First-in-human phase I clinical trial of RG7356, an anti-CD44 humanized antibody, in patients with advanced, CD44-expressing solid tumors

Abstract

Transmembrane glycoprotein CD44 is overexpressed in various malignancies. Interactions between CD44 and hyaluronic acid are associated with poor prognosis, making CD44 an attractive therapeutic target. We report results from a first-in-human phase I trial of RG7356, a recombinant anti-CD44 immunoglobulin G1 humanized monoclonal antibody, in patients with advanced CD44-expressing solid malignancies.Sixty-five heavily pretreated patients not amenable to standard therapy were enrolled and received RG7356 intravenously biweekly (q2w) or weekly (qw) in escalating doses from 100 mg to 2,250 mg. RG7356 was well tolerated. Most frequent adverse events were fever, headache and fatigue. Dose-limiting toxicities included headache (1,500 mg q2w and 1,350 mg qw) and febrile neutropenia (2,250 mg q2w). The maximum tolerated dose with q2w dosing was 1,500 mg, but was not defined for qw dosing due to early study termination. Clinical efficacy was modest; 13/61 patients (21%) experienced disease stabilization lasting a median of 12 (range, 6-35) weeks. No apparent dose- or dose schedule-dependent changes in biological activity were reported from blood or tissue analyses. Tumor-targeting by positron emission tomography (PET) using 89Zr-labeled RG7356 was observed for doses ≥200 mg (q2w) warranting further investigation of this agent in combination regimens.

Keywords: RG7356; advanced CD44-expressing solid malignancies; advanced solid tumors; anti-CD44 humanized antibody; phase I trial.

Figure 1. RG7356 serum concentration versus time plot in patients in Arm A who received the biweekly (q2w) (A) and weekly (qw) (B) dosing schedules

Figure 2. Waterfall plot showing best response of individual patients according to RECIST criteria

45 patients had tumor lesion evaluation during the study. Abbreviations: PD (progressive disease); SD (stable disease).

Figure 3

RG7356 induces a temporary reduction from baseline of CD14⁺ peripheral blood monocytes after first infusion (A), does not seem to have an effect on macrophage tumor infiltration (B), and generates a temporary release in cytokines. The latter seems to be independent of dose and/or dose-schedules (C-F). Dose-limiting toxicities (DLTs) occurred in 3 patients during the study: grade 3 febrile neutropenia on study day 18 and 2 cases of headache on study days 4 and 8 (C-F). Abbreviations: C (cycle); D (day); EOI (end of infusion); IL (interleukin); MCP-1 (monocyte chemoattractant protein-1); q2w (biweekly). A. Plot of mean changes from baseline of percent of CD14+ (± standard deviation) at RG7356 doses ≥300 mg for the q2w schedule. B. Waterfall plot of percent change in CD68+ macrophages. C.-F. Individual cytokine profiles.

Figure 3

RG7356 induces a temporary reduction from baseline of CD14⁺ peripheral blood monocytes after first infusion (A), does not seem to have an effect on macrophage tumor infiltration (B), and generates a temporary release in cytokines. The latter seems to be independent of dose and/or dose-schedules (C-F). Dose-limiting toxicities (DLTs) occurred in 3 patients during the study: grade 3 febrile neutropenia on study day 18 and 2 cases of headache on study days 4 and 8 (C-F). Abbreviations: C (cycle); D (day); EOI (end of infusion); IL (interleukin); MCP-1 (monocyte chemoattractant protein-1); q2w (biweekly). A. Plot of mean changes from baseline of percent of CD14+ (± standard deviation) at RG7356 doses ≥300 mg for the q2w schedule. B. Waterfall plot of percent change in CD68+ macrophages. C.-F. Individual cytokine profiles.

Figure 3

RG7356 induces a temporary reduction from baseline of CD14⁺ peripheral blood monocytes after first infusion (A), does not seem to have an effect on macrophage tumor infiltration (B), and generates a temporary release in cytokines. The latter seems to be independent of dose and/or dose-schedules (C-F). Dose-limiting toxicities (DLTs) occurred in 3 patients during the study: grade 3 febrile neutropenia on study day 18 and 2 cases of headache on study days 4 and 8 (C-F). Abbreviations: C (cycle); D (day); EOI (end of infusion); IL (interleukin); MCP-1 (monocyte chemoattractant protein-1); q2w (biweekly). A. Plot of mean changes from baseline of percent of CD14+ (± standard deviation) at RG7356 doses ≥300 mg for the q2w schedule. B. Waterfall plot of percent change in CD68+ macrophages. C.-F. Individual cytokine profiles.

Figure 4. ⁸⁹Zr-RG7356 uptake in tumor lesions

Representative images of lymph node metastases in left upper neck of a patient with advanced CD44-positive head and neck cancer. Upper row: ⁸⁹Zr-RG7356 PET images acquired 5 days post injection. From left to right: axial, coronal and sagittal slices (8 mm) PET images fused with low-dose CT. Enhanced tracer uptake in malignant lymph nodes is shown (indicated by red center cross, SUV_max 3.9). Lower row: ¹⁸F-FDG PET images fused with low-dose CT (similar orientation as ⁸⁹Zr-PET; SUV_max 7.8). Note that spatial distribution of ¹⁸F-FDG and ⁸⁹Zr-RG7356 within the lesion is similar with central hypoactivity corresponding to necrosis.