Abstract
Significant unmet medical needs exist in the treatment of acute myeloid leukemia (AML), higher risk myelodysplastic syndromes (HR-MDS), and chronic myelomonocytic leukemia (CMML), particularly in patients who relapse after initial therapy or are ineligible for allogeneic stem cell transplant. Relapsed/refractory (R/R) AML, HR-MDS and CMML patients have short survival times, with medians ranging from a few months to around a year, depending on the disease and prior treatments (Platzbecker 2021, Isidori 2021, Liapsis 2021). Immunotherapy efforts have been limited by the lack of tumor-specific surface targets for myeloid malignancies that avoid undesirable toxicities due to their expression on normal hematopoietic cells.
Targeting HLA-restricted peptides (pHLA) derived from intracellular cancer antigens provides a novel therapeutic avenue. One of these peptides, CG1 (Cathepsin G protein-derived 9-mer peptide FLLPTGAEA), is a naturally processed, HLA-A*02:01 restricted nonameric peptide derived from full length Cathepsin G that is highly expressed across several primary leukemia cell lines while being largely non-detectable or low level in normal cells of the myeloid lineage (Alatrash 2017).
CBX-250 is a TCR-mimetic bispecific T Cell Engager that selectively binds the CG1/HLA-A2*02:01 pHLA complex with high affinity. In preclinical models, CBX-250 demonstrates potent T-cell mediated cytotoxicity, robust anti-leukemic activity in vivo, and a favorable safety profile with no detectable binding to normal tissues or cytokine release in the absence of target expression (Lee 2024).
This is a Phase 1, first-in-human, open-label, dose-escalation multicenter study aimed at assessing the safety, tolerability, and preliminary efficacy of CBX-250, in HLA-A*02:01 positive patients with R/R AML, HR-MDS, or CMML (NCT06994676).
Patients eligible for inclusion are aged ≥12 years, HLA-A*02:01 positive, have an Eastern Cooperative Oncology Group performance of 0-1 (if aged ≥18 years), Karnofsky Performance Scale of ≥70 (if aged ≥16 years and <18 years) or Lansky PS of ≥70 (if aged <16 years), and have histological confirmation of advanced hematologic malignancy including: R/R AML, as defined by standardized criteria (e.g., European LeukemiaNet criteria, Dohner 2022) after standard of care therapy; R/R high or very high risk MDS as per the Revised International Prognostic Scoring System (IPSS-R; Greenberg 2012) or Molecular International Prognostic Scoring System (IPPS-M, Bernard 2022) who are resistant or refractory to 4-6 cycles of hypomethylating agents; R/R CMML who are resistant or refractory to 4-6 cycles of hypomethylating agents (HMA; decitabine or azacitidine).
The primary objective of this study is to determine safety, and the maximum tolerated dose, or if different, recommended phase 2 dose of CBX-250. CBX-250 is administered once weekly in 28-day cycles via subcutaneous injection following fixed step-up dosing. A quantitative systems pharmacology-based minimum anticipated biological effect level modeling approach was used to determine the starting dose, schedule (Starting dose Day 1, ½ log increase on Day 4, another ½ log increase to target dose on Day 7 and then weekly thereafter), and route of administration (subcutaneous) to minimize the potential for toxicity while avoiding exposing patients to likely subtherapeutic doses. Dose escalation is guided by the Keyboard design (Yan 2017), which is a flexible Bayesian model-assisted design. Cleared dose levels may be backfilled to add an additional 12 patients if they have previously satisfied dose escalation criteria and if preliminary clinical activity is observed. Patients will continue CBX-250 until progressive disease or unacceptable toxicity.
Primary endpoints include the occurrence of dose-limiting-toxicities and the frequency, duration, and severity of treatment-emergent adverse events (AEs); treatment-related AEs; AEs of special interest and serious AEs. Secondary endpoints include the assessment of pharmacokinetic parameters, and antileukemic activity as measured by percentage of patients who achieve complete remission, objective response rate, time to response, duration of response, progression-free survival, and overall survival.
The study is actively enrolling, and accrual is planned at approximately twelve sites across the USA.
