizona
United States	Allegheny Health Network Cancer Institute	Pittsburgh	Pennsylvania
United States	University of Pittsburgh - Hillman Cancer Center	Pittsburgh	Pennsylvania
United States	Oregon Health and Science University Knight Cancer Institute	Portland	Oregon
United States	Mayo Clinic	Rochester	Minnesota
United States	Stanford University	Stanford	California
United States	University of Kansas Cancer Center	Westwood	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
Miltenyi Biomedicine GmbH

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Response Rate	ORR	through study completion, up to 2 years
Secondary	Complete Response Rate	CRR	1 and 6 months
Secondary	Duration of Response	DOR	Up to 2 years
Secondary	Overall Response Rate	ORR	1 and 6 months
Secondary	Best Overall Response	BOR	2 years
Secondary	Progression Free Survival	PFS	Up to 2 years
Secondary	Overall Survival	OS	Up to 2 years
Secondary	Type, frequency, and severity of adverse events	Safety	Up to 2 years
Secondary	Incidence of anti-MD-CART2019.1 antibodies	Bioanalytical	Up to 2 years
Secondary	Phenotype of MB-CART2019.1	Bioanalytical	Up to 2 years
Secondary	Persistence of MB-CART2019.1	Bioanalytical	Up to 2 years
Secondary	Quality of Life (QoL) assessments [EQ-5D-5L]	Health Outcomes - Standardized 5 question measure of health status developed by the EuroQol Group	Up to 2 years
Secondary	Patient-Reported Outcome (PRO) assessment [FACT-Lym]	Health Outcomes - To address health-related quality-of-life (HRQL) issues for Non-Hodgkin's lymphoma (NHL) patients	Up to 2 years
Secondary	Pharmacodynamics [Levels of cytokines in blood]	Bioanalytical	Up to 2 years
Secondary	Correlation of tumor CD19 and CD20 antigen expression with disease progression and relapse	Bioanalytical	Up to 2 years

External Links

•   Miltenyi Biomedicine DALY II Trial Website
•   Miltenyi Biomedicine Website