Phase 1 trial of carfilzomib (PR-171) in combination with vorinostat (SAHA) in patients with relapsed or refractory B-cell lymphomas

Holkova, Beata; Kmieciak, Maciej; Bose, Prithviraj; Yazbeck, Victor; Barr, Paul M.; Tombes, Mary Beth; Shrader, Ellen; Weir-Wiggins, Caryn; Rollins, April D.; Cebula, Erin; Pierce, Emily; Herr, Megan M.; Sankala, Heidi; Hogan, Kevin T.; Wan, Wen; Feng, Changyong; Peterson, Derick R.; Fisher, Richard I.; Grant, Steven; Friedberg, Jonathan W.

doi:10.3109/10428194.2015.1075019

Cited by 22 publications

(12 citation statements)

References 44 publications

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“…However, combined exposure induced more pronounced tumor growth suppression in a xenograft MCL model and a significant improvement in survival compared to single agents, arguing that this strategy may preferentially kill lymphoma versus normal cells. In this context, a recent phase I trial in patients with refractory NHL has demonstrated that a regimen combining CFZ with the pan-HDACI vorinostat is tolerable and displays some, albeit modest activity (49). If a more selective HDACI induces less toxicity, higher drug doses and greater regimen activity may be possible.…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Interactions between the HDAC6 Inhibitor Ricolinostat (ACY1215) and the Irreversible Proteasome Inhibitor Carfilzomib in Non-Hodgkin Lymphoma Cells

Dasmahapatra

Patel

Friedberg

et al. 2014

Molecular Cancer Therapeutics

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Interactions between the HDAC6 inhibitor ricolinostat (ACY1215) and the irreversible proteasome inhibitor Carfilzomib (CFZ) were examined in non-Hodgkin’s lymphoma models, including diffuse large B-cell (DLBCL), mantle cell (MCL) and double-hit lymphoma cells. Marked in vitro synergism was observed in multiple cell types associated with activation of cellular stress pathways (e.g., JNK1/2, ERK1/2, and p38) accompanied by increases in DNA damage (γH2A.X), G2M arrest, and the pronounced induction of mitochondrial injury and apoptosis. Combination treatment with CFZ and ricolinostat increased reactive oxygen species (ROS), while the antioxidant TBAP attenuated DNA damage, JNK activation, and cell death. Similar interactions occurred in bortezomib-resistant and double-hit DLBCL, MCL, and primary DLBCL cells, but not in normal CD34+ cells. However, ricolinostat did not potentiate inhibition of chymotryptic activity by CFZ. shRNA knock-down of JNK1 (but not MEK1/2), or pharmacologic inhibition of p38, significantly reduced CFZ/ricolinostat lethality, indicating a functional contribution of these stress pathways to apoptosis. Combined exposure to CFZ and ricolinostat also markedly down-regulated the cargo-loading protein HR23B. Moreover, HR23B knock-down significantly increased CFZ- and ricolinostat-mediated lethality, suggesting a role for this event in cell death. Finally, combined in vivo treatment with CFZ and ricolinostat was well tolerated and significantly suppressed tumor growth and increased survival in an MCL xenograft model. Collectively, these findings indicate that CFZ and ricolinostat interact synergistically in NHL cells through multiple stress-related mechanisms, and suggest that this strategy warrants further consideration in NHL.

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Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Interactions between the HDAC6 Inhibitor Ricolinostat (ACY1215) and the Irreversible Proteasome Inhibitor Carfilzomib in Non-Hodgkin Lymphoma Cells

Dasmahapatra

Patel

Friedberg

et al. 2014

Molecular Cancer Therapeutics

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“…Preclinical data have shown synergy between HDACI and proteasomal inhibition via apoptosis in DLBCL [49]. This was tested in a phase I trial of carfilzomib in combination with vorinostat in R/R DLBCL [50]. The combination was well tolerated and 2/20 patients had stable disease.…”

Section: Discussionmentioning

confidence: 99%

A phase II study of belinostat (PXD101) in relapsed and refractory aggressive B-cell lymphomas: SWOG S0520

Puvvada

Liu

Rimsza

et al. 2016

Leukemia & Lymphoma

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Recent advances in diffuse large B-cell lymphomas (DLBCL) underscore the importance of tumor microenvironment in escaping host response. One mechanism is loss of major histocompatibility Class II antigens (MHCII) associated with decreased tumor infiltrating T lymphocytes (TIL) and poor survival. Transcription of MHCII is controlled by CIITA which in turn is regulated by histone acetylation. In this study, we hypothesized that HDAC inhibition with belinostat increases MHCII, CIITA expression, TIL and improves patient outcomes. Primary objective was evaluation of toxicity and response. Twenty-two patients were enrolled. Belinostat was well tolerated with mild toxicity. Two partial responses were observed at 5,13 months after registration for an overall response rate (ORR) of 10.5% (95 % CI 1.3-33.1%), and 3 patients had stable disease for 4.7, 42.3+, and 68.4+ months with minimum 3-year follow-up. Included correlative studies support the hypothesis and serve as the basis for SWOG S0806 combining Vorinostat with R-CHOP.

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“…Combinations of some of these novel agents with other novel or traditional agents have been explored (Table 3). Some recent clinical trials indicate that a newer proteasome inhibitor (Carfilzomib) can be combined with other agents including bendamustine, BEAM regimen followed with ASCT or CDK9 inhibitor although neurotoxicity may be a limiting factor [126–129]. Lenalidomide, an immunomodulatory agent, has shown promising results in MCL cases refractory to bortezomib, and in cases previously treated with other agents or combinations [124,130].…”

Section: Treatment Of Relapse/refractory MCLmentioning

confidence: 99%

Mantle cell lymphoma in the era of precision medicine-diagnosis, biomarkers and therapeutic agents

et al. 2016

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Despite advances in the development of clinical agents for treating Mantle Cell Lymphoma (MCL), treatment of MCL remains a challenge due to complexity and frequent relapse associated with MCL. The incorporation of conventional and novel diagnostic approaches such as genomic sequencing have helped improve understanding of the pathogenesis of MCL, and have led to development of specific agents targeting signaling pathways that have recently been shown to be involved in MCL. In this review, we first provide a general overview of MCL and then discuss about the role of biomarkers in the pathogenesis, diagnosis, prognosis, and treatment for MCL. We attempt to discuss major biomarkers for MCL and highlight published and ongoing clinical trials in an effort to evaluate the dominant signaling pathways as drugable targets for treating MCL so as to determine the potential combination of drugs for both untreated and relapse/refractory cases. Our analysis indicates that incorporation of biomarkers is crucial for patient stratification and improve diagnosis and predictability of disease outcome thus help us in designing future precision therapies. The evidence indicates that a combination of conventional chemotherapeutic agents and novel drugs designed to target specific dysregulated signaling pathways can provide the effective therapeutic options for both untreated and relapse/refractory MCL.

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Phase 1 trial of carfilzomib (PR-171) in combination with vorinostat (SAHA) in patients with relapsed or refractory B-cell lymphomas

Cited by 22 publications

References 44 publications

In Vitro and In Vivo Interactions between the HDAC6 Inhibitor Ricolinostat (ACY1215) and the Irreversible Proteasome Inhibitor Carfilzomib in Non-Hodgkin Lymphoma Cells

In Vitro and In Vivo Interactions between the HDAC6 Inhibitor Ricolinostat (ACY1215) and the Irreversible Proteasome Inhibitor Carfilzomib in Non-Hodgkin Lymphoma Cells

A phase II study of belinostat (PXD101) in relapsed and refractory aggressive B-cell lymphomas: SWOG S0520

Mantle cell lymphoma in the era of precision medicine-diagnosis, biomarkers and therapeutic agents

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