E7777 Before CAR-T Therapy for Lymphoma

Overseen By Cancer Center Clinical Trials Office

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Masonic Cancer Center, University of Minnesota

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

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of the drug E7777 (Denileukin diftitox) when administered before CAR-T cell therapy for certain types of lymphoma, including diffuse large B-cell lymphoma and follicular lymphoma. Researchers aim to determine the safest dose of E7777 that can be tolerated before starting the usual chemotherapy and CAR-T treatment. Suitable candidates have lymphoma that has returned or has not responded to other treatments and are at high risk of treatment failure with CAR-T therapy. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this potentially groundbreaking 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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

In earlier studies, E7777, also known as denileukin diftitox, has shown promise in treating certain types of lymphoma. Research suggests that patients generally tolerate this treatment well. Specifically, studies with patients who have cutaneous T-cell lymphoma (a type of skin cancer) found that E7777 was safe to use, with many patients experiencing manageable side effects.

However, like any medical treatment, E7777 can cause side effects. Some patients reported mild to moderate reactions, such as flu-like symptoms or skin rashes. There is also a warning that it might be harmful if given to pregnant women, so discussing this with a doctor is important if there is any chance of pregnancy.

Overall, current research indicates that the treatment appears safe for most people. It's always best to talk with healthcare providers to understand the potential risks and benefits before joining a clinical trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for lymphoma?

Researchers are excited about E7777 for lymphoma because it offers a potentially new approach to treatment. Unlike standard therapies that often rely on chemotherapy or immunotherapy drugs, E7777 is a modified form of a diphtheria toxin that specifically targets and kills cancer cells while sparing healthy ones. This targeted action could mean fewer side effects and more effective outcomes. Additionally, E7777 is administered as a single dose before CAR-T therapy, which might enhance the effectiveness of the subsequent treatment. This novel combination could pave the way for more efficient and tolerable lymphoma treatments.

What evidence suggests that E7777 might be an effective treatment for lymphoma?

Studies have shown that E7777, an improved version of Denileukin Diftitox, may help treat certain types of lymphoma, such as cutaneous T-cell lymphoma (CTCL). Research suggests that E7777 remains effective even when the body develops resistance, allowing it to continue working well over time. In some studies, patients received a dose of 9 micrograms per kilogram, and the results were promising. In this trial, participants will receive different doses of E7777, including 5, 7, and 9 micrograms per kilogram, to determine the optimal dose before CAR-T therapy. These findings suggest that E7777 might benefit people with relapsed or hard-to-treat diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma grade 3, especially when used before CAR-T therapy. While most data comes from similar conditions, E7777's ability to target and destroy cancer cells offers hope for those considering this treatment. ^{1 5 6 7 8}

Who Is on the Research Team?

Veronika Bachanova, MD

Principal Investigator

Masonic Cancer Center, University of Minnesota

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• E7777

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.

How Is the Trial Designed?

Group I: MTD from phase 1 Experimental Treatment 6 Interventions

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 6 Interventions

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 6 Interventions

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 6 Interventions

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+

Published Research Related to This Trial

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]

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]

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 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]

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]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO-24-01549

Efficacy and Safety of Denileukin Diftitox-Cxdl, an Improved ... Efficacy and safety results show that DD-cxdl would potentially fulfill a serious, unmet medical need for patients with R/R CTCL. Introduction.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40009571/

Effect of E7777 Immunogenicity on Pharmacokinetics ... Here, we describe the association between E7777 (at 9 μg/kg) and ADAs, and its effect on pharmacokinetics (PK), efficacy, and safety. Of 91 patients with ...

3. ashpublications.org ashpublications.org/blood/article/140/Supplement%201/1491/492558/Efficacy-and-Safety-of-E7777-improved-purity

Efficacy and Safety of E7777 (improved purity Denileukin ... Efficacy and safety of E7777 (improved purity Denileukin diftitox [ONTAK]) in patients with relapsed or refractory cutaneous T-cell lymphoma: results from ...

4. ascpt.onlinelibrary.wiley.com ascpt.onlinelibrary.wiley.com/doi/full/10.1111/cts.70166

Effect of E7777 Immunogenicity on Pharmacokinetics, Efficacy ... These results indicate that the presence of ADAs decreased E7777 exposure over time but did not adversely impact efficacy and safety in patients with CTCL.

5. clfoundation.org clfoundation.org/LYMPHIRNews

LYMPHIR™ (denileukin diftitox-cxdl) The basis of the approval is clinical safety and efficacy data from trial E7777-G000-302. ... Lymphoma: Results from Pivotal Study 302. Blood 2022; 140 ( ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39700456/

Efficacy and Safety of Denileukin Diftitox-Cxdl, an Improved ... Efficacy and safety results show that DD-cxdl would potentially fulfill a serious, unmet medical need for patients with R/R CTCL.

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2020/103767s5144lbl.pdf

This label may not be the latest approved by FDA. For current ... Risk Summary. Based on its mechanism of action, denileukin diftitox may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)] ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT01871727

A Trial of E7777 in Persistent and Recurrent Cutaneous T- ... The purpose of this trial is to assess the efficacy of E7777 in participants with recurrent or persistent Cutaneous T-Cell Lymphoma (CTCL) in Stage I - III ...