Circularly Permuted TRAIL (CPT) Combined with Thalidomide and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study (CPT-MM301)

Chen, Wenming

Oral and Poster Abstracts
Oral
653. Myeloma/Amyloidosis: Therapy, excluding Transplantation: Relapsed/Refractory Multiple Myeloma

multiple myeloma, Biological, apoptosis, Adult, Diseases, Therapies, Biological Processes, Plasma Cell Disorders, Lymphoid Malignancies, Study Population, Clinically relevant

Wenming Chen, MD¹^*, Zhongjun Xia, MD, PhD², Baijun Fang³^*, Chengcheng Fu⁴^*, Wei Li, MD⁵^*, Linhua Yang⁶^*, Xiao-yan Ke⁷^*, Hua Jiang, MD⁸^*, Jianyu Weng⁹^*, Li Liu, MD¹⁰^*, Yaozhong Zhao¹¹^*, Xuejun Zhang¹²^*, Aichun Liu, MD¹³^*, Zhongxia Huang¹⁴^*, Qingzhi Shi¹⁵^*, Yuhuan Gao¹⁶^*, Xiequn Chen¹⁷^*, Ling Pan, MD, PhD¹⁸^*, Zhen Cai, MD, PhD¹⁹^*, Zhao Wang, MD²⁰^*, Yafei Wang²¹^*, Yaqun Fan²²^*, Ming Hou²³, Yigai Ma²⁴^*, Jianda Hu, MD, PhD²⁵, Jianfeng Zhou, MD, PhD²⁶^*, Jing Liu, MD, PhD²⁷^*, Xiaohong Zhang²⁸^*, Haitao Meng, MD, PhD²⁹^*, Xuzhang Lu, PhD³⁰^*, Bintao Huang³¹^*, Li Fei³², Hanyun Ren, MD³³, Zonghong Shao, PhD³⁴, Hebing Zhou³⁵^*, Yu Hu, MD³⁶^* and Shifang Yang, PhD³⁷

¹Department of Hematology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
²Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
³Department of Hematology, Henan Cancer Hospital,Henan Cancer Hospital Affiliated to Zhengzhou University, Zhengzhou, China
⁴Department of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Suzhou, China
⁵Department of Hematology, The First Hospital of Jilin University, Changchun, China
⁶Department of Hematology, The Second Hospital of Shanxi Medical University, Taiyuan, China
⁷Department of Hematology and Lymphoma Research Center, Peking University, Third Hospital, Beijing, China
⁸Department of Hematology, Chang Zheng Hospital,Second Military Medical University, Shanghai, China
⁹Department of Hematology, Guangdong General Hospital,Guangdong Academy of Medical Sciences, Guangzhou, China
¹⁰Tangdu Hospital, Air Force Medical University, Xi'an, China
¹¹Department of Lymphoma Center, Institute of Hematology and Blood Diseases Hospital,Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, China
¹²Department of Hematology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
¹³Department of Hematology and Lymphology, Harbin Medical University Cancer Hospital, Harbin, China
¹⁴Department of Hematology, Beijing Chao-yang Hospital,Capital Medical University, Beijing, China
¹⁵Department of Hematology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
¹⁶Department of Hematology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
¹⁷Department of Hematology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
¹⁸Department of Hematology, West China Hospital,Sichuan University, Chengdu, China
¹⁹Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
²⁰Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
²¹Department of Hematology, Tianjin Medical University Cancer Institute and Hospital,National Clinical Research Center for Cancer,Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
²²Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, Medical College of Xiamen University, Xiamen, China
²³Department of Hematology, Qilu Hospital, Shandong University, Jinan, China
²⁴Departmentof Hematology, China-Japan Friendship Hospital, Beijing, China
²⁵Fujian Medical University Union Hospital, Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fuzhou, China
²⁶Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
²⁷Department of Hematology, The Third Xiangya Hospital of Central South University, Changsha, China
²⁸Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
²⁹Department of Hematology, The First Affiliated Hospital,School of Medicine,Zhejiang University, Hangzhou, China
³⁰Department of Hematology, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, China
³¹Department of Hematology, The Affiliated Hospital of Inner Mongolia Medical University, Inner Mongolia, China
³²the First Affiliated Hospital of Nanchang University, Nanchang, China
³³Department of Hematology, Peking University First Hospital, Beijing, China
³⁴Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
³⁵Department of Hematology, Beijing Luhe Hospital,Capital Medical University, Beijing, China
³⁶Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
³⁷Beijing Sunbio Biotech Co., Ltd., Beijing, China

Objective

CPT, a recombinant permuted human TNF-related apoptosis-inducing ligand (TRAIL), is a first-in-human anti-myeloma drug targeting death receptor 4/5. CPT was found to be a safe and effective anti-myeloma drug as a monotherapy and combined with thalidomide and dexamethasone (TD) in phase 1 and 2 studies for relapsed or refractory multiple myeloma (RRMM) patients. In order to verify the effectiveness and safety of CPT, we have conducted this multi-center, double-blind, placebo-controlled phase 3 study.

Methods

In this study, 417 RRMM patients previously treated with two or more lines of therapies were randomly assigned (2:1) to receive CPT+TD (CPT group) vs. placebo+TD (control group) from March 4, 2015 to July 3, 2019 in 36 centers of China.

CPT or placebo at a dose of 10 mg/kg was intravenously administered on days 1 to 5, both groups receive dexamethasone 40 mg orally on days 1 to 4, and thalidomide 150mg daily, 28 days per cycle until to disease progressions or unacceptable toxicity. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), overall response rate (ORR), time to progression (TTP), time to response (TTR), duration of response (DOR), health related quality of life (HRQoL) and safety.

Results

Of the 417 patients enrolled, 415 patients received CPT+TD (n=276) or placebo+TD (n=139) treatment. The demographic, baseline disease and clinical characteristic of the two groups were comparable. The median age of the patients was 59 years, and the median time from the initial diagnosis of multiple myeloma (MM) to participating this trial was 2.6 years. The median number of lines of prior therapies was 3. Proteasome inhibitors (PI) and immunomodulators (IMiD) were previously used in 74% and 86.5% of patients, respectively.

At date cutoff, the primary endpoint of PFS was significantly longer in the CPT group than in the control group (median 5.5 vs. 3.1 months; hazard ratio [HR] 0.619; P<0.0001) (Figure). The key secondary endpoints, including ORR (30.4% vs. 13.7%, P=0.0002) and OS (median 21.8 vs.17.0 months; HR, 0.723; P=0.0166) were also significantly improved in the CPT group than in the control group (Figure). Subgroup analysis of PFS, OS and ORR showed the superiority of CPT+TD over placebo +TD in almost all subgroups (Figure). It is particularly interesting to note that CPT exhibited excellent efficacy consistently with PFS, OS and ORR in the subgroups of patients with a poor prognosis, including those with refractory MM, with previous PI and IMiD therapies, and those received >3 lines of prior therapies. PFS and ORR were also significantly improved in the patients with PI and IMiD double-refractory MM. The other secondary endpoints including TTP, DOR and HRQoL also showed the superiority of the CPT group over the control group. To date of cutoff, the events of disease progressions or death occurred in 203 patients (73.6%) in the CPT group vs.111 patients (79.9%) in the control group.

The serious adverse events (SAE) rates were similar in the CPT group and the control group (40.6% vs. 37.4%), as were the death rates during the treatments (7.6% vs. 8.6%). Treatment-emergent adverse events (TEAEs) with at least a 10% greater frequency in the CPT group vs. the control group were elevated alanine transaminase (ALT), elevated aspartate transaminase (AST), elevated lactate dehydrogenase (LDH), increased monocyte counts, hypocalcaemia and upper respiratory tract infections. The data suggested that CPT may induce hepatotoxicity in patients, most of which were grade 1 or 2 and reversible. Grade 3 or 4 TEAEs observed in the CPT group and the control group included decreased neutrophil counts (26.8% vs. 26.6%), pneumonia (25% vs. 23.7%) and hyperglycemia (21% vs. 12.2%).

Conclusions

This study demonstrated that CPT was an effective drug for the treatment of RRMM patients, even in the multi-line treated MM patients and PI and/or IMIDs refractory MM patients. The combination of CPT with TD significantly prolonged the PFS and OS, increased the ORR. CPT combined with TD was well tolerated, the adverse events were mild, transient and reversible. CPT is expected to be the first available anti-myeloma drug that targets death receptor 4/5.

Disclosures: Yang: Beijing Sunbio Biotech Co., Ltd: Current Employment.

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416 Circularly Permuted TRAIL (CPT) Combined with Thalidomide and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study (CPT-MM301)