First-in-human trial of tocilizumab in combination with a standard induction chemotherapy in newly diagnosed acute myeloid leukemia patients: The phase 1 TOCILAM study.

7028 Background: Numerous studies have pointed out the pathological role of deregulated expression of Interleukin-6 (IL-6) in cancers. In acute myeloid leukemia (AML), IL-6 promotes chemo-resistance and correlates with poor prognosis. One explanation is that AML cells express IL-6 receptor (R) and self-produce IL-6 at once, favouring blast proliferation and survival. Therefore, IL-6 blockade may represent a new promising therapeutic strategy for AML. Here, we have tested Tocilizumab (Toci), an anti-IL-6R antibody, in combination with a standard AML induction chemotherapy. Methods: This was a monocentric Phase 1 study testing three escalating doses of Toci (4, 6 and 8 mg/kg) administered at day (d) 8 of a standard AML induction chemotherapy (Idarubicine 8 mg/m² d1 to d5 + cytarabine 100 mg/m² d1 to d7). All adults ( > = 18 yo) with a newly diagnosed (excluding patients (pts) with a favorable risk according to ELN-2017 classification if < 60 yo) or a relapsed/refractory AML were eligible. The main objective was to determine the maximum tolerated dose of Toci for further phase 2/3 studies. Patients had to be included 2 by 2, according to a continual reassessment method while targeting a related-experimental drug toxicity level < 30%. A maximum of 12 pts had to be included. Toxicity was evaluated using NCI version5 criteria. Responses were evaluated according to ELN-2017 criteria between d30/d45 of induction. Also, IL-6 and Toci plasma levels were assessed. All pts gave informed consent and the trial was registered at Clinical trials under NCT04547062. Results: Between Dec/2020 and Dec/2022, 12 pts were treated, including 2 pts at 4 mg/Kg, 2 at 6 mg/kg and 8 at 8 mg/kg of Toci. The median age was 66 yo (range: 56-73), all pts had a newly diagnosed AML, ELN risk was intermediate: 25%; unfavorable: 75%. No dose limiting toxicity related to Toci was documented. Two pts died during induction, 1 of infection and 1 of cerebral haemorrhage. Complete remission (CR) rate for evaluable pts was 90% (n = 9/10). After induction, 7 received a consolidation and 7 were allo-transplanted. With a median follow-up of 600d, 4 patients have relapsed and 7 have died, 1-y OS and LFS were estimated at 43% (21-88%) and 39% (19-82%), respectively. Dosages of IL-6 (pg/mL) showed a significant increase after Toci injection (median 23,2 (2.6-53.5) vs 202,9 (21.1-6189.2) after 8d and 481,5 (53.8-7327.4) after 15d), suggesting a good saturation of the targets (IL6-R) on AML cells and a potential anti-leukemic effect. Median dosages of Toci (µg/ml) were higher 8d and 15d after injection at L2 (34.8; 17.2) and L3 (38.5; 12.9) compared to L 1 (10.9; 1.4). Conclusions: The combination of Toci to a standard AML intensive induction appears to be very safe providing both high CR rate and the expected biological effect. We now recommend a dose of 8 mg/kg of Toci given at d8 of induction for further phase 2/3 studies. Clinical trial information: NCT04547062 .