Rituximab (Rtx) + Tafasitamab in Combination With Allogeneic NK Cells for Treatment of Relapsed/Refractory (r/r) B-cell Non-Hodgkin Lymphoma (NHL)

November 4, 2025 updated by: Paolo Caimi, MD

Phase I Clinical Trial of Rituximab (Rtx) and Tafasitamab in Combination With Allogeneic NK Cells for Treatment of Relapsed/Refractory (r/r) B-cell Non-Hodgkin Lymphoma

This research study is for people who have relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL) that has not responded to two or more lines of therapy. The purpose of this study is to identify the recommended dose of allogeneic NK cells in combination with IL-2, Tafasitamab and Rituximab for the treatment of relapsed or refractory B-cell non-Hodgkin's lymphoma.

NK cells are an investigational (experimental) treatment which means they are not approved by the Food and Drug Administration (FDA). NK cells are a type of lymphocyte that's part of the body's natural immune system, and they can kill cancer cells by creating pores in the cancer cell membranes and inducing apoptosis (programmed cell death).

Participants in this study will receive lymphodepleting chemotherapy, as well as Allogeneic NK cells, Tafasitamab and Interleukin-2 (IL-2) by an intravenous (IV) infusion. Participants are expected to complete one cycle, and they may be eligible to complete a second cycle of the same regiment if they have stable disease, partial or complete remission at the end of the first cycle. Participants will be in this study for about 12 months.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

More than 80,000 cases of non-Hodgkin lymphoma (NHL) are diagnosed each year in the United States (US), with nearly 20,000 people dying from this group of diseases annually. There are several subgroups of NHL, with the B cell lymphomas being much more common than T-cell lymphomas. B cell lymphomas include multiple different diseases, including some that are more aggressive (like diffuse large B cell lymphoma (DLBCL) and others), as well as those with a slower progression (i.e. indolent lymphomas like follicular lymphoma (FL)). Over the past 20 years, there have been advances in the treatment of most NHL subtypes. However, disease recurrence continues to be frequent and happens in more than a third of people with DLBCL and in most people with indolent lymphomas. A treatment called anti CD19 chimeric antigen receptor T-cell therapies (CAR T-cell) have helped to treat relapsed and primary refractory lymphomas. However, CAR-T cells therapies are limited by the cost and logistics of manufacture. Additionally, relapses are common (40-60%) in people treated with CAR-T cells, and people who experience these relapses have poor survival outcomes.

While CAR-T cells still receive a lot of attention, there is a growing interest in using other strategies including NK cells combined with monoclonal antibodies or molecules developed to activate NK cells against tumors. NK cells are lymphocytes, a type of immune cell, that can naturally fight cancer cells. They are important in fighting cancer and can do so without needing to recognize specific cell markers. Allogeneic, non-HLA-matched NK cells have been found to be safe and not associated with the development of graft-versus-host disease. It is still important to improve the manufacture, application, and efficacy of NK cell therapy. Breakthroughs in ex vivo NK cell expansion have allowed for large doses to be made, which may address some of these limitations.

This study uses a "universal donor" of ex vivo expanded NK cell product that is made at a lab at Case Western Reserve University. These NK cells are "experimental," meaning that they are not approved by the Food and Drug Administration (FDA). Participants in this study will receive these NK cells in addition to other standard cancer treatments for NHL.

Study Type

Interventional

Enrollment (Estimated)

15

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Paolo Caimi, MD
  • Phone Number: (216) 445-4635
  • Email: caimip@ccf.org

Study Locations

  • United States
    • Ohio
      • Cleveland, Ohio, United States, 44195
        • Case Comprehensive Cancer Center, Cleveland Clinic Foundation Taussig Cancer Institute
        • Principal Investigator:
          • Paolo Caimi, MD
        • Contact:
      • Cleveland, Ohio, United States, 44106
        • Case Comprehensive Cancer Center, University Hospitals Seidman Cancer Center
        • Contact:
        • Principal Investigator:
          • Changchun (George) Deng, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Age 18 years or older
  • Diagnosis of B-cell NHL (indolent and aggressive subtypes) including diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS), high grade B-cell lymphoma (HGBCL), primary mediastinal B-cell lymphoma (PMBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL), and mantle cell lymphoma (MCL)
  • Participants must have measurable disease as defined by Lugano 2014 criteria for NHL or iwCLL 2018 criteria for CLL. For NHL, measurable disease is defined as ≥1 measurable lesion (nodal or extra nodal) ≥1.5 cm in longest diameter by CT or PET/CT. For CLL, iwCLL criteria includes: presence of lymphocytosis (e.g., ALC ≥5 × 10⁹/L), lymphadenopathy ≥1.5 cm, and/or disease-related cytopenias (anemia, thrombocytopenia).
  • Relapsed and/or refractory after two or more lines of systemic therapy, including prior CD19 and/or CD20 directed therapies
  • For participants who have received a prior CD19 or CD20 directed therapy, the presence of CD19 and/or CD20 expression (by flow cytometry and/or immunohistochemistry) must be demonstrated on a post-treatment relapse biopsy
  • ECOG Performance Status </= 2
  • Preserved organ function as defined by: Total bilirubin </= 1.5X upper limit of normal; AST/ALT </= 2.5 X upper limit of normal; Calculated creatinine clearance >/= 30mL/min estimated by Cockcroft Gualt formula; cardiac ejection fraction >/= 45% and no more than mild/trace pericardial effusion on a recent echocardiogram; and adequate pulmonary function with oxygen saturation >/= 92% on room air.
  • Participants must have the ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Second active malignancy (other than non-melanoma skin cancer or carcinoma in situ e.g. cervix, bladder, breast) that would confound interpretation of toxicity assessment or limit survival to prevent evaluation of therapy per discretion of principal investigator. Malignancies treated curatively or with hormonal therapy could be included after discussion with the principal investigator
  • Less than 28 days elapsed between prior treatment with investigational agent(s) and study enrollment
  • New York Heart Association class III-IV congestive heart failure
  • Cardiovascular disorders including unstable angina pectoris, clinically significant cardiac arrhythmias, myocardial infarction or stroke (including transient ischemic attack, or other ischemic event) within 6 months prior to registration
  • Known human immunodeficiency virus infection or acquired immunodeficiency syndrome related illness, except well controlled HIV with viral load <200 copies/mL on antiretroviral therapy
  • Pregnant or breastfeeding women are excluded from this study because therapy may be associated with the potential for teratogenic or abortifacient effects. Women of childbearing potential must have a negative serum pregnancy test. Because there is an unknown, but potential risk for adverse events in nursing infants' secondary to treatment of the mother with NK cells, breastfeeding should be discontinued. These potential risks may also apply to other agents used in this study
  • Morphologic and/or cytogenetic features consistent with diagnosis of myelodysplastic syndrome on the most recent bone marrow biopsy prior to initiation of therapy
  • Serologic status reflecting active hepatitis B or C infection. Participants that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. (PCR positive participants will be excluded)
  • Participants with history of clinically relevant CNS pathology such as epilepsy, seizure disorders, paresis, aphasia, uncontrolled cerebrovascular disease, severe brain injuries, dementia and Parkinson's disease
  • Active central nervous system or leptomeningeal involvement by lymphoma. Participants with untreated brain metastases/CNS disease will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurological and other adverse events. Participants with a history of CNS or meningeal involvement must be in a documented remission by CSF evaluation and contrast enhanced MRI imaging for at least 90 days prior to registration
  • History of active autoimmune disease (i.e. rheumatoid arthritis, systemic lupus erythematosus) with requirement of systemic immunosuppressive medications other than low dose steroids [i.e. maximum of 15mg prednisone equivalent] within the last 6 months

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Rtx + Tafasitamab in combination with allogeneic NK Cells
This arm includes dose escalation for allogeneic NK cells. All other therapies are given according to standard of care. The length of the treatment period is 28 days per cycle. Participants will be expected to complete one cycle and may have the option to complete a second cycle unless there is evidence of disease progression at the end of the first cycle.
Drug: Allogeneic NK cells

Allogeneic NK cells are given intravenously (IV) weekly for 3 weeks on Days 0, 7, 14.

Dose escalation will be conducted using a Bayesian optimal interval (BOIN) design starting at dose level 1 (500 x 106 cells) and proceeding to dose level 2 (1,000 x 106 cells) if criteria are met.

Drug: Rituximab
Rtx is dosed at 375mg/m2 and give once (on Day -5 for Cycle 1 and Day 0 for Cycle 2, if applicable).
Other Names:
  • Rtx
Drug: Tafasitamab
Tafasitamab is dosed at 12 mg/kg and given intravenously (IV) weekly for 3 weeks on Days 0,7,14).
Drug: Interleukin-2
Interleukin-2 is dosed at 5 million IU and given weekly for 3 weeks on Days 0,7,14.
Drug: Fludarabine/cyclophosphamide
Fludarabine is dosed at 30 mg/m2/d with dose adjustment for renal function, and cyclophosphamide is dosed at 500 mg/m2/d. These are given on 3 days (Days -5 to -3).
Other Names:
  • Flu/Cy

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Dose limiting toxicity (DLT)
Time Frame: Up to 42 days
Non hematologic AEs will be measured during cycle 1 (first 28 days) and hematologic AEs will be measured during the first 42 days for all dose levels. DLTs are graded for severity by the Common Terminology Criteria for Adverse Events v5.0 (CTCAEv5.0) criteria.
Up to 42 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of adverse events (AEs)
Time Frame: Up to 12 months
Up to 12 months
Timing of adverse events (AEs)
Time Frame: Up to 12 months
Up to 12 months
Severity of adverse events (AEs)
Time Frame: Up to 12 months
AE severity will be graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0
Up to 12 months
Complete response (CR) rate
Time Frame: Day 28
CR is defined as complete disappearance of all detectable clinical evidence of disease, and disease-related symptoms if present prior to therapy and measured according to the 2014 Lugano Response for Malignant Lymphoma criteria.
Day 28
Complete response (CR) rate
Time Frame: Day 100
CR is defined as complete disappearance of all detectable clinical evidence of disease, and disease-related symptoms if present prior to therapy and measured according to the 2014 Lugano Response for Malignant Lymphoma criteria.
Day 100
Overall response rate (ORR)
Time Frame: Day 28
ORR is defined as the rate of participants who had CR and partial response (PR). CR is defined as complete disappearance of all detectable clinical evidence of disease, and disease-related symptoms if present prior to therapy and measured according to the 2014 Lugano Response for Malignant Lymphoma criteria. PR is defined as not meeting criteria for CR but having an improvement in symptom criteria specified by the 2014 Lugano Response for Malignant Lymphoma criteria.
Day 28
Overall response rate (ORR)
Time Frame: Day 100
ORR is defined as the rate of participants who had CR and partial response (PR). CR is defined as complete disappearance of all detectable clinical evidence of disease, and disease-related symptoms if present prior to therapy and measured according to the 2014 Lugano Response for Malignant Lymphoma criteria. PR is defined as not meeting criteria for CR but having an improvement in symptom criteria specified by the 2014 Lugano Response for Malignant Lymphoma criteria.
Day 100
Overall survival (OS)
Time Frame: Up to 12 months
OS is defined as the time from infusion until death from any cause, or until last contact if alive
Up to 12 months
Event-free survival (EFS)
Time Frame: Up to 12 months
EFS is defined as the time from infusion until the first occurrence of an event (relapse, progression, or death from any cause), or until last contact if no event occurs.
Up to 12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Paolo Caimi, MD

Collaborators

Incyte Corporation

Investigators

  • Principal Investigator: Paolo Caimi, MD, Case Comprehensive Cancer Center, Cleveland Clinic

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

December 1, 2025

Primary Completion (Estimated)

December 1, 2027

Study Completion (Estimated)

December 1, 2027

Study Registration Dates

First Submitted

November 4, 2025

First Submitted That Met QC Criteria

November 4, 2025

First Posted (Estimated)

November 6, 2025

Study Record Updates

Last Update Posted (Estimated)

November 6, 2025

Last Update Submitted That Met QC Criteria

November 4, 2025

Last Verified

November 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CASE1425

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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