Rigosertib in combination with azacitidine in patients with myelodysplastic syndromes or acute myeloid leukemia: Results of a phase 1 study

Navada, Shyamala C.; Odchimar-Reissig, Rosalie; Pemmaraju, Naveen; Alvarado, Yesid; Ohanian, Maro; John, Rosmy B.; Demakos, Erin P.; Zbyszewski, Patrick S.; Maniar, Manoj; Woodman, Richard C.; Fruchtman, Steven

doi:10.1016/j.leukres.2020.106369

Cited by 19 publications

(9 citation statements)

References 21 publications

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“…We next examined potential drug combinations to enhance efficacy. Rigosertib was combined with cisplatin or vincristine (included in the clinically used rapid-COJEC regimen), filanesib (a mitotic inhibitor with strong anti-neuroblastoma effects [17] ), or azacitidine (effective in combination with rigosertib in other malignancies [28] ). Combination testing was performed in LU-NB-1 and LU-NB-2 models using 6 × 6 matrices and cell viability and cell death analyses ( Figs.…”

Section: Resultsmentioning

confidence: 99%

Anti-tumor effects of rigosertib in high-risk neuroblastoma

Radke

Hansson

Sjölund

et al. 2021

Translational Oncology

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Highlights Analysis of multiple tumor types reveal neuroblastoma sensitivity to rigosertib. Neuroblastoma 2D and 3D organoid models are sensitive to rigosertib. Rigosertib causes G2M cell cycle arrest rather than inhibition of Ras binding domains. Rigosertib prolongs survival of MYCN - amplified patient-derived xenograft tumors. Combination of rigosertib and vincristine is synergistic against neuroblastoma.

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Section: Resultsmentioning

confidence: 99%

Anti-tumor effects of rigosertib in high-risk neuroblastoma

Radke

Hansson

Sjölund

et al. 2021

Translational Oncology

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“…Negative results were recently reported from the phase 3 INSPIRE study on single-agent rigosertib in MDS patients after HMA treatment failure (NCT02562443). Regarding the combination of oral rigosertib and parenteral azacitidine, phase 1 results of a phase 1/2 study in MDS and AML patients showed a safety profile similar to single-agent azacitidine and responses in 7/9 MDS/ CMML patients and 2/7 AML patients [113]. Another novel drug that is under active investigation in combination with azacitidine is the NEDD8-activating enzyme inhibitor pevonedistat.…”

Section: Combination Treatments With An Hma Backbonementioning

confidence: 99%

Hypomethylating agents (HMA) for the treatment of acute myeloid leukemia and myelodysplastic syndromes: mechanisms of resistance and novel HMA-based therapies

et al. 2021

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Aberrant DNA methylation plays a pivotal role in tumor development and progression. DNA hypomethylating agents (HMA) constitute a class of drugs which are able to reverse DNA methylation, thereby triggering the re-programming of tumor cells. The first-generation HMA azacitidine and decitabine have now been in standard clinical use for some time, offering a valuable alternative to previous treatments in acute myeloid leukemia and myelodysplastic syndromes, so far particularly in older, medically non-fit patients. However, the longer we use these drugs, the more we are confronted with the (almost inevitable) development of resistance. This review provides insights into the mode of action of HMA, mechanisms of resistance to this treatment, and strategies to overcome HMA resistance including next-generation HMA and HMA-based combination therapies.

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“…An exception to the above-mentioned inefficacy of KIs other than FLT3 inhibitors was the activity of rigosertib, an inhibitor of RAS signaling pathways, when used alone or in combination with azacitidine, a nucleoside analog, for the treatment of myelodysplastic syndrome (MDS) patients. The ORR and bone marrow responses for this patient cohort demonstrated encouraging results, and the observed AEs did not represent an impairment for continuous therapy, even when analyzed in a drug combination regimen [ 81 , 103 ].…”

Section: Aml and Myeloproliferative Disordersmentioning

confidence: 97%

“…The other half of the analyzed studies focused primarily on lymphoid malignancies, especially of B-cell origin, and had phosphatidylinositol 3-kinase (PI3K) and Bruton’s tyrosine kinase (BTK) being the most targeted kinases ( Figure 3 ). A large spectrum of different KIs and treatment protocols were covered, and kinase inhibition was mainly evaluated as a single-agent strategy in the treatment of R/R hematologic disorders, with only 10 out of 32 clinical trials associating KI usage with another cytotoxic agent [ 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 ].…”

Section: Recent Prospects Into Clinical Investigationsmentioning

confidence: 99%

Kinase Inhibition in Relapsed/Refractory Leukemia and Lymphoma Settings: Recent Prospects into Clinical Investigations

et al. 2021

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Cancer is still a major barrier to life expectancy increase worldwide, and hematologic neoplasms represent a relevant percentage of cancer incidence rates. Tumor dependence of continuous proliferative signals mediated through protein kinases overexpression instigated increased strategies of kinase inhibition in the oncologic practice over the last couple decades, and in this review, we focused our discussion on relevant clinical trials of the past five years that investigated kinase inhibitor (KI) usage in patients afflicted with relapsed/refractory (R/R) hematologic malignancies as well as in the pharmacological characteristics of available KIs and the dissertation about traditional chemotherapy treatment approaches and its hindrances. A trend towards investigations on KI usage for the treatment of chronic lymphoid leukemia and acute myeloid leukemia in R/R settings was observed, and it likely reflects the existence of already established treatment protocols for chronic myeloid leukemia and acute lymphoid leukemia patient cohorts. Overall, regimens of KI treatment are clinically manageable, and results are especially effective when allied with tumor genetic profiles, giving rise to encouraging future prospects of an era where chemotherapy-free treatment regimens are a reality for many oncologic patients.

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Rigosertib in combination with azacitidine in patients with myelodysplastic syndromes or acute myeloid leukemia: Results of a phase 1 study

Cited by 19 publications

References 21 publications

Anti-tumor effects of rigosertib in high-risk neuroblastoma

Anti-tumor effects of rigosertib in high-risk neuroblastoma

Hypomethylating agents (HMA) for the treatment of acute myeloid leukemia and myelodysplastic syndromes: mechanisms of resistance and novel HMA-based therapies

Kinase Inhibition in Relapsed/Refractory Leukemia and Lymphoma Settings: Recent Prospects into Clinical Investigations

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