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

Hou, Jian; Qiu, Lugui; Zhao, Yaozhong; Zhang, Xuejun; Liu, Yan; Wang, Zhao; Zhou, Fang; Leng, Yun; Yang, Shiming; Xi, Hao; Wang, Fuxu; Zhu, Bing; Chen, Wen-Ming; Peng, Wei; Zheng, Xiangjun

doi:10.1097/coc.0000000000000404

Cited by 10 publications

(7 citation statements)

References 14 publications

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“…Overall, the efficacy outcomes in this study were consistent with the results of the phase 2 trial, in which improvements in PFS and ORR were observed in patients of the aponermin plus TD group compared with those in the TD group [ 22 ]. The safety profile in the study was also consistent with previous studies, with hepatotoxicity as the major adverse reaction of aponermin [ 18 , 19 , 22 ].…”

Section: Discussionsupporting

confidence: 89%

“…In the phase 1b study in patients with relapsed or refractory multiple myeloma (RRMM) [ 18 ], aponermin monotherapy was well tolerated with doses ranging 5–15 mg/kg. An overall response rate (ORR) of 18.5% was achieved across dose ranges.…”

Section: Introductionmentioning

confidence: 99%

“…An overall response rate (ORR) of 18.5% was achieved across dose ranges. In the phase 2 study of aponermin combined with thalidomide in RRMM patients [ 19 ], a higher ORR (22.0% vs. 16.7%) and more cases of complete response (CR) or near CR (12.2% vs. 0) were observed compared to the aforementioned phase 1b results [ 18 ] at the same dose level, even though the patients were more heavily pretreated in the phase 2 trial.…”

Section: Introductionmentioning

confidence: 99%

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Aponermin or placebo in combination with thalidomide and dexamethasone in the treatment of relapsed or refractory multiple myeloma (CPT-MM301): a randomised, double-blinded, placebo-controlled, phase 3 trial

Xia,

Leng,

Fang

et al. 2023

BMC Cancer

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Background Aponermin, a circularly permuted tumor necrosis factor-related apoptosis-inducing ligand, is a potential death receptor 4/5-targeted antitumour candidate. Previous phase 1/2 studies have demonstrated the efficacy of aponermin in patients with relapsed or refractory multiple myeloma (RRMM). To confirm the superiority of aponermin plus thalidomide and dexamethasone (aponermin group) over placebo plus thalidomide and dexamethasone (placebo group) in RRMM, a randomized, double-blinded, placebo controlled phase 3 trial was performed. Methods Four hundred seventeen patients with RRMM who had previously received at least two regimens were randomly assigned (2:1) to receive aponermin, thalidomide, and dexamethasone or placebo, thalidomide, and dexamethasone. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall survival (OS) and overall response rate (ORR). Results A total of 415 patients received at least one dose of trial treatment (276 vs. 139). The median PFS was 5.5 months in the aponermin group and 3.1 months in the placebo group (hazard ratio, 0.62; 95% confidence interval [CI], 0.49–0.78; P < 0.001). The median OS was 22.4 months for the aponermin group and 16.4 months for the placebo group (hazard ratio, 0.70; 95% CI, 0.55–0.89; P = 0.003). Significantly higher rates of ORR (30.4% vs. 13.7%, P < 0.001) and very good partial response or better (14.1% vs. 2.2%, P < 0.0001) were achieved in the aponermin group than in the placebo group. Treatment with aponermin caused hepatotoxicity in some patients, as indicated by the elevated alanine transaminase, aspartate transaminase, or lactate dehydrogenase levels (52.2% vs. 24.5%, 51.1% vs. 19.4% and 44.9% vs. 21.6%, respectively), mostly grade 1/2, transient and reversible. The main grade 3/4 adverse events included neutropenia, pneumonia and hyperglycemia. The incidence of serious adverse events was similar between the two groups (40.6% vs. 37.4%). There was no evidence that aponermin leads to hematological toxicity, nephrotoxicity, cardiotoxicity, or secondary tumors. Conclusions Aponermin plus thalidomide and dexamethasone significantly improved PFS, OS and ORR with manageable side effects in RRMM patients who had received at least two prior therapies. These results support the use of aponermin, thalidomide, and dexamethasone as a treatment option for RRMM patients. Trial registration The trial was registered at http://www.chictr.org.cn as ChiCTR-IPR-15006024, 17/11/2014.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Aponermin or placebo in combination with thalidomide and dexamethasone in the treatment of relapsed or refractory multiple myeloma (CPT-MM301): a randomised, double-blinded, placebo-controlled, phase 3 trial

Xia,

Leng,

Fang

et al. 2023

BMC Cancer

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“…CPT (circularly permuted TRAIL) is a recombinant human mutant of Apo2L/TRAIL developed by Beijing Sunbio Biotech, Co. Ltd. in China, and was tested in relapsed and refractory multiple myeloma as a single agent [115,116], or in combination with thalidomide (T), or in combination with thalidomide and dexamethasone (TD) [117,118]. Median PFS was 6.7 months in the CPT + TD group compared with 3.1 months for the TD group [118].…”

Section: Extrinsic Pathway Targetingmentioning

confidence: 99%

Novel Apoptosis-Inducing Agents for the Treatment of Cancer, a New Arsenal in the Toolbox

Greer

Lipkowitz

Takebe

2019

Cancers

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: Evasion from apoptosis is an important hallmark of cancer cells. Alterations of apoptosis pathways are especially critical as they confer resistance to conventional anti-cancer therapeutics, e.g., chemotherapy, radiotherapy, and targeted therapeutics. Thus, successful induction of apoptosis using novel therapeutics may be a key strategy for preventing recurrence and metastasis. Inhibitors of anti-apoptotic molecules and enhancers of pro-apoptotic molecules are being actively developed for hematologic malignancies and solid tumors in particular over the last decade. However, due to the complicated apoptosis process caused by a multifaceted connection with cross-talk pathways, protein–protein interaction, and diverse resistance mechanisms, drug development within the category has been extremely challenging. Careful design and development of clinical trials incorporating predictive biomarkers along with novel apoptosis-inducing agents based on rational combination strategies are needed to ensure the successful development of these molecules. Here, we review the landscape of currently available direct apoptosis-targeting agents in clinical development for cancer treatment and update the related biomarker advancement to detect and validate the efficacy of apoptosis-targeted therapies, along with strategies to combine them with other agents.

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“…In fact, several therapies that use this pathway to kill tumor cells are currently under development [24,52]. In this regard, phase I, II and III clinical trials are being developed using TRAIL or modi ed forms of this molecule in monotherapy or in combination with other therapies (dexamethasone and/or thalidomide) in patients with relapsed MM, with quite encouraging results [33,34,53,54].…”

Section: Discussionmentioning

confidence: 99%

Multiple Mechanisms Contribute to Acquired TRAIL Resistance in Multiple Myeloma

Ticona-Pérez,

Chen,

Pandiella

et al. 2024

Preprint

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Multiple Myeloma (MM) prognosis has recently improved thanks to the incorporation of new therapies to the clinic. Nonetheless, it is still a non-curable malignancy. Targeting cancer cells with agents inducing cell death has been an appealing alternative investigated over the years, as is the case of TRAIL, an agonist of DR4 and DR5 death receptors. This pathway, involved in apoptosis triggering, has demonstrated efficacy on MM cells. In this research, we have investigated the sensitivity of a panel of MM cells to this agent and generated TRAIL-resistant models by continuous culture of sensitive cells with this peptide. Using genomic and biochemical approaches, the mechanisms underlying resistance were investigated. In TRAIL-resistant cells, a strong reduction in cell-surface receptor levels was detected and impaired the apoptotic machinery to respond to the treatment, enabling cells to efficiently form the Death Inducing Signalling Complex. In addition, an upregulation of the inhibitory protein c-FLIP was detected. Even though the manipulation of these proteins was able to modify cellular responses to TRAIL, it was not complete, pointing to other mechanisms involved in TRAIL resistance.

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

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

Cited by 10 publications

References 14 publications

Aponermin or placebo in combination with thalidomide and dexamethasone in the treatment of relapsed or refractory multiple myeloma (CPT-MM301): a randomised, double-blinded, placebo-controlled, phase 3 trial

Aponermin or placebo in combination with thalidomide and dexamethasone in the treatment of relapsed or refractory multiple myeloma (CPT-MM301): a randomised, double-blinded, placebo-controlled, phase 3 trial

Novel Apoptosis-Inducing Agents for the Treatment of Cancer, a New Arsenal in the Toolbox

Multiple Mechanisms Contribute to Acquired TRAIL Resistance in Multiple Myeloma

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