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.

Targeting Cancer Stemness in the Clinic: From Hype to Hope

“…Unfortunately, in earlier studies with bivatuzumab mertansine, an antibody-drug conjugate (ADC) specific for CD44v6, fatal drug-related cutaneous adverse events were observed, likely linked to the targeting of normal skin progenitors, which has led to the termination of clinical development (Tijink et al, 2006). However, a newer recombinant, humanized monoclonal anti-CD44 antibody, RG7356 was well tolerated in a phase 1 study of 44 AML patients, of whom 1 had CR, 1 had PR, and 1 had SD with hematologic improvement (Vey et al, 2016). In this study, RG7356 treatment resulted in an increase in macrophage recruitment and decrease in stem-like AML blasts along with blast differentiation into CD34 -/CD38 + cells.…”

Stem cells in cancer initiation and progression

“…Consistent with this, blocking SDF-1/CXCR4 signaling can influence leukemia differentiation (Tavor et al, 2004). Clinical trials aimed at defining the impact of blocking CD98 (Bixby et al, 2015), CD44 (Vey et al, 2016), and CXCR4 (Martínez-Cuadrón et al, 2018; Uy et al, 2012) signaling have shown some promise and indicate that better targeting agents and/or combinatorial therapy could be beneficial in controlling disease progression.…”

Anticorpos monoclonais no tratamento oncológico: revisão de literatura para o atendimento ao paciente e manejo das reações infusionais

“…Isso deve ser feito uma hora antes do início da infusão. Também devem ser administrados analgésico, antipirético oral (por exemplo, Paracetamol 1000 mg) e anti-histamínicos orais, pelo menos, 30 minutos antes da infusão, com o intuito de reduzir a ocorrência dessas reações 3,8,14,17,28,32 .…”