NCT06071624

Chimeric Antigen Receptor T Cell Therapy Redirected to CD4 (CD4CAR)as a Second Line Treatment for Chronic Myelomonocytic Leukemia, CMML.

CD4CAR T Cell Therapy for CMML

• Status: Recruiting
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 30 (estimated)
• Sponsor: Huda Salman · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

This study is designed as a single arm open label traditional Phase I, 3+3, study of CD4-directed chimeric antigen receptor engineered T-cells (CD4CAR) in subjects with relapsed or refractory CMML. Specifically, the study will evaluate the safety and feasibility of CD4CAR T-cells.

Detailed description

The study will be performed as a dose-escalation protocol. Due to the relatively low incidence and prevalence of cluster of differentiation 4-positive (CD4+) hematological malignancies and the associated aggressive nature of these diseases and the sequel of treatment failure, the investigators expect to recruit 20 subjects at Indiana University with an expected dropout rate of 25% primarily due to rapid progression or death and screen and or manufacturing failure. Taking this into account, the investigators expect to treat 15 subjects. The study will utilize autologous CD4CAR T-cells that are engineered to express a chimeric antigen receptor (CAR) targeting CD4 that is linked to the cluster of differentiation 28 (CD28), 4-1BB, cluster of differentiation 3-zeta (CD3ζ) signaling chains (third generation CAR). At entry, disease status will be staged. Qualifying subjects will be leukapheresed to obtain large numbers of peripheral blood mononuclear cells (PBMC) for the manufacturing. Next, participants will receive conditioning chemotherapy. If tumor burden is sufficiently reduced (screening step), participants will receive CD4CAR cells by infusion on Day 0 of treatment. If the disease progresses during the manufacturing period participants may be excluded from the study. Minimal chemotherapy to keep the disease under control in the meanwhile is allowed if deemed necessary by investigators. A single dose of CD4CAR transduced T cells will consist of the cell number for the dose level to be infused. Post-infusion monitoring of CD4CAR T-cells: Subjects will have blood drawn for cytokine levels, CD4CAR Transgene Copy Number (PCR) and flow cytometry in order to evaluate the presence of CD4CAR cells on days 0, 1, 3, 5, 7, 14, and 28 following infusion (or as clinically needed). Cytokines levels will be evaluated per schedule above in addition to and as needed every 8 +/- 2 hours as feasible if/when CRS occurs and until resolution. Active monitoring of fungal and viral infections during treatment while utilizing standard prophylaxis recommended for HIV-positive subjects with T-cell aplasia and those undergoing allogeneic stem cell transplant. Investigators plan to collect data about clinicoradiologic measurements of residual tumor burden starting on day 7 and weekly afterward until Day 28 and then monthly for 6 months. This will be followed by quarterly clinical evaluations for the next two (2) years with a medical history, physical examination, and comprehensive blood testing. After these short- and intermediate-term evaluations are performed, these subjects will enter a rollover study to assess for disease-free survival (DFS), relapse, and the development of other health problems or malignancies where follow-up will be up to twice a year by phone and a questionnaire for an additional thirteen (13) years. The treating physician will decide to proceed with allogeneic or autologous transplant when needed. Dose of CD4CAR description: the main objective of this study is to establish a recommended dose and/or schedule of CD4CAR. The guiding principle for dose escalation in phase I is to avoid unnecessary exposure of subjects to sub-therapeutic doses (i.e., to treat as many subjects as possible within the therapeutic dose range) while preserving safety and maintaining rapid accrual. Investigators will use the rule-based traditional Phase I "3+3" design for the evaluation of safety. Based on lab experience in mice the starting dose (dose level 1) for the first cohort of three subjects in phase I portion of the study will be 8x10\^5 cells. The dose escalation or de-escalation will follow a modified Fibonacci sequence as below. If more than one subject out of the first cohort of three subjects in dose level 1 experience dose limiting toxicity (DLT), the trial will be placed on hold. If zero or one out of three subjects in the first cohort of dose level 1 experience DLT, three more subjects will be enrolled at dose level 1; the dose escalation continues until at least two subjects among a cohort of six subjects experience DLT (i.e., ≥33% of subjects with a DLT at this dose level) If one of the first three subjects in dose level 1 experiences a DLT, three more subjects will be treated at dose level 1. If none of the three subjects or only one of the 6 subjects in the dose level 1 experiences a DLT, the dose escalation continues to the dose level 2 If one of the first three subjects in dose level 2 experience a DLT, three more subjects will be treated at dose level 2 If none of the three subjects or only one of the 6 subjects in the dose level2 experiences a DLT, the dose escalation continues to the dose level 3 If one of the first three subjects in dose level 3 experiences a DLT, three more subjects will be treated at dose level 3 If none of the three subjects or only one of the 6 subjects in the dose level 3 experiences a DLT, dose level 3 will be declared the maximum tolerated dose (MTD) and will be used as the recommended phase II dose (RP2D) for the phase II portion of the study. In summary, the dose escalation continues until at least two subjects among a cohort of six subjects experience DLT (i.e., ≥33% of subjects with a DLT at that dose level). The recommended dose for phase II trials is defined as one dose level below this toxic dose level. Since some grade 3 and possibly 4 toxicities are highly likely to be reversible, grade 3 infectious, hematological and vascular toxicities will not be considered DLTs mandating dose reduction. Also allergic or infusion-related reactions ≤ grade 3 will not be counted as DLTs. There will be no intra-subject dose escalation or reduction. To allow for full spectrum toxicity duration evaluation and reporting, no subjects within the same or a different cohort will be initiated on lymphodepleting chemotherapy sooner than 28 days from the initiation date of the preceding subject.

Conditions

• Chronic Myelomonocytic Leukemia

Interventions

Type	Name	Description
BIOLOGICAL	CD4CAR	CD4CAR cells transduced with a lentiviral vector to express the single-chain variable fragment (scFv) nucleotide sequence of the anti-CD4 molecule derived from humanized monoclonal ibalizumab and the intracellular domains of CD28 and 4-1BB co-activators fused to the CD3ζ T-cell activation signaling domain administered by IV infusions as a single dose

Timeline

• Start date: 2024-02-21
• Primary completion: 2028-12-01
• Completion: 2043-12-01
• First posted: 2023-10-06
• Last updated: 2026-03-18

Locations

4 sites across 1 country: United States

Regulatory

• FDA-regulated drug study