Dose-Escalation and Dose-Expansion Study to Evaluate the Safety and Tolerability of Anti-CD7 Allogeneic CAR T-Cells (WU-CART-007) in Patients With CD7+ Hematologic Malignancies
- Conditions
- Monomorphic Epitheliotropic Intestinal T-Cell LymphomaAnaplastic Large Cell LymphomaT-Cell Non-Hodgkin LymphomaAcute Myeloid LeukemiaT Cell Prolymphocytic LeukemiaExtranodal NK/T-cell LymphomaAngioimmunoblastic T-cell LymphomaEnteropathy-Associated T-Cell LymphomaAdult T Cell LymphomaSezary Syndrome
- Interventions
- Registration Number
- NCT05377827
- Lead Sponsor
- Washington University School of Medicine
- Brief Summary
Effective treatment options for relapsed/refractory acute myeloid leukemia (AML) and T-cell non-Hodgkin lymphoma (T-NHL) represent a significant unmet medical need. CAR T therapy has offered durable remissions and potential cures in some forms of hematologic malignancy, including B-cell acute lymphoblastic leukemia. In AML, however, CAR T approaches have been limited by the lack of suitable antigens, as most myeloid markers are shared with normal hematopoietic stem cells and targeting of these antigens by CAR T therapy leads to undesirable hematologic toxicity. Similarly, T-NHL has not yet benefited from CAR T therapy due to a lack of suitable markers. One potential therapeutic target is CD7, which is expressed normally on mature T-cells and NK-cells but is also aberrantly expressed on \~30% of acute myeloid leukemias. CAR T therapy for patients with CD7+ AML and T-NHL will potentially offer a new therapeutic option which has a chance of offering durable benefit.
WU-CART-007 is a CD7-directed, genetically modified, allogeneic, fratricide-resistant chimeric antigen receptor (CAR) T-cell product for the treatment of CD7+ hematologic malignancies. These cells have two key changes from conventional, autologous CAR T-cells. First, because CD7 is present on normal T-cells including conventional CAR T products, CD7 is deleted from WU CART-007. This allows for targeting of CD7 without the risk of fratricide (killing of WU-CART-007 cells by other WU-CART-007 cells). Second, the T cell receptor alpha constant (TRAC) is also deleted. This makes WU CART 007 cells incapable of recognizing antigens other than CD7 and allows for the use of an allogeneic product without causing Graft-versus-Host-Disease (GvHD).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 6
Not provided
Patients will be excluded from study entry for any of the following:
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Received systemic anticancer therapy (including investigational therapy) or radiotherapy < 28 days or 5 half-lives, whichever is shorter, prior to the start of lymphodepleting chemotherapy with the exception of bridging treatment as defined by protocol.
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Received any T-cell lytic or toxic antibody (e.g., alemtuzumab) within 8 weeks prior to lymphodepleting chemotherapy.
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Subjects who have received a prior allogeneic HCT are excluded if any of the following criteria are present:
- < 100 days post alloHCT
- < 6 weeks from prior donor leukocyte infusion
- Presence of acute or extensive chronic GVHD requiring systemic immunosuppression except for prednisone ≤ 10 mg or equivalent.
- < 28 days from last dose of systemic immunosuppressive therapy (eg. calcineurin inhibitors, immunosuppressive antibodies, mycophenolate mofetil, ruxolitinib, ibrutinib) except for prednisone ≤ 10 mg or equivalent.
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Previous treatment with any anti-CD7 directed therapy.
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Known hypersensitivity to one or more of the study agents.
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Active or latent Hepatitis B or active Hepatitis C without previous curative treatment.
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Confirmed HIV infection.
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History of concurrent second cancers requiring active, ongoing systemic treatment with the exception of adjuvant hormonal therapy for breast or prostate cancer.
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Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum or urine pregnancy test at time of enrollment and within 7 days of starting lymphodepleting chemotherapy.
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Serious active infection or another serious underlying medical condition that in the opinion of the treating physician would impair the ability of the patient to receive protocol treatment including, but not limited to symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia or serious, unstable neurologic symptoms.
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Symptomatic, uncontrolled hypotension.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Dose Escalation Cohort A: WU-CART-007 T-NHL WU-CART-007 Patients will receive preparative lymphodepletion in the week prior to WU-CART-007, after which WU-CART-007 will be infused 3 days following the last dose of chemotherapy at the assigned dose level. Dose Expansion Cohort A: WU-CART-007 T-NHL WU-CART-007 Patients will receive preparative lymphodepletion in the week prior to WU-CART-007, after which WU-CART-007 will be infused 3 days following the last dose of chemotherapy at the recommended phase II dose. Dose Escalation Cohort B: WU-CART-007 leukemia WU-CART-007 Patients will receive preparative lymphodepletion in the week prior to WU-CART-007, after which WU-CART-007 will be infused 3 days following the last dose of chemotherapy at the assigned dose level. Dose Expansion Cohort B: WU-CART-007 leukemia WU-CART-007 Patients will receive preparative lymphodepletion in the week prior to WU-CART-007, after which WU-CART-007 will be infused 3 days following the last dose of chemotherapy at the recommended phase II dose.
- Primary Outcome Measures
Name Time Method Recommended phase II dose (Dose Escalation only) Through completion of day 42 for all Part A participants (estimated to be 18 months and 42 days) -The recommended phase II dose (RP2D) will be determined independently for each disease cohort (CD7+ AML and T-NHL). The RP2D will not be greater than the maximum tolerated dose (MTD). However, the RP2D may be a lower dose level in certain circumstances:
* If emerging toxicity at the MTD is unpredictable or undesirable for other reasons.
* If clear evidence of efficacy is noted at lower doses with a cleaner safety profile.
* If the cellular pharmacokinectic (cPK) profile that emerges results in similar numbers of clonal cells over time that is independent of administered dose level.
* If longer follow-up on earlier patient cohorts suggests the emergence of delayed toxicity.Number of participants with complete metabolic response or partial metabolic response (Dose expansion only - Cohort A) Through completion of response assessments (estimated to be 24 months) -Per Lugano criteria for patients with T-cell lymphoma (T-NHL). Per Global Response Criteria for cutaneous T-cell lymphoma (CTCL). Per the T-PLL International Study Group criteria for T-cell prolymphocytic leukemia (T-PLL)
Number of participants with complete remission, complete remission with incomplete blood count recovery, complete remission with partial hematologic recovery, or morphologic leukemia free state (Dose expansion only - Cohort B) Through completion of response assessments (estimated to be 24 months) -Per modified 2017 ELN criteria for patients with AML
- Secondary Outcome Measures
Name Time Method Number of participants with treatment-emergent adverse events as measured by CTCAE v 5.0 From start of treatment through completion of follow-up (estimated to be 24 months) -Treatment-emergent adverse events are those with an onset on or after the initiation of therapy, and, with the exception of cytokine release syndrome and neurotoxicity
Number of participants with cytokine release syndrome From start of treatment through Day 7 (estimated to be 8 days) -Cytokine release syndrome will be graded accorded to the ASTCT Consensus Guidelines
Number of participants with immune effector cell-associated neurotoxicity syndrome (ICANS) as measured by ASTCT Consensus Grading From start of treatment through Day 7 (estimated to be 8 days) Duration of remission (DoR) (Dose Expansion only) Through completion of response assessments (estimated to be 24 months) * DoR for patients who achieve CR/CRi/CRMLFS/PR is measured from the time measurement criteria are met for CR/CRi/CRh/MLFS/PR (whichever is first recorded) until the first date that relapse is objectively documented.
* Also includes patients who were treated at the recommended phase II dose in Dose Escalation.Relapse-free survival (RFS) (Dose Expansion only) Through completion of follow-up (estimated to be 24 months) * RFS is defined for patients who achieve CR/CRi/CRh/MLFS/PR as the duration of time measurement criteria are met for CR/CRi/CRh/MLFS/PR (whichever is first recorded) to time of relapse or death, whichever occurs first.
* Also includes patients who were treated at the recommended phase II dose in Dose Escalation.Event-free survival (EFS) (Dose Expansion only) Through completion of follow-up (estimated to be 24 months) * EFS is defined for all patients and measured from the date of entry on study until treatment failure, relapse from CR, or death from any cause.
* Also includes patients who were treated at the recommended phase II dose in Dose Escalation.Overall survival (OS) (Dose Expansion only) Through completion of follow-up (estimated to be 24 months) * OS is defined as the time from date of entry on study to time of death.
* Also includes patients who were treated at the recommended phase II dose in Dose Escalation.
Trial Locations
- Locations (1)
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States