Ph I/II Study of E7777 Prior to CAR-T for R/R LBCL

Phase I/II Trial Using E7777 to Enhance Regulatory T-Cell Depletion Prior to CAR-T Therapy for Relapsed/Refractory Large B-Cell Lymphomas

This is a multicenter Phase I study to determine the maximum tolerated dose (MTD) of E7777 when given prior to cyclophosphamide/fludarabine (CY/Flu) lymphodepletion (LD) chemotherapy and an FDAapproved CAR-T product Tisagenlecleucel/Kymriah, Axicabtagene Ciloleucel/Yescarta, or lisocabtagene maraleucel/Breyanzi) for the treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma grade 3 who are at a higher risk for failure of CAR-T therapy

Study Overview

• Status: Suspended
• Conditions: Diffuse Large B Cell Lymphoma; DLBCL; High-grade B-cell Lymphoma; DLBCL Arising From Follicular Lymphoma
• Intervention / Treatment: Drug: E7777; Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Tisagenlecleucel; Drug: Axicabtagene Ciloleucel; Drug: Lisocabtagene Maraleucel Intravenous Suspension

Detailed Description

E7777 is a recombinant fusion toxin consisting of full-length human IL-2 fused to the catalytic domains of diphtheria toxin. This trial is designed to augment lymphodepletion prior to CAR-T cells by administration of a targeted immunotoxin against CD25-expressing T-cells. CD25 is expressed at high levels on Tregs but also on activated effector T cells. The use of the CAR-T cell product and associated apheresis and LD chemotherapy is considered standard of care (SOC).

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota, Masonic Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of a relapse or refractory (r/r) B cell lymphoma, for which treatment with tisagenleucel (Kymriah), Axicabtagene (Yescarta) or Lisocabtagene Maraleucel (Breyanzi) is planned, including :
• diffuse large B-cell lymphoma (DLBCL) not otherwise specified,
• high grade B-cell lymphoma
• DLBCL arising from follicular lymphoma
• Primary mediastinal B cell lymphoma
• Follicular lymphoma grade 3B
• And considered at high risk for progression after CAR-T therapy by meeting one or more of the following factors:
• refractory to last line of therapy/remission of less than 12 months

• myc over expression >40% in any prior biopsy or bcl2/bcl6 and c-myc re-arrangement (double/triple hit)

  • 2 sites of extranodal disease
• IPI ≥ 3
• Elevated LDH at the time of relapse
• Has secured coverage for Kymriah, Yescarta,Breyanzi administration
• Age 18 years or older at the time of signing the consent
• ECOG Performance status of 0, 1, or 2
• Adequate bone marrow reserve (may be transfusion dependent)
• Adequate organ function at enrollment and within 14 days of planned E7777 treatment as defined in Section 4.1.7

• Hemodynamically stable and LVEF ≥ 50% confirmed by echocardiogram or MUGA

  • Grade 1 dyspnea (CTCAE v5) and SpO2 > 91% on room air
• Sexually active females of child-bearing potential and males with partners of child bearing potential must agree to use effective contraception during therapy
• Provides voluntary written consent prior to the performance of any research related activities.

Exclusion Criteria:

• Pregnant or breastfeeding - Females of childbearing potential must have a blood test or urine study within 14 days prior to study enrollment to rule out pregnancy. All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (i.e., bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing)
• Known bone marrow involvement, if history of bone marrow involvement must have a BM biopsy to rule-out current involvement
• Prior allogeneic transplant
• Ocular disease or complaints visual acuity impairment, color or shape distortion, or blurred vision - potential participants are required to have an ophthalmological examine as part of screening
• Active CNS involvement by malignancy (history of CNS disease with negative CSF by flow cytometry and/or stable findings on brain MRI are acceptable)
• Uncontrolled active hepatitis B or hepatitis C
• Active or inactive HIV infection
• Untreated active bacterial, viral or fungal infection (e.g. blood culture positive ≤ 72 hours prior to enrollment)
• History of heart failure or pulmonary edema, evidence of pleural effusion or active lower extremity edema
• Uncontrolled unstable angina and/or myocardial infarction within 3 months of enrollment
• Investigational medicinal product within the last 7 days prior to apheresis or CAR-T infusion

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose level 1 : E7777 at 5 mcg/kg; Single dose of E7777 given on Day -7 two days prior to the start of lymphodepleting chemotherapy	Drug: E7777; E7777 is a recombinant fusion toxin consisting of full-length human IL-2 fused to the catalytic domains of diphtheria toxin. E7777 is preferentially bound to and internalized by cells expressing the high affinity form (CD25+) of the IL-2 receptor.; Drug: Fludarabine; Fludarabine 25 mg/m2 IV daily for 3 days. Days -5, -4 and -3. Taken in combination with Cyclophosphamide; Drug: Cyclophosphamide; Cyclophosphamide 250 mg/m2 IV daily for 3 days starting with the first dose of fludarabine. Days -5, -4 and -3.; Drug: Tisagenlecleucel; Patient will receive one FDA approved CAR-T product - Tisagenlecleucel/Kymriah, Axicabtagene Ciloleucel/Yescarta, or lisocabtagene maraleucel/Breyanzi) for the treatment of relapsed/refractory diffuse large B-cell lymphoma; Other Names: kymriah; Drug: Axicabtagene Ciloleucel; Patient will receive one FDA approved CAR-T product - Tisagenlecleucel/Kymriah, Axicabtagene Ciloleucel/Yescarta, or lisocabtagene maraleucel/Breyanzi) for the treatment of relapsed/refractory diffuse large B-cell lymphoma; Other Names: Yescarta; Drug: Lisocabtagene Maraleucel Intravenous Suspension; Patient will receive one FDA approved CAR-T product - Tisagenlecleucel/Kymriah, Axicabtagene Ciloleucel/Yescarta, or lisocabtagene maraleucel/Breyanzi) for the treatment of relapsed/refractory diffuse large B-cell lymphoma; Other Names: Breyanzi
Experimental: Dose level 1 : E7777 at 7 mcg/kg; Single dose of E7777 given on Day -7 two days prior to the start of lymphodepleting chemotherapy	Drug: E7777; E7777 is a recombinant fusion toxin consisting of full-length human IL-2 fused to the catalytic domains of diphtheria toxin. E7777 is preferentially bound to and internalized by cells expressing the high affinity form (CD25+) of the IL-2 receptor.; Drug: Fludarabine; Fludarabine 25 mg/m2 IV daily for 3 days. Days -5, -4 and -3. Taken in combination with Cyclophosphamide; Drug: Cyclophosphamide; Cyclophosphamide 250 mg/m2 IV daily for 3 days starting with the first dose of fludarabine. Days -5, -4 and -3.; Drug: Tisagenlecleucel; Patient will receive one FDA approved CAR-T product - Tisagenlecleucel/Kymriah, Axicabtagene Ciloleucel/Yescarta, or lisocabtagene maraleucel/Breyanzi) for the treatment of relapsed/refractory diffuse large B-cell lymphoma; Other Names: kymriah; Drug: Axicabtagene Ciloleucel; Patient will receive one FDA approved CAR-T product - Tisagenlecleucel/Kymriah, Axicabtagene Ciloleucel/Yescarta, or lisocabtagene maraleucel/Breyanzi) for the treatment of relapsed/refractory diffuse large B-cell lymphoma; Other Names: Yescarta; Drug: Lisocabtagene Maraleucel Intravenous Suspension; Patient will receive one FDA approved CAR-T product - Tisagenlecleucel/Kymriah, Axicabtagene Ciloleucel/Yescarta, or lisocabtagene maraleucel/Breyanzi) for the treatment of relapsed/refractory diffuse large B-cell lymphoma; Other Names: Breyanzi
Experimental: Dose level 1 : E7777 at 9 mcg/kg; Single dose of E7777 given on Day -7 two days prior to the start of lymphodepleting chemotherapy	Drug: E7777; E7777 is a recombinant fusion toxin consisting of full-length human IL-2 fused to the catalytic domains of diphtheria toxin. E7777 is preferentially bound to and internalized by cells expressing the high affinity form (CD25+) of the IL-2 receptor.; Drug: Fludarabine; Fludarabine 25 mg/m2 IV daily for 3 days. Days -5, -4 and -3. Taken in combination with Cyclophosphamide; Drug: Cyclophosphamide; Cyclophosphamide 250 mg/m2 IV daily for 3 days starting with the first dose of fludarabine. Days -5, -4 and -3.; Drug: Tisagenlecleucel; Patient will receive one FDA approved CAR-T product - Tisagenlecleucel/Kymriah, Axicabtagene Ciloleucel/Yescarta, or lisocabtagene maraleucel/Breyanzi) for the treatment of relapsed/refractory diffuse large B-cell lymphoma; Other Names: kymriah; Drug: Axicabtagene Ciloleucel; Patient will receive one FDA approved CAR-T product - Tisagenlecleucel/Kymriah, Axicabtagene Ciloleucel/Yescarta, or lisocabtagene maraleucel/Breyanzi) for the treatment of relapsed/refractory diffuse large B-cell lymphoma; Other Names: Yescarta; Drug: Lisocabtagene Maraleucel Intravenous Suspension; Patient will receive one FDA approved CAR-T product - Tisagenlecleucel/Kymriah, Axicabtagene Ciloleucel/Yescarta, or lisocabtagene maraleucel/Breyanzi) for the treatment of relapsed/refractory diffuse large B-cell lymphoma; Other Names: Breyanzi
Experimental: MTD from phase 1; Single dose of E7777 (Maximum tolerated dose level identified in phase 1) given on Day -7 two days prior to the start of lymphodepleting chemotherapy	Drug: E7777; E7777 is a recombinant fusion toxin consisting of full-length human IL-2 fused to the catalytic domains of diphtheria toxin. E7777 is preferentially bound to and internalized by cells expressing the high affinity form (CD25+) of the IL-2 receptor.; Drug: Fludarabine; Fludarabine 25 mg/m2 IV daily for 3 days. Days -5, -4 and -3. Taken in combination with Cyclophosphamide; Drug: Cyclophosphamide; Cyclophosphamide 250 mg/m2 IV daily for 3 days starting with the first dose of fludarabine. Days -5, -4 and -3.; Drug: Tisagenlecleucel; Patient will receive one FDA approved CAR-T product - Tisagenlecleucel/Kymriah, Axicabtagene Ciloleucel/Yescarta, or lisocabtagene maraleucel/Breyanzi) for the treatment of relapsed/refractory diffuse large B-cell lymphoma; Other Names: kymriah; Drug: Axicabtagene Ciloleucel; Patient will receive one FDA approved CAR-T product - Tisagenlecleucel/Kymriah, Axicabtagene Ciloleucel/Yescarta, or lisocabtagene maraleucel/Breyanzi) for the treatment of relapsed/refractory diffuse large B-cell lymphoma; Other Names: Yescarta; Drug: Lisocabtagene Maraleucel Intravenous Suspension; Patient will receive one FDA approved CAR-T product - Tisagenlecleucel/Kymriah, Axicabtagene Ciloleucel/Yescarta, or lisocabtagene maraleucel/Breyanzi) for the treatment of relapsed/refractory diffuse large B-cell lymphoma; Other Names: Breyanzi

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Establish maximum tolerated dose (MTD)	The primary objective of this Phase I study is to establish a maximum tolerated dose (MTD) of E7777 when given prior to standard of care CAR-T therapy product for the treatment of relapsed/refractory B-cell lymphoma who are at a higher risk for failure of CAR-T therapy.	1 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants experiencing adverse events	Number of participants experiencing adverse events related to E7777 to determine safety of the E7777	100 days Post E7777 infusion
Number of participants experiencing disease free survival (DFS)	Number of participants experiencing disease free survival (DFS) at 1 year	1 year Post E7777 infusion
Number of participants experiencing overall survival (OS)	Number of participants experiencing overall survival (DFS) at 1 year	1 year Post E7777 infusion
Number of non-relapse mortality incidents at day 100	Number of participants experiencing non-relapse mortality at day 100 post E7777 infusion	100 days Post E7777 infusion
Number of Grade 3 or 4 cytokine release syndrome (CRS) incidents	Number of participants experiencing Grade 3 or 4 cytokine release syndrome (CRS) after CAR-T cell therapy.	28 Days Post E7777 infusion
Number of Grade 3 or 4 immune effector cell associated neurotoxicity (ICAN) syndrome incidents	Number of participants experiencing Grade 3 or 4 immune effector cell associated neurotoxicity (ICAN) syndrome after CAR-T cell therapy.	28 Days Post E7777 infusion
Number of participants experiencing dose limiting toxicity events	Dose Limiting Toxicity (DLT) is defined as any of the following events based on CTCAE v5 from the 1st infusion of E7777 through 21 days after the administration of CAR-T: Grade 4 infusion related reaction (IRR) associated with E7777; Grade 4 or Grade 3 capillary leak syndrome (CLS); Grade 3 or 4 liver function test abnormality that do not resolve to <Grade 2 within 5 days; Grade 3 or 4 non-hematologic toxicity event that occurs after the administration of E7777 and before lymphodepleting therapy; Any adverse event that results in a delay of lymphodepleting therapy for more than 72 hours and attributed to E7777; Any Grade 5 adverse event	28 Days Post E7777 infusion

Collaborators and Investigators

• Sponsor: Masonic Cancer Center, University of Minnesota
• Investigators: Principal Investigator: Veronika Bachanova, MD, Masonic Cancer Center, University of Minnesota

Publications and helpful links

General Publications

• Mahdi HS, Woodall-Jappe M, Singh P, Czuczman MS. Targeting regulatory T cells by E7777 enhances CD8 T-cell-mediated anti-tumor activity and extends survival benefit of anti-PD-1 in solid tumor models. Front Immunol. 2023 Oct 27;14:1268979. doi: 10.3389/fimmu.2023.1268979. eCollection 2023.

Study record dates

Study Major Dates

• Study Start (Actual): June 9, 2021
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: April 19, 2021
• First Submitted That Met QC Criteria: April 19, 2021
• First Posted (Actual): April 22, 2021

Study Record Updates

• Last Update Posted (Actual): January 15, 2026
• Last Update Submitted That Met QC Criteria: January 14, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: E7777; Tisagenlecleucel; Axicabtagene; Lisocabtagene
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Lymphoma; Hemic and Lymphatic Diseases; Lymphoma, Large B-Cell, Diffuse; Organic Chemicals; Hydrocarbons; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Cyclophosphamide; fludarabine; axicabtagene ciloleucel; tisagenlecleucel; E7777 fusion protein
• Other Study ID Numbers: 2020LS100; MT2020-27 (Other Identifier: University of Minnesota Masonic Cancer Center)

Drug and device information, study documents

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