Recombinant Circularly Permuted TRAIL (CPT) for the Treatment of Relapsed or Refractory Multiple Myeloma: An Open-Label, Multicenter Phase II Clinical Trial

Abstract

78 Background: Circularly permuted TRAIL (CPT) is a recombinant mutant of human Apo2L/TRAIL developed by Beijing Sunbio Biotech Co., Ltd. as a targeted therapy for multiple myeloma and other hematologic malignancies. CPT is a dual pro-apoptotic receptor agonist that directly activates both pro-apoptotic receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5). CPT selectively induces apoptosis in a variety of cancer cells, while sparing most normal cells in preclinical models. Objective: CPT has shown preliminary activities for patients with relapsed or refractory multiple myeloma (Rel/Ref MM) in phase I study. The aim of this phase II study is to investigate the effect and safety of CPT for Rel/Ref MM patients. Methods: In this multi-center, open-label, single arm phase II study, twenty-seven Rel/Ref MM patients were enrolled to receive CPT treatment alone at the dose of 2.5 mg/kg/day intravenously, once daily for 14 consecutive days of each 21-day cycle. Clinical responses to CPT after 2 cycle's treatment were assessed by an independent review committee according to the criteria of the European Group for Blood and Marrow Transplantation (EBMT). Results: Among the 27 patients, one patient (3.7%) achieved near complete response (nCR) and eight patients (29.63%) exhibited partial response (PR). The overall response rate (ORR) was 33.3%. The median PFS was not reached within 2 cycle's treatment. The drug related adverse events (≥10%) included fever, AST/ALT elevation, leucopenia, neutropenia, rash, thrombocytopenia, and LDH elevation. The severe adverse events were occurred in 3 patients (11%), one of them was CPT-related liver injury. Anti-drug antibodies were detected in 6 patients without reduced efficacy or increased toxicities. Conclusions: The CPT is a very effective and well-tolerated new agent for Rel/Ref MM, and it is worthy to be further studied. Disclosures: Yang: Beijing Sunbio Biotech Co. Ltd.: Employment. Cui:Beijing Sunbio Biotech Co. Ltd.: Employment.

A multicenter, open‐label phase II study of recombinant CPT (Circularly Permuted TRAIL) plus thalidomide in patients with relapsed and refractory multiple myeloma

“…Compared with wild‐type Apo2L/TRAIL, CPT has better stability and slightly longer half‐life in mice, rats, and humans, and also displays better antitumor activity without significant toxicity against normal cells . In previous clinical trials , CPT monotherapy was well tolerated in patients with relapsed and/or refractory MM (RRMM), with no dose‐limiting toxicity (DLT) or maximal tolerated dose (MTD) with CPT doses up to 15 mg/kg. Approximately 20–30% of patients achieved partial response (PR) or better.…”

Death receptors as targets in cancer

“…Early preclinical studies evaluating CPT demonstrated its potential anti‐tumoral properties alone and in association with chemotherapy in vitro and in vivo on several tumour types (Fang et al ., ; Tang et al ., 2005; 2008; Zhang et al ., ; Wang et al ., ). A phase Ib dose escalation study (Chen et al ., 2012b) and a phase II multi‐centre open‐label single‐arm study (Chen et al ., 2012c) have been performed on relapsed or refractory multiple myeloma patients. CPT was either given intravenously for 5 consecutive days each 21 days for four cycles with increasing concentrations ranging from 5 to 15 mg·kg −1 per day or administered at 2.5 mg·kg −1 per day for 14 consecutive days of each 21‐day cycle for two cycles.…”

The TRAIL in the Treatment of Human Cancer: An Update on Clinical Trials

“…Moreover, CPT exhibited more robust pro-apoptotic activity than dulanermin ( Fang et al, 2005 ). However, patients who were enrolled in the second phases of clinical testing experienced mostly partial responses, whereas novel severe side effects were reported, such as CPT-mediated liver injury ( Chen et al, 2012 ).…”