Phase I Study of Tremelimumab Monotherapy or in Combination With Durvalumab in Japanese Patients With Advanced Solid Tumors or Malignant Mesothelioma

Abstract

Background: The primary objective of this phase I, open-label trial was to assess safety and tolerability of tremelimumab monotherapy and combination therapy with durvalumab in Japanese patients with advanced cancer. Tremelimumab is a fully human monoclonal antibody against CTLA-4 in clinical trials; durvalumab is a monoclonal antibody against PD-L1 for the treatment of bladder and lung cancer.

Methods: In part 1, tremelimumab 3 or 10 mg/kg was given every 4 weeks (Q4W) for 6 doses, and thereafter every 12 weeks until discontinuation (n = 8); subsequently tremelimumab 10 mg/kg Q4W for 6 doses/Q12W and thereafter until discontinuation was administered in 41 patients with malignant pleural or peritoneal mesothelioma (MPM). In part 2, tremelimumab 10 mg/kg (Q4W for 6 doses followed by Q12W for 3 doses) was given in combination with durvalumab 15 mg/kg (Q4W for 13 doses) in cohort 1 (n = 4). In cohort 2 (n = 6), tremelimumab 1 mg/kg (Q4W for 4 doses) was given in combination with durvalumab 20 mg/kg (Q4W for 4 doses followed by 10 mg/kg Q2W for 22 doses), while in cohort 3 (n = 6), fixed-dose tremelimumab 75 mg Q4W for 4 doses plus durvalumab 1500 mg Q4W for 13 doses was given.

Results: In part 1, no dose-limiting toxicities (DLTs) for tremelimumab 3 or 10 mg/kg (Q4W for 6 doses/Q12W thereafter until discontinuation) were observed. Six (75%) patients reported treatment-related adverse events (trAEs). In the MPM dose-expansion cohort, 38 (92.7%) patients reported trAEs. In part 2, one DLT (Grade 4 myasthenia gravis) was reported for tremelimumab 10 mg/kg (Q4W for 6 doses/Q12W for 3 doses) plus durvalumab 15 mg/kg (Q4W for 13 doses). One DLT (Grade 4 hyperglycemia) was reported for tremelimumab 75 mg (Q4W for 4 doses) plus durvalumab 1500 mg (Q4W for 13 doses). Fourteen (87.5%) patients reported trAEs. Tremelimumab demonstrated low immunogenicity; 1 (16.7%) patient developed antidrug antibodies.

Conclusion: Tremelimumab 10 mg/kg (Q4W/Q12W), tremelimumab 1 mg/kg (Q4W) plus durvalumab 20 mg/kg (Q4W/10 mg/kg Q2W), and fixed-dose tremelimumab 75 mg (Q4W) plus durvalumab 1500 mg (Q4W) were safe and tolerable.ClinicalTrials.gov Identifier: NCT02141347 (https://ichgcp.net/clinical-trials-registry/NCT02141347).

Keywords: Japanese; durvalumab; immunotherapy; malignant mesothelioma; tremelimumab.

Published by Oxford University Press 2022.

Figures

Figure 1.

Study design.

Figure 2.

Waterfall plot of best percentage change from baseline in tumor size for (A) tremelimumab 3 mg/kg and (B) tremelimumab 10 mg/kg in dose escalation.

Figure 3.

Waterfall plot of best percentage change from baseline in tumor size in (A) combination multiple dosing and (B) MPM dose expansion.

Figure 4.

Kaplan-Meier plots of (A) progression-free survival and (B) overall survival in MPM dose expansion.

Figure 5.

Geometric mean (±SD) serum concentration (μg/mL) versus time of (A) tremelimumab 10 mg/kg dose 1 in dose escalation; (B) tremelimumab 10 mg/kg dose 2 onward in dose escalation; (C) tremelimumab cycle 1-cycle 2 pre-dosing in combination multiple dosing; (D) tremelimumab cycle 2 onward in combination multiple dosing; (E) durvalumab cycle 1-cycle 2 pre-dosing in combination multiple dosing; and (F) durvalumab cycle 2 onward in combination multiple dosing.