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

NCT04855253 | Suspended Phase 1 DMC FDA Drug

• 2 other identifiers: 2020LS100MT2020-27
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

DLBCL; Diffuse Large B Cell Lymphoma; High-grade B-cell Lymphoma; DLBCL Arising From Follicular Lymphoma

Keywords

E7777; Axicabtagene; Lisocabtagene; Tisagenlecleucel

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (7)

• Number of participants experiencing adverse events

  100 days Post E7777 infusion

• Number of participants experiencing disease free survival (DFS)

  1 year Post E7777 infusion

• Number of participants experiencing overall survival (OS)

  1 year Post E7777 infusion

• Number of non-relapse mortality incidents at day 100

  100 days Post E7777 infusion

• Number of Grade 3 or 4 cytokine release syndrome (CRS) incidents

  28 Days Post E7777 infusion

Study Arms (4)

Dose level 1 : E7777 at 5 mcg/kg

EXPERIMENTAL

Single dose of E7777 given on Day -7 two days prior to the start of lymphodepleting chemotherapy

Drug: E7777; Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Tisagenlecleucel; Drug: Axicabtagene Ciloleucel; Drug: Lisocabtagene Maraleucel Intravenous Suspension

Dose level 1 : E7777 at 7 mcg/kg

EXPERIMENTAL

Single dose of E7777 given on Day -7 two days prior to the start of lymphodepleting chemotherapy

Drug: E7777; Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Tisagenlecleucel; Drug: Axicabtagene Ciloleucel; Drug: Lisocabtagene Maraleucel Intravenous Suspension

Dose level 1 : E7777 at 9 mcg/kg

EXPERIMENTAL

Single dose of E7777 given on Day -7 two days prior to the start of lymphodepleting chemotherapy

Drug: E7777; Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Tisagenlecleucel; Drug: Axicabtagene Ciloleucel; Drug: Lisocabtagene Maraleucel Intravenous Suspension

MTD from phase 1

EXPERIMENTAL

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; Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Tisagenlecleucel; Drug: Axicabtagene Ciloleucel; Drug: Lisocabtagene Maraleucel Intravenous Suspension

Interventions

Fludarabine DRUG

Fludarabine 25 mg/m2 IV daily for 3 days. Days -5, -4 and -3. Taken in combination with Cyclophosphamide

Dose level 1 : E7777 at 5 mcg/kg; Dose level 1 : E7777 at 7 mcg/kg; Dose level 1 : E7777 at 9 mcg/kg; MTD from phase 1

Cyclophosphamide DRUG

Cyclophosphamide 250 mg/m2 IV daily for 3 days starting with the first dose of fludarabine. Days -5, -4 and -3.

Dose level 1 : E7777 at 5 mcg/kg; Dose level 1 : E7777 at 7 mcg/kg; Dose level 1 : E7777 at 9 mcg/kg; MTD from phase 1

Tisagenlecleucel DRUG

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

Also known as: kymriah

Dose level 1 : E7777 at 5 mcg/kg; Dose level 1 : E7777 at 7 mcg/kg; Dose level 1 : E7777 at 9 mcg/kg; MTD from phase 1

Lisocabtagene Maraleucel Intravenous Suspension DRUG

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

Also known as: Breyanzi

Dose level 1 : E7777 at 5 mcg/kg; Dose level 1 : E7777 at 7 mcg/kg; Dose level 1 : E7777 at 9 mcg/kg; MTD from phase 1

E7777 DRUG

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.

Dose level 1 : E7777 at 5 mcg/kg; Dose level 1 : E7777 at 7 mcg/kg; Dose level 1 : E7777 at 9 mcg/kg; MTD from phase 1

Axicabtagene Ciloleucel DRUG

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

Also known as: Yescarta

Dose level 1 : E7777 at 5 mcg/kg; Dose level 1 : E7777 at 7 mcg/kg; Dose level 1 : E7777 at 9 mcg/kg; MTD from phase 1

Eligibility Criteria

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

You may qualify if:

• 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)
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Masonic Cancer Center, University of Minnesota: lead

Study Sites (1)

University of Minnesota, Masonic Cancer Center

Minneapolis, Minnesota, 55455, United States

Location

Related Publications (1)

• 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.

  PMID: 38022532 DERIVED

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse

Interventions

E7777 fusion protein; fludarabine; Cyclophosphamide; tisagenlecleucel; axicabtagene ciloleucel

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Officials

• Veronika Bachanova, MD

  Masonic Cancer Center, University of Minnesota

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The Phase I study consists of two components: dose finding to establish a maximum tolerated dose (MTD) of E7777 and a small extension component to provide an estimate of efficacy at the MTD. A single dose of E7777 is given on Day -7, two days prior to the start of lymphodepleting chemotherapy. Up to 3 dose levels will be tested. The MTD is determined by using the continual reassessment method (CRM). Enrollment begins with Dose Level 1 using a cohort of two patients. Twenty one (21) days after the 2nd patient's CAR-T cell infusion the next cohort of 2 patients are assigned to the most appropriate strategy based on updated toxicity probabilities corresponding to the desired maximum toxicity rate of ≤ 25% as determined by the study statistician (or designee). Enrollment continues in cohorts of 2 separated by a minimum of 28 days until 20 patients are enrolled or 10 sequential patients are enrolled at the same dose level. No intra-cohort staggering is required.

Study Record Dates

• First Submitted: April 19, 2021
• First Posted: April 22, 2021
• Study Start: June 9, 2021
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: January 15, 2026

Record last verified: 2026-01

Locations

US (1)