E7777 Before CAR-T Therapy for Lymphoma

Overseen by Veronika Bachanova, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Masonic Cancer Center, University of Minnesota

Disqualifiers: Pregnancy, Bone marrow involvement, CNS involvement, others

No Placebo Group

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

This is a single institution Phase I study to determine the maximum tolerated dose (MTD) of E7777 when given prior to cyclophosphamide/fludarabine (CY/Flu) lymphodepletion (LD) chemotherapy and Kymriah, a commercial tisagenlecleucel product, for the treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are at a higher risk for failure of CAR-T therapy.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that you should not have taken any investigational medicinal products within the last 7 days before certain procedures in the trial.

How does the drug E7777 differ from other treatments for lymphoma?

E7777 is a unique drug for lymphoma because it is a fusion protein combining diphtheria toxin and interleukin-2, which targets and kills cancer cells by binding to their IL-2 receptors. It is an improved version of denileukin diftitox, with higher purity and potency, and is administered intravenously over five consecutive days in a 21-day cycle. ^{1 2 3 4 5}

Research Team

Veronika Bachanova, MD

Principal Investigator

Masonic Cancer Center, University of Minnesota

Eligibility Criteria

Adults with relapsed/refractory large B-cell lymphoma at high risk after CAR-T therapy, who have not had allogeneic transplants or CNS malignancy involvement, and are not pregnant. They must have adequate organ function, no severe heart issues or uncontrolled infections, and agree to use birth control.

Inclusion Criteria

My blood counts meet the required levels and my bone marrow is not affected by my disease.

Adequate organ function at enrollment and within 14 days of planned E7777 treatment including: renal function: eGFR ≥ 50 mL/min/1.73 m^2, liver function: ALT ≤ 3 times the upper limit of normal (ULN) for age, AST ≤ 3 times the ULN, total bilirubin ≤ 2.0 mg/dl with the exception of patients with Gilbert syndrome; may be included if their total bilirubin is ≤ 3.0 x ULN and direct bilirubin ≤ 1.5 x ULN (if liver is involved by lymphoma, the exception are allowed upon approval of PI), albumin ≥ 3.0 g/dl, Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea (CTCAE v5) and pulse oxygenation SpO2 > 91% on room air. Pulmonary function tests within 28 days of enrollment: >50% corrected DLCO and FEV1, Hemodynamically stable and LVEF ≥ 50% confirmed by echocardiogram or MUGA, Life expectancy ≥12 weeks in the opinion of the enrolling investigator as documented in the medical record, Women of child bearing potential and sexually active males with partners of child bearing potential must agree to use birth control for at least 30 days after study treatment or at least at least 4 months after the final dose of CY, whichever is longer Female participants: Two forms of birth control, one of which must be a barrier method, for example: use of intrauterine device (IUD) or oral contraceptives, plus a barrier method such as a condom, diaphragm or cervical cap Male participants: If possible to father a child (unless a successful vasectomy with confirmed azoospermia) participant and female partner, must use adequate contraception, Written voluntary consent prior to the performance of any research related tests or procedures

I am at high risk for cancer progression after CAR-T therapy due to one or more specific factors.

Exclusion Criteria

I haven't taken any experimental drugs in the week before my cell collection or CAR-T therapy.

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)

I am living with HIV.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single dose of E7777 followed by lymphodepleting chemotherapy and Kymriah therapy

4 weeks

Multiple visits for administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of adverse events and survival outcomes

1 year

Regular follow-up visits

Long-term follow-up

Participants are monitored for long-term outcomes such as disease-free survival and overall survival

1 year

Treatment Details

Interventions

• E7777 (Immunomodulator)

Trial Overview The trial is testing the maximum tolerated dose of E7777 given before standard chemotherapy (CY/Flu) and Kymriah for treating high-risk patients with diffuse large B-cell lymphoma who might not respond well to CAR-T therapy alone.

Participant Groups

Group I: MTD from phase 1 Experimental Treatment 1 Intervention

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

Group II: Dose level 1 : E7777 at 9 mcg/kg Experimental Treatment 1 Intervention

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

Group III: Dose level 1 : E7777 at 7 mcg/kg Experimental Treatment 1 Intervention

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

Group IV: Dose level 1 : E7777 at 5 mcg/kg Experimental Treatment 1 Intervention

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

Who Is Running the Clinical Trial?

Masonic Cancer Center, University of Minnesota

Lead Sponsor

Trials

285

Recruited

15,700+

Dr. Melissa A. Geller

Masonic Cancer Center, University of Minnesota

Chief Medical Officer since 2022

MD from University of Minnesota

Dr. Jeffrey Miller

Masonic Cancer Center, University of Minnesota

Chief Executive Officer

MD from University of Minnesota

Findings from Research

E7777, a new treatment for relapsed/refractory peripheral and cutaneous T-cell lymphoma, was found to be well tolerated at a maximum recommended dose of 9 μg/kg/day, with careful management of side effects like fatigue and electrolyte imbalances.

The treatment showed preliminary antitumor activity with an objective response rate of 38% in a phase I study involving 13 patients, indicating that further research on E7777 for T-cell lymphomas is justified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

E7777 in Japanese patients with relapsed/refractory peripheral and cutaneous T-cell lymphoma: A phase I study. Ohmachi, K., Ando, K., Ogura, M., et al.[2021]

Denileukin Diftitox (DD), a fusion protein that targets IL-2 receptors on tumor cells, has shown a 36.1% objective response rate in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL), indicating comparable efficacy to existing therapies.

E7777, the improved formulation of DD, has a maximum tolerated dose of 9 μg/kg/day and is associated with a high incidence of grade 3 or higher adverse events (94.6%), necessitating ongoing safety monitoring, especially for serious conditions like capillary leak syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Preclinical and clinical researches of Denileukin Diftitox (Genetical Recombination) (Remitoro®), a novel agent for T-cell lymphoma]. Shiiba, H., Takechi, A., Asakura, S., et al.[2022]

E7777, a recombinant cytotoxic fusion protein, demonstrated an objective response rate of 36% in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) during a phase II study involving 37 patients.

The treatment showed a manageable safety profile, with common adverse events including increased liver enzymes and hypoalbuminemia, indicating that while E7777 is effective, careful monitoring of side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of E7777 in Japanese patients with relapsed/refractory peripheral and cutaneous T-cell lymphoma. Kawai, H., Ando, K., Maruyama, D., et al.[2021]

The combination of E7777, a new formulation of denileukin diftitox, with anti-PD-1 antibody therapy significantly enhanced anti-tumor activity and improved overall survival in murine models of colon and liver cancer, compared to either treatment alone.

E7777 was found to be safe and well-tolerated, effectively counterbalancing the Treg cell infiltration caused by anti-PD-1 therapy, suggesting a synergistic effect that could optimize cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Mahdi, HS., Woodall-Jappe, M., Singh, P., et al.[2023]

Denileukin diftitox demonstrated significant efficacy in treating relapsed/refractory T-cell non-Hodgkin lymphoma, with an objective response rate of 48.1% among 27 patients, including complete responses in six patients and partial responses in seven patients.

The treatment was well tolerated, with most adverse reactions being mild (grade 1/2) and no severe (grade 4-5) toxicities reported, suggesting a favorable safety profile for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of denileukin diftitox for relapsed/refractory T-cell non-Hodgkin lymphoma. Dang, NH., Pro, B., Hagemeister, FB., et al.[2013]

References

1. England pubmed.ncbi.nlm.nih.gov

E7777 in Japanese patients with relapsed/refractory peripheral and cutaneous T-cell lymphoma: A phase I study. [2021]

2. Japan pubmed.ncbi.nlm.nih.gov

[Preclinical and clinical researches of Denileukin Diftitox (Genetical Recombination) (Remitoro®), a novel agent for T-cell lymphoma]. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Phase II study of E7777 in Japanese patients with relapsed/refractory peripheral and cutaneous T-cell lymphoma. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

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. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Phase II trial of denileukin diftitox for relapsed/refractory T-cell non-Hodgkin lymphoma. [2013]