Frontline Risk-Adapted Optimization of Novel Targeted Immunotherapy Evaluation in High-Risk MCL (FRONTIER)

Phase II Multicenter Trial of MB-CART2019.1 (Zamtocabtagene Autoleucel) Therapy as Frontline Consolidation for High-Risk Mantle Cell Lymphoma

FRONTIER is a prospective, single arm, open label, multi-center, Phase II study of MB-CART2019.1 (Zamtocabtagene Autoleucel) therapy as frontline consolidation for high-risk Mantle Cell Lymphoma (MCL) participants

Study Overview

• Status: Not yet recruiting
• Conditions: Mantle Cell Lymphoma (MCL)
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Fludarabine; Biological: zamtocabtagene autoleucel (MB-CART2019.1)

Detailed Description

This is a prospective, single arm, open label, multi-center, Phase II study of MB-CART2019.1 (Zamtocabtagene Autoleucel) therapy as frontline consolidation for high-risk Mantle Cell Lymphoma participants. Participants will be enrolled on the study after diagnosis and before the end of their second cycle of induction therapy.

Eligible patients will receive a single intravenous infusion of MB-CART2019.1 cells at a dose of 2.5x10^6 cells/kg following lymphodepleting chemotherapy. The goal is 52 participants in total who receive MB-CART2019.1 therapy. Additional participants may be screened, consented, registered, and treated in order to reach accrual goals. Participants will be followed on the trial for 1-year post-infusion. Assessment of survival annually through 15 years after infusion will be completed using the CIBMTR infrastructure.

• Study Type: Interventional
• Enrollment (Estimated): 52
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Sadie Swift; Phone Number: 617-218-0044; Email: clinicaltrials@miltenyi.com
• Study Contact Backup: Name: Erick Flores; Phone Number: 617-218-0044; Email: clinicaltrials@miltenyi.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of MCL requires histologic confirmation by either overexpression of cyclin D1 OR presence of t(11;14) (q13; q32) translocation

  1. Subject should have a tumor biopsy sample (at least 5 unstained slides of tissue or tissue block) available prior to MB-CART2019.1 infusion, preferably collected pre-induction.
  2. If archival tissue is not available, the patient may be enrolled after discussion with the protocol chair and/or protocol officer

• High Risk Disease at diagnosis, defined as having at least ONE of the criteria below:

  1. High risk MIPI-c (as calculated by https://www.european-mcl.net/home/scores-mipi-mipi-c-19.html)
  2. Simplified MIPI high-risk ≥6.2
  3. TP53 mutation OR ≥50% TP53 expression by IHC
  4. Complex Karyotype [e.g. 3 or more cytogenetic abnormalities, excluding the presence or absence of t(11:14)]
  5. Ki67≥ 50%
  6. Blastoid or pleomorphic histology with Ki-67 ≥30%
  7. Leptomeningeal Disease at diagnosis
  8. NOTCH1 mutation

• Received 2 cycles of appropriate systemic induction therapy, which includes a CD20 antibody +/- cytotoxic therapy +/- oral targeted therapy (e.g., BTKi, immunomodulatory imid drugs), with the following considerations:

  1. CD20 antibody alone does not count towards a cycle of treatment
  2. Induction cycles do not have to be identical
  3. For BTKis and/or lenalidomide a cycle is defined as 14-28 days and will be based on institutional treatment regimens.
  4. Intrathecal chemotherapy will not count towards a cycle of treatment
  5. Radiation therapy will not count towards a cycle of treatment
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening. ECOG performance status of 2 at screening is allowed if the decrease in performance status is attributed to lymphoma

• Disease response assessment of either complete response, partial response, or stable disease by Lugano 2014 criteria assessed by 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) (preferred) or contrast enhanced CT scans including neck/chest/abdomen/pelvis [37] after 2 cycles of induction therapy. If the participant has history of CNS disease, then he/she must have no history of or active parenchymal disease on magnetic resonance imaging (MRI)

  a. Leptomeningeal alone disease is allowable if it is not clinically progressive or worsening from baseline assessment

• A creatinine clearance (as estimated by direct urine collection, Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI], or Cockcroft-Gault Equation or institutional standard) ≥ 45 mL/min
• Subjects of childbearing or child fathering potential must be willing to practice birth control from the time of enrollment on this study until the follow-up period of the study

Exclusion Criteria:

• Unable to give informed consent
• Any disease progression that occurs during the first 2 induction cycles
• A creatinine clearance (as estimated by direct urine collection, Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI], or Cockcroft-Gault Equation or institutional standard) < 45 mL/min
• Cardiac ejection fraction (EF) < 45% as determined by an echocardiogram (ECHO) or Multigated Radionuclide Acquisition scan (MUGA) (if range is provided, the upper value of the range may be used for assessing eligibility)
• Resting O2 saturation < 92% 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 unless related to bone marrow infiltration by mantle cell lymphoma. No short-acting granulocyte colony-stimulating factor (G-CSF) use within 7 days of ANC evaluation
• Platelet count < 50,000/µL unless related to bone marrow infiltration or hypersplenism by mantle cell lymphoma. No transfusions within 7 days of assessment.
• Absolute CD3 count < 50/μL at screening
• Absolute lymphocyte count (ALC) < 100/μL within 7 days of apheresis
• Known history of infection with human immunodeficiency virus (HIV)
• Known active infection with hepatitis B (hepatitis B surface antigen [HBsAg] positive). If there is a history of treated hepatitis B, the viral load must be polymerase chain reaction (PCR) negative; antiviral prophylaxis is required if HBsAg negative and anti-hepatitis B core (HBc) positive
• Known active infection with hepatitis C virus (anti-HCV antibody positive). If patient has a positive hepatitis C antibody, the viral load must be undetectable per quantitative PCR and/or nucleic acid testing
• No seizure history within 6 months prior to enrollment
• Known history of cerebral vascular accident (CVA) within prior 12 months
• Known history or presence of autoimmune CNS disease, such as multiple sclerosis, optic neuritis or other immunologic /or inflammatory diseases
• Presence of active CNS disorder that, in the judgment of the investigator, may impair the ability to evaluate neurotoxicity

• Uncontrolled bacterial, viral, or fungal infection at the time of enrollment.

  a. Uncontrolled is defined as currently taking medication and with progression or no clinical improvement on adequate medical treatment

• Pregnant or breast-feeding woman

• Previous or concurrent malignancy with the following exceptions:

  1. Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to study entry)
  2. In situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 2 years prior to the study
  3. Adequately treated breast or prostate carcinoma on hormonal therapies such as Lupron or tamoxifen and in clinical remission of ≥ 2 years -or- low-grade untreated prostate cancer under observation
  4. A primary malignancy which has been completely resected / treated with curative intent and in complete remission of ≥ 2 years
  5. Subjects with prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with safety and efficacy assessment are eligible for this trial after discussion with protocol chair or protocol officer
• Severely immunocompromised participants e.g. due to current systemic 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
• For systemic therapy or radiation therapy, at least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed at the time of scheduled leukapheresis
• BTKis can be continued through apheresis until one day prior to start of lymphodepletion
• Baseline neurologic deficits 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 in this study
• Refusal or inability to participate in additional lentiviral gene therapy long-term follow-up (LTFU) protocol
• Prior CAR-T therapy for any indication or systemic gene-modifying therapy for B cell lymphoma
• Prior allogeneic stem cell transplant for any indication.
• Prior bispecific T cell engaging (BITE) antibodies for cancer therapy
• Prior T cell receptor-engineered T cell therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Single, open label	Drug: Cyclophosphamide; Lymphodepleting chemotherapy; Drug: Fludarabine; Lymphodepleting chemotherapy; Biological: zamtocabtagene autoleucel (MB-CART2019.1); chimeric antigen receptor T-cell (CAR-T) therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)	The primary endpoint is PFS at 1-year following MB2019.1 CAR T cell infusion. PFS is defined as the time interval from CAR T cell infusion until a PFS event occurs.	1 year post-infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment Response	Treatment response will be assessed using Lugano Criteria (Cheson et al, 2014). Both best overall response and Day 90 response following CAR T cell infusion will be evaluated.	1 year
Overall Survival (OS)	Events for OS include deaths from any cause. OS is defined as the time interval from CAR T cell infusion until death.	1 year post-infusion
Duration of Complete Response (DOCR)	DOCR is defined as the time from a participant's first achieving a CR until either a disease progression occurs per 2014 Lugano or IPCG criteria or death, whichever occurs first. DOCR will be evaluated in the set of participants who achieve a CR.	1 year post-infusion
Non-relapse Mortality (NRM)	Events for NRM include deaths without prior relapse/progression of the underlying malignancy. Relapse/progression is treated as a competing risk for NRM.	1 year post-infusion
Relapse/progression	Relapse/progression events will be determined per Lugano criteria.	1 year post-infusion
IEC Related Toxicities	CRS, ICANS, and IEC-HS will be determined per ASTCT criteria. The incidence and severity of each of these toxicities within 28 days of CAR T cell infusion will be reported. The incidence and severity of Grade 3 or higher ICANS occurring after Day 28 post-CAR T cell infusion will be reported.	Up to 1 year post-infusion
Event-free Survival (EFS)	Events for EFS include clinical progression, additional anti-lymphoma treatment initiation (oral therapy, radiation) in the absence of clinical progression, and death. EFS is defined as the time interval from CAR T cell infusion until an EFS event occurs.	1 year-post infusion

Collaborators and Investigators

• Sponsor: Miltenyi Biomedicine GmbH
• Collaborators: National Cancer Institute (NCI); National Heart, Lung, and Blood Institute (NHLBI)

Publications and helpful links

Helpful Links

• Miltenyi Biomedicine Website

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): September 1, 2029
• Study Completion (Estimated): March 1, 2030

Study Registration Dates

• First Submitted: April 28, 2026
• First Submitted That Met QC Criteria: April 28, 2026
• First Posted (Actual): May 6, 2026

Study Record Updates

• Last Update Posted (Actual): May 6, 2026
• Last Update Submitted That Met QC Criteria: April 28, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Immunotherapy; Lymphoma, Non-Hodgkin; MCL; CAR-T Cell; TP53; Mantle Cell Lymphoma; CAR; High-risk; Lymphoma, B-Cell; Chimeric Antigen Receptor; B-Cell Non-Hodgkin Lymphoma; Frontline; T cell infusion; CD19/CD20-directed CAR-T Cells; Zamtocabtagene autoleucel
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma; Hemic and Lymphatic Diseases; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma, Mantle-Cell; Organic Chemicals; Hydrocarbons; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Cyclophosphamide; fludarabine
• Other Study ID Numbers: PROJ112909; U24HL138660 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No