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A phase I study of ontuxizumab, a humanized monoclonal antibody targeting endosialin, in Japanese patients with solid tumors.

ABSTRACT: Background We conducted a first-in-Japanese, phase I study of ontuxizumab, a humanized, anti-endosialin monoclonal antibody, to confirm its tolerability, safety, and pharmacokinetics, and identify exploratory efficacy. Methods This was a multicenter, multiple-dose, open-label study in Japanese patients aged ?20 years with solid tumors, including gastric cancer (GC) or advanced hepatocellular carcinoma (HCC), who had failed standard chemotherapy. The study comprised two parts: part 1 (dose-escalation; ontuxizumab 2-12 mg/kg weekly) and part 2 (cohort-expansion; 4 or 8 mg/kg weekly, or 12 mg/kg biweekly). Results Fifteen patients were treated in part 1, and 31 in part 2 (16 patients with GC and 15 with HCC). In part 1, the most common treatment-related, treatment-emergent adverse event (TEAE) was fatigue (20%); no patients had grade???3 treatment-related TEAEs. In part 2, the most common treatment-related TEAEs were constipation, malaise, hiccups, and increased bilirubin; treatment-related grade 3 TEAEs occurred in two patients with HCC. In part 1, no patients achieved a partial response, and 6/15 (40%) had stable disease (SD). In part 2, 2/15 patients (13.3%) with GC and 8/15 (53.3%) with HCC had SD. Tumor shrinkage was observed in 5/15 HCC patients (33.3%). Conclusions Ontuxizumab, up to a dosage of 12 mg/kg weekly, was generally safe and well tolerated in this population, with no dose-limiting toxicities. The maximum tolerated dose was not reached; 8 mg/kg weekly or 12 mg/kg biweekly were the recommended dosages. We observed long-term disease stabilization in GC and extraskeletal chondrosarcoma, and tumor shrinkage in gastrointestinal stromal tumor and HCC. Trial registration: NCT01773434 ( ClinicalTrials.gov ).

SUBMITTER: Doi T

PROVIDER: S-EPMC6736902 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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A phase I study of ontuxizumab, a humanized monoclonal antibody targeting endosialin, in Japanese patients with solid tumors.

Doi Toshihiko T Aramaki Takeshi T Yasui Hirofumi H Muro Kei K Ikeda Masafumi M Okusaka Takuji T Inaba Yoshitaka Y Nakai Kenya K Ikezawa Hiroki H Nakajima Ryo R

Investigational new drugs 20190109 5

Background We conducted a first-in-Japanese, phase I study of ontuxizumab, a humanized, anti-endosialin monoclonal antibody, to confirm its tolerability, safety, and pharmacokinetics, and identify exploratory efficacy. Methods This was a multicenter, multiple-dose, open-label study in Japanese patients aged ≥20 years with solid tumors, including gastric cancer (GC) or advanced hepatocellular carcinoma (HCC), who had failed standard chemotherapy. The study comprised two parts: part 1 (dose-escala ...[more]

PMID: 30623276

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Project description:BackgroundActivation of leukemia inhibitory factor (LIF) is linked to an immunosuppressive tumor microenvironment (TME), with a strong association between LIF expression and tumor-associated macrophages (TAMs). MSC-1 (AZD0171) is a humanized monoclonal antibody that binds with high affinity to LIF, promoting antitumor inflammation through TAM modulation and cancer stem cell inhibition, slowing tumor growth. In this phase I, first-in-human, open-label, dose-escalation study, MSC-1 monotherapy was assessed in patients with advanced, unresectable solid tumors.Materials and methodsUsing accelerated-titration dose escalation followed by a 3 + 3 design, MSC-1 doses of 75-1500 mg were administered intravenously every 3 weeks (Q3W) until progression or unmanageable toxicity. Additional patients were enrolled in selected cohorts to further evaluate safety, pharmacokinetics (PK), and pharmacodynamics after escalation to the next dose had been approved. The primary objective was characterizing safety and determining the recommended phase II dose (RP2D). Evaluating antitumor activity and progression-free survival (PFS) by RECIST v1.1, PK and immunogenicity were secondary objectives. Exploratory objectives included pharmacodynamic effects on circulating LIF and TME immune markers.ResultsForty-one patients received treatment. MSC-1 monotherapy was safe and well tolerated at all doses, with no dose-limiting toxicities. The maximum tolerated dose was not reached and the RP2D was determined to be 1500 mg Q3W. Almost half of the patients had treatment-related adverse events (TRAEs), with no apparent trends across doses; no patients withdrew due to TRAEs. There were no objective responses; 23.7% had stable disease for ≥2 consecutive tumor assessments. Median PFS was 5.9 weeks; 23.7% had PFS >16 weeks. On-treatment changes in circulating LIF and TME signal transducers and activators of transcription 3 signaling, M1:M2 macrophage populations, and CD8+ T-cell infiltration were consistent with the hypothesized mechanism of action.ConclusionsMSC-1 was very well tolerated across doses, with prolonged PFS in some patients. Biomarker and preclinical data suggest potential synergy with checkpoint inhibitors.

Dataset Information

A phase I study of ontuxizumab, a humanized monoclonal antibody targeting endosialin, in Japanese patients with solid tumors.

Publications

A phase I study of ontuxizumab, a humanized monoclonal antibody targeting endosialin, in Japanese patients with solid tumors.

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