Resolve AML 001: An Adaptive Open-Label Multicentre Phase 1/2 Trial, to Determine the Recommended Phase 2 Dose of Cctx-001, and to Assess Safety, Tolerability, and Clinical Activity in Patients with r/r AML

Background

Acute myeloid leukemia (AML) is the most frequent acute leukemia in adults. Therapy consists of combination chemotherapy and targeted agents, depending on the underlying driver mutations, yet the only curative option is allogeneic hematopoietic stem cell transplantation (HSCT). Patient with refractory disease or relapsing (r/r) have a dismal prognosis, with approximately 6 months survival. Accordingly, there is a high medical need for new effective treatments.

CCTx-001 is an autologous chimeric antigen receptor T (CAR T) cell therapy that uses a 3^rd generation Interleukin-1 Receptor Accessory Protein (IL-1RAP)-directed lentiviral CAR. IL-1RAP is a co-receptor of the IL-1 receptor family including IL-1, IL-33, and IL-36. IL-1RAP potentiates multiple oncogenic signaling pathways to promote leukemia cell proliferation and is selectively expressed in myeloid blasts, but not on healthy hematopoietic stem cells. In preclinical experiments, IL-1RAP-directed CAR T-cells have shown promising antileukemic activity (Trad 2022, Nicod 2023).

Methods

The RESOLVE-AML 001 seamless adaptive Phase 1/2 study (CCTx-001-AML-001) is investigating the safety and anti-leukemic activity of CCTx-001 in adult patients with r/r AML. Patients must have active primary refractory or relapsing AML (WHO 2022), including relapse post allogeneic HSCT and must be fit enough for CAR T-cell therapy. Patients with APL, CNS involvement or uncontrolled medical conditions, including systemic infection, autoimmune disorders) are excluded.

The Phase 1 part will evaluate increasing doses of CCTx-001 to identify the recommended Phase 2 dose (RP2D) or optimal biological dose. The dose-escalation in Phase 1 will follow a Bayesian Optimal Interval (BOIN) design based on the occurrence of dose limiting toxicities (DLTs) (Yuan 2016) (Dohner 2022). It is a design which is easy to implement, flexible in cohort size, and with predefined stopping rules. The primary objective for the phase 1 is to evaluate the safety and tolerability and to define the RP2D of CCTx-001.

The Phase 2 (dose expansion) part will comprise a larger cohort of patients with r/r AML and will aim to evaluate the clinical activity and further assess the safety of CCTx-001 in this population at RP2D.

Dosing of CCTx-001 is based on bodyweight (viable transduced T cells/kg) up to a maximum weight of 80 kg, at which the dose will be capped. A total of 5 different dose levels (DL) may be tested: 0.1x10⁶ cells/kg (DL -1); 0.5×10⁶ cells/kg (DL1); 1×10⁶ cells/kg (DL2); 5×10⁶ cells/kg (DL3), and 10×10⁶ cells/kg (DL4).

Patients will receive the assigned dose of CCTx-001 after lymphodepletion (LDC) with fludarabine IV (4D 30 mg/m²) and cyclophosphamide IV (3D 300 mg/m²).

The decision on dose escalation or de-escalation is be based upon recommendations from the Safety Review Committee (SRC), following the review of any DLTs that occurred at the current dose level (DL) and considering the accumulated safety information including lower grade AEs from all DLs. The phase 1 will enroll up to 30 DLT evaluable patients.

90 patients will need to be enrolled in the Phase 2 expansion. The primary objective for the phase 2 is to evaluate the clinical activity assessed by the composite complete response rate by an Independent Review Committee based on ELN 2022 criteria (Dohner 2022).

The trial received EU CTIS approval in July 2024.

Clinical trial information: CTIS 2023-506865-71-00

References

Dohner, H., et al. (2022). "Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN." Blood 140(12): 1345-1377.

Nicod, C., et al. (2023). "CAR-T cells targeting IL-1RAP produced in a closed semiautomatic system are ready for the first phase I clinical investigation in humans." Curr Res Transl Med 71(2): 103385.

Trad, R., et al. (2022). "Chimeric antigen receptor T-cells targeting IL-1RAP: a promising new cellular immunotherapy to treat acute myeloid leukemia." J Immunother Cancer 10(7).

Yuan, Y., et al. (2016). "Bayesian Optimal Interval Design: A Simple and Well-Performing Design for Phase I Oncology Trials." Clin Cancer Res 22(17): 4291-4301.