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

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).

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