Diffuse Large B Cell Lymphoma, DLBCL, DLBCL Arising From Follicular Lymphoma, High-grade B-cell Lymphoma
Conditions
Keywords
E7777, Axicabtagene, Lisocabtagene, Tisagenlecleucel
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
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).
Interventions
DRUGE7777
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.
DRUGFludarabine
Fludarabine 25 mg/m2 IV daily for 3 days. Days -5, -4 and -3. Taken in combination with Cyclophosphamide
DRUGCyclophosphamide
Cyclophosphamide 250 mg/m2 IV daily for 3 days starting with the first dose of fludarabine. Days -5, -4 and -3.
DRUGTisagenlecleucel
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
DRUGAxicabtagene 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
DRUGLisocabtagene 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
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Establish maximum tolerated dose (MTD) | 1 month | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants experiencing disease free survival (DFS) | 1 year Post E7777 infusion | Number of participants experiencing disease free survival (DFS) at 1 year |
| Number of participants experiencing overall survival (OS) | 1 year Post E7777 infusion | Number of participants experiencing overall survival (DFS) at 1 year |
| Number of non-relapse mortality incidents at day 100 | 100 days Post E7777 infusion | Number of participants experiencing non-relapse mortality at day 100 post E7777 infusion |
| Number of participants experiencing adverse events | 100 days Post E7777 infusion | Number of participants experiencing adverse events related to E7777 to determine safety of the E7777 |
| Number of Grade 3 or 4 immune effector cell associated neurotoxicity (ICAN) syndrome incidents | 28 Days Post E7777 infusion | Number of participants experiencing Grade 3 or 4 immune effector cell associated neurotoxicity (ICAN) syndrome after CAR-T cell therapy. |
| Number of participants experiencing dose limiting toxicity events | 28 Days Post E7777 infusion | 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 |
| Number of Grade 3 or 4 cytokine release syndrome (CRS) incidents | 28 Days Post E7777 infusion | Number of participants experiencing Grade 3 or 4 cytokine release syndrome (CRS) after CAR-T cell therapy. |
Countries
United States
Outcome results
None listed