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

NCT07225439 | Not Yet Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: CASE1425
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Non Hodgkin Lymphoma; B-cell Non Hodgkin Lymphoma; Diffuse Large B Cell Lymphoma; High-grade B-cell Lymphoma; Primary Mediastinal Large B Cell Lymphoma; Follicular Lymphoma; Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma; Marginal Zone Lymphoma; Mantle Cell Lymphoma

Keywords

NK cells; Natural Killer cells

Outcome Measures

Primary Outcomes (1)

• Dose limiting toxicity (DLT)

  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 Outcomes (9)

• Incidence of adverse events (AEs)

  Up to 12 months

• Timing of adverse events (AEs)

  Up to 12 months

• Severity of adverse events (AEs)

  Up to 12 months

• Complete response (CR) rate

  Day 28

• Complete response (CR) rate

  Day 100

Study Arms (1)

Rtx + Tafasitamab in combination with allogeneic NK Cells

EXPERIMENTAL

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; Drug: Rituximab; Drug: Tafasitamab; Drug: Interleukin-2; Drug: Fludarabine/cyclophosphamide

Interventions

Allogeneic NK cells DRUG

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.

Rtx + Tafasitamab in combination with allogeneic NK Cells

Rituximab DRUG

Rtx is dosed at 375mg/m2 and give once (on Day -5 for Cycle 1 and Day 0 for Cycle 2, if applicable).

Also known as: Rtx

Rtx + Tafasitamab in combination with allogeneic NK Cells

Tafasitamab DRUG

Tafasitamab is dosed at 12 mg/kg and given intravenously (IV) weekly for 3 weeks on Days 0,7,14).

Rtx + Tafasitamab in combination with allogeneic NK Cells

Interleukin-2 DRUG

Interleukin-2 is dosed at 5 million IU and given weekly for 3 weeks on Days 0,7,14.

Rtx + Tafasitamab in combination with allogeneic NK Cells

Fludarabine/cyclophosphamide DRUG

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).

Also known as: Flu/Cy

Rtx + Tafasitamab in combination with allogeneic NK Cells

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Paolo Caimi, MD: lead
• Incyte Corporation: collaborator

Study Sites (2)

Case Comprehensive Cancer Center, University Hospitals Seidman Cancer Center

Cleveland, Ohio, 44106, United States

Location

Case Comprehensive Cancer Center, Cleveland Clinic Foundation Taussig Cancer Institute

Cleveland, Ohio, 44195, United States

Location

Related Publications (13)

• Non-Hodgkin Lymphoma - Cancer Stat Facts [Internet]. [cited 2024 Jul 31]. Available from: https://seer.cancer.gov/statfacts/html/nhl.html

  BACKGROUND

• Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002 Jan 24;346(4):235-42. doi: 10.1056/NEJMoa011795.

  PMID: 11807147 BACKGROUND

• Duell J, Maddocks KJ, Gonzalez-Barca E, Jurczak W, Liberati AM, De Vos S, Nagy Z, Obr A, Gaidano G, Abrisqueta P, Kalakonda N, Andre M, Dreyling M, Menne T, Tournilhac O, Augustin M, Rosenwald A, Dirnberger-Hertweck M, Weirather J, Ambarkhane S, Salles G. Long-term outcomes from the Phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. Haematologica. 2021 Sep 1;106(9):2417-2426. doi: 10.3324/haematol.2020.275958.

  PMID: 34196165 BACKGROUND

• Sehn LH, Herrera AF, Flowers CR, Kamdar MK, McMillan A, Hertzberg M, Assouline S, Kim TM, Kim WS, Ozcan M, Hirata J, Penuel E, Paulson JN, Cheng J, Ku G, Matasar MJ. Polatuzumab Vedotin in Relapsed or Refractory Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2020 Jan 10;38(2):155-165. doi: 10.1200/JCO.19.00172. Epub 2019 Nov 6.

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• Caimi PF, Ai W, Alderuccio JP, Ardeshna KM, Hamadani M, Hess B, Kahl BS, Radford J, Solh M, Stathis A, Zinzani PL, Havenith K, Feingold J, He S, Qin Y, Ungar D, Zhang X, Carlo-Stella C. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021 Jun;22(6):790-800. doi: 10.1016/S1470-2045(21)00139-X. Epub 2021 May 11.

  PMID: 33989558 BACKGROUND

• Byrd JC, Harrington B, O'Brien S, Jones JA, Schuh A, Devereux S, Chaves J, Wierda WG, Awan FT, Brown JR, Hillmen P, Stephens DM, Ghia P, Barrientos JC, Pagel JM, Woyach J, Johnson D, Huang J, Wang X, Kaptein A, Lannutti BJ, Covey T, Fardis M, McGreivy J, Hamdy A, Rothbaum W, Izumi R, Diacovo TG, Johnson AJ, Furman RR. Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016 Jan 28;374(4):323-32. doi: 10.1056/NEJMoa1509981. Epub 2015 Dec 7.

  PMID: 26641137 BACKGROUND

• Eichhorst B, Niemann CU, Kater AP, Furstenau M, von Tresckow J, Zhang C, Robrecht S, Gregor M, Juliusson G, Thornton P, Staber PB, Tadmor T, Lindstrom V, da Cunha-Bang C, Schneider C, Poulsen CB, Illmer T, Schottker B, Nosslinger T, Janssens A, Christiansen I, Baumann M, Frederiksen H, van der Klift M, Jager U, Leys MBL, Hoogendoorn M, Lotfi K, Hebart H, Gaska T, Koene H, Enggaard L, Goede J, Regelink JC, Widmer A, Simon F, De Silva N, Fink AM, Bahlo J, Fischer K, Wendtner CM, Kreuzer KA, Ritgen M, Bruggemann M, Tausch E, Levin MD, van Oers M, Geisler C, Stilgenbauer S, Hallek M; GCLLSG, the HOVON and Nordic CLL Study Groups, the SAKK, the Israeli CLL Association, and Cancer Trials Ireland. First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia. N Engl J Med. 2023 May 11;388(19):1739-1754. doi: 10.1056/NEJMoa2213093.

  PMID: 37163621 BACKGROUND

• ASCO Daily News [Internet]. [cited 2024 Jul 31]. How Do CAR T Cells Fit Into the Evolving Non-Hodgkin Lymphoma Treatment Landscape? Available from: https://dailynews.ascopubs.org/doi/10.1200/ADN.24.201682

  BACKGROUND

• Di Blasi R, Le Gouill S, Bachy E, Cartron G, Beauvais D, Le Bras F, Gros FX, Choquet S, Bories P, Feugier P, Casasnovas O, Bay JO, Mohty M, Joris M, Gastinne T, Sesques P, Tudesq JJ, Vercellino L, Morschhauser F, Gat E, Broussais F, Houot R, Thieblemont C. Outcomes of patients with aggressive B-cell lymphoma after failure of anti-CD19 CAR T-cell therapy: a DESCAR-T analysis. Blood. 2022 Dec 15;140(24):2584-2593. doi: 10.1182/blood.2022016945.

  PMID: 36122385 BACKGROUND

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  PMID: 36226535 BACKGROUND

• Derigs P, Bethge WA, Kramer I, Holtick U, von Tresckow B, Ayuk F, Penack O, Vucinic V, von Bonin M, Baldus C, Mougiakakos D, Wulf G, Schnetzke U, Stelljes M, Fante M, Schroers R, Kroeger N, Dreger P; German Lymphoma Alliance and the German Registry for Stem Cell Transplantation. Long-Term Survivors after Failure of Chimeric Antigen Receptor T Cell Therapy for Large B Cell Lymphoma: A Role for Allogeneic Hematopoietic Cell Transplantation? A German Lymphoma Alliance and German Registry for Stem Cell Transplantation Analysis. Transplant Cell Ther. 2023 Dec;29(12):750-756. doi: 10.1016/j.jtct.2023.09.008. Epub 2023 Sep 13.

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  PMID: 28472904 BACKGROUND

• Olson JA, Leveson-Gower DB, Gill S, Baker J, Beilhack A, Negrin RS. NK cells mediate reduction of GVHD by inhibiting activated, alloreactive T cells while retaining GVT effects. Blood. 2010 May 27;115(21):4293-301. doi: 10.1182/blood-2009-05-222190. Epub 2010 Mar 16.

  PMID: 20233969 BACKGROUND

MeSH Terms

Conditions

Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Follicular; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell, Marginal Zone; Lymphoma, Mantle-Cell

Interventions

Rituximab; resiniferatoxin; tafasitamab; Interleukin-2; fludarabine; Cyclophosphamide

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Hematologic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Lymphokines; Biological Factors; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Officials

• Paolo Caimi, MD

  Case Comprehensive Cancer Center, Cleveland Clinic

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Paolo Caimi, MD

CONTACT

(216) 445-4635; caimip@ccf.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: November 4, 2025
• First Posted: November 6, 2025
• Study Start: December 1, 2025
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027
• Last Updated: November 6, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)