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A Phase1b Dose Escalation Study of Recombinant Circularly Permuted TRAIL in Patients With Relapsed or Refractory Multiple Myeloma

Hou, Jian, MD, PhD*; Qiu, Lugui, MD; Zhao, Yaozhong, MD; Zhang, Xuejun, MD, PhD; Liu, Yan, MD§; Wang, Zhao, MD, PhD; Zhou, Fang, MD; Leng, Yun, MD#; Yang, Shifang, PhD**; Xi, Hao, BS*; Wang, Fuxu, MD; Zhu, Bing, PhD**; Chen, Wenming, MD#; Wei, Peng, PhD**; Zheng, Xiangjun, MS**

American Journal of Clinical Oncology: October 2018 - Volume 41 - Issue 10 - p 1008–1014
doi: 10.1097/COC.0000000000000404
Original Articles: Hematopoietic

Objectives: Circularly permuted tumor necrosis factor-related apoptosis-inducing ligand (CPT), or CPT, is a novel antitumor drug candidate. This phase 1b study evaluated the safety, tolerability, pharmacokinetics (PK), and efficacy of single-agent CPT in patients with relapsed or refractory multiple myeloma (RRMM), and aimed to identify the recommended dose for the phase 2 study.

Materials and Methods: Patients received single or multiple doses (once daily for 5 consecutive days per 21-d cycle) of CPT intravenous infusion at doses of 5, 6.5, 8, 10, and 15 mg/kg, to determine the maximum tolerated dose, dose-limiting toxicities, safety, and tolerability. PK were evaluated. Preliminary efficacy was assessed after each treatment cycle.

Results: Twenty-nine RRMM patients received CPT. Neither the dose-limiting toxicity nor the maximum tolerated dose were identified. The most common treatment-related adverse events were liver enzyme elevations (eg, elevation of aspartate aminotransferase and alanine aminotransferase), hematological abnormalities (eg, leukopenia and neutropenia), fever, fatigue, and vomiting. CPT had a terminal half-life of 0.90 to 1.27 hours at the 5 dose levels, and no accumulation was observed with repeated doses. Safety and PK profiles were similar across the 5 dose cohorts. The overall response rate (complete and partial response) was 18.5%. The clinical benefit rate (complete, partial, and minimal response) was 33.3%. Sixteen patients did not respond to CPT (no change and progressive disease). Patients treated with higher doses of CPT appeared to have better responses.

Conclusions: CPT was safe and well tolerated by RRMM patients, and doses between 8 and 15 mg/kg were recommended for the phase 2 study.

*Department of Hematology, Chang Zheng Hospital, Second Military Medical University, Shanghai

Department of Lymphoma Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin

Department of Hematology, Second Hospital of Hebei Medical University, Shijiazhuang, Hebei

§Departmentof Hematology, Peking University Third Hospital

Department of Hematology, Beijing Friendship Hospital

#Department of Hematology, Beijing Chao-Yang Hospital, Capital Medical University

**Beijing Sunbio Biotech Co. Ltd

Department of Hematology, Jinan Military General Hospital, Jinan, Shandong, China

Supported by Beijing Sunbio Biotech Co. Ltd. S.Y., B.Z., P.W., and X.Z. are employees of Beijing Sunbio Biotech Co. Ltd.

The authors declare no conflicts of interest.

Reprints: Wenming Chen, MD, Department of Hematology, Beijing Chao-Yang Hospital, Capital Medical University, 8 Gongren Tiyuchang Nanlu, Chaoyang District, Beijing 100020, China. E-mail: xybxx@ccmu.edu.cn.

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