A phase Ib study of utomilumab (PF-05082566) in combination with mogamulizumab in patients with advanced solid tumors.

Abstract

BACKGROUND:

Expressed on activated T and natural killer cells, 4-1BB/CD137 is a costimulatory receptor that signals a series of events resulting in cytokine secretion and enhanced effector function. Targeting 4-1BB/CD137 with agonist antibodies has been associated with tumor reduction and antitumor immunity. C-C chemokine receptor 4 (CCR4) is highly expressed in various solid tumor indications and associated with poor prognosis. This phase Ib, open-label study in patients with advanced solid tumors assessed the safety, efficacy, pharmacokinetics, and pharmacodynamics of utomilumab (PF-05082566), a human monoclonal antibody (mAb) agonist of the T-cell costimulatory receptor 4-1BB/CD137, in combination with mogamulizumab, a humanized mAb targeting CCR4 reported to deplete subsets of regulatory T cells (Tregs).

METHODS:

Utomilumab 1.2-5 mg/kg or 100 mg flat dose every 4 weeks plus mogamulizumab 1 mg/kg (weekly in Cycle 1 followed by biweekly in Cycles ≥2) was administered intravenously to 24 adults with solid tumors. Blood was collected pre- and post-dose for assessment of drug pharmacokinetics, immunogenicity, and pharmacodynamic markers. Baseline tumor biopsies from a subset of patients were also analyzed for the presence of programmed cell death-ligand 1 (PD-L1), CD8, FoxP3, and 4-1BB/CD137. Radiologic tumor assessments were conducted at baseline and on treatment every 8 weeks.

RESULTS:

No dose-limiting toxicities occurred and the maximum tolerated dose was determined to be at least 2.4 mg/kg per the time-to-event continual reassessment method. No serious adverse events related to either treatment were observed; anemia was the only grade 3 non-serious adverse event related to both treatments. Utomilumab systemic exposure appeared to increase with dose. One patient with PD-L1-refractory squamous lung cancer achieved a best overall response of partial response and 9 patients had a best overall response of stable disease. No patients achieved complete response. Objective response rate was 4.2% (95% confidence interval: 0.1-21.1%) per RECIST 1.1. Depletion of Tregs in peripheral blood was accompanied by evidence of T-cell expansion as assessed by T-cell receptor sequence analysis.

CONCLUSIONS:

The combination of utomilumab/mogamulizumab was safe and tolerable, and may be suitable for evaluation in settings where CCR4-expressing Tregs are suppressing anticancer immunity.

TRIAL REGISTRATION:

ClinicalTrials.gov identifier: NCT02444793.

• Authors: Ezra E W Cohen, Michael J Pishvaian, Dale R Shepard, Ding Wang, Jared Weiss, Melissa L Johnson, Christine H Chung, Ying Chen, Bo Huang, Craig B Davis, Francesca Toffalorio, Aron Thall, Steven F Powell
• Journal: Journal for immunotherapy of cancer (J Immunother Cancer) Vol. 7 Issue 1 Pg. 342 (12 04 2019) ISSN: 2051-1426 [Electronic] England
• PMID: 31801624 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Humanized
• Biomarkers, Tumor
• Immunoglobulin G
• utomilumab
• mogamulizumab

Topics

• Aged
• Antibodies, Monoclonal, Humanized (administration & dosage, adverse effects, pharmacokinetics)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Biomarkers, Tumor
• Biopsy
• Disease Management
• Drug Monitoring
• Female
• Humans
• Immunoglobulin G (administration & dosage, adverse effects)
• Immunohistochemistry
• Male
• Middle Aged
• Neoplasm Staging
• Neoplasms (diagnosis, drug therapy, etiology, mortality)
• Tomography, X-Ray Computed