Phase I clinical study of RG7356, an anti-CD44 humanized antibody, in patients with acute myeloid leukemia

Abstract

RG7356, a recombinant anti-CD44 immunoglobulin G1 humanized monoclonal antibody, inhibits cell adhesion and has been associated with macrophage activation in preclinical models. We report results of a phase I dose-escalation study of RG7356 in relapsed/refractory acute myeloid leukemia (AML).Eligible patients with refractory AML, relapsed AML after induction chemotherapy, or previously untreated AML not eligible for intensive chemotherapy were enrolled and received intravenous RG7356 at dosages ≤ 2400 mg every other week or ≤ 1200 mg weekly or twice weekly; dose escalation started at 300 mg.Forty-four patients (median age, 69 years) were enrolled. One dose-limiting toxicity occurred (grade 3 hemolysis exacerbation) after one 1200 mg dose (twice-weekly cohort). The majority of adverse events were mild/moderate. Infusion-related reactions occurred in 64% of patients mainly during cycle 1. Two patients experienced grade 3 drug-induced aseptic meningitis. Pharmacokinetics increased supraproportionally, suggesting a target-mediated drug disposition (TMDD) at ≥ 1200 mg. Two patients achieved complete response with incomplete platelet recovery or partial response, respectively. One patient had stable disease with hematologic improvement.RG7356 was generally safe and well tolerated. Maximum tolerated dose was not reached, but saturation of TMDD was achieved. The recommended dose for future AML evaluations is 2400 mg every other week.

Keywords: RG7356; anti-CD44 humanized antibody; cell adhesion; phase I trial; relapsed/refractory acute myeloid leukemia.

Figure 1. Mean RG7356 concentration for cycle 1

Abbreviations: qw, weekly; q2w, every 2 weeks.

Figure 2. Leukemic stem cell (LSC) differentiation during treatment with RG7356

LSC differentiation during treatment with RG7356 (patient 3015, 600 mg, twice weekly dose regimen, on treatment for 26 cycles). LSC differentiation is shown by reduction of percentage of CD34⁺ blasts and percentage increase of CD34⁻/CD38⁺ blasts in the bone marrow. Hematologic improvement (HI) is shown by absolute neutrophil count (ANC) increase (green line).

Figure 3. Macrophage and leukemic stem cell changes during treatment with RG7356

A. Macrophage (CD68) frequency and B. leukemic stem cell (CD34) reduction in the bone marrow was shown by immunohistochemistry analysis at baseline (pre-dose cycle 1, day 1 [C1D1]) and on treatment (pre-dose cycle 3, day 1 [C3D1]).