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First-in-Human RNA Polymerase I Transcription Inhibitor CX-5461 in Patients with Advanced Hematologic Cancers: Results of a Phase I Dose-Escalation Study.
Cancer Discov. 2019 08; 9(8):1036-1049.CD

Abstract

RNA polymerase I (Pol I) transcription of ribosomal RNA genes (rDNA) is tightly regulated downstream of oncogenic pathways, and its dysregulation is a common feature in cancer. We evaluated CX-5461, the first-in-class selective rDNA transcription inhibitor, in a first-in-human, phase I dose-escalation study in advanced hematologic cancers. Administration of CX-5461 intravenously once every 3 weeks to 5 cohorts determined an MTD of 170 mg/m2, with a predictable pharmacokinetic profile. The dose-limiting toxicity was palmar-plantar erythrodysesthesia; photosensitivity was a dose-independent adverse event (AE), manageable by preventive measures. CX-5461 induced rapid on-target inhibition of rDNA transcription, with p53 activation detected in tumor cells from one patient achieving a clinical response. One patient with anaplastic large cell lymphoma attained a prolonged partial response and 5 patients with myeloma and diffuse large B-cell lymphoma achieved stable disease as best response. CX-5461 is safe at doses associated with clinical benefit and dermatologic AEs are manageable.

SIGNIFICANCE:

CX-5461 is a first-in-class selective inhibitor of rDNA transcription. This first-in-human study establishes the feasibility of targeting this process, demonstrating single-agent antitumor activity against advanced hematologic cancers with predictable pharmacokinetics and a safety profile allowing prolonged dosing. Consistent with preclinical data, antitumor activity was observed in TP53 wild-type and mutant malignancies.This article is highlighted in the In This Issue feature, p. 983.

Authors+Show Affiliations

Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Victoria, Australia.Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.The ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, Australian National University, Australian Capital Territory, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.The ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, Australian National University, Australian Capital Territory, Australia.Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Victoria, Australia. Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.Senhwa Biosciences, Inc., New Taipei City, Taiwan, Republic of China.Senhwa Biosciences, Inc., New Taipei City, Taiwan, Republic of China.Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia. Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia. Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia. Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia. Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia.Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia. Department of Medicine, St. Vincent's Hospital, University of Melbourne, Parkville, Victoria, Australia.Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia. Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. The ACRF Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, Australian National University, Australian Capital Territory, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia. Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia. School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia.Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. gretchen.poortinga@petermac.org Simon.Harrison@petermac.org. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia. Department of Medicine, St. Vincent's Hospital, University of Melbourne, Parkville, Victoria, Australia.Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Victoria, Australia. gretchen.poortinga@petermac.org Simon.Harrison@petermac.org. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.

Pub Type(s)

Clinical Trial, Phase I
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31092402

Citation

Khot, Amit, et al. "First-in-Human RNA Polymerase I Transcription Inhibitor CX-5461 in Patients With Advanced Hematologic Cancers: Results of a Phase I Dose-Escalation Study." Cancer Discovery, vol. 9, no. 8, 2019, pp. 1036-1049.
Khot A, Brajanovski N, Cameron DP, et al. First-in-Human RNA Polymerase I Transcription Inhibitor CX-5461 in Patients with Advanced Hematologic Cancers: Results of a Phase I Dose-Escalation Study. Cancer Discov. 2019;9(8):1036-1049.
Khot, A., Brajanovski, N., Cameron, D. P., Hein, N., Maclachlan, K. H., Sanij, E., Lim, J., Soong, J., Link, E., Blombery, P., Thompson, E. R., Fellowes, A., Sheppard, K. E., McArthur, G. A., Pearson, R. B., Hannan, R. D., Poortinga, G., & Harrison, S. J. (2019). First-in-Human RNA Polymerase I Transcription Inhibitor CX-5461 in Patients with Advanced Hematologic Cancers: Results of a Phase I Dose-Escalation Study. Cancer Discovery, 9(8), 1036-1049. https://doi.org/10.1158/2159-8290.CD-18-1455
Khot A, et al. First-in-Human RNA Polymerase I Transcription Inhibitor CX-5461 in Patients With Advanced Hematologic Cancers: Results of a Phase I Dose-Escalation Study. Cancer Discov. 2019;9(8):1036-1049. PubMed PMID: 31092402.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - First-in-Human RNA Polymerase I Transcription Inhibitor CX-5461 in Patients with Advanced Hematologic Cancers: Results of a Phase I Dose-Escalation Study. AU - Khot,Amit, AU - Brajanovski,Natalie, AU - Cameron,Donald P, AU - Hein,Nadine, AU - Maclachlan,Kylee H, AU - Sanij,Elaine, AU - Lim,John, AU - Soong,John, AU - Link,Emma, AU - Blombery,Piers, AU - Thompson,Ella R, AU - Fellowes,Andrew, AU - Sheppard,Karen E, AU - McArthur,Grant A, AU - Pearson,Richard B, AU - Hannan,Ross D, AU - Poortinga,Gretchen, AU - Harrison,Simon J, Y1 - 2019/05/15/ PY - 2018/12/12/received PY - 2019/04/11/revised PY - 2019/05/10/accepted PY - 2019/5/17/pubmed PY - 2020/8/6/medline PY - 2019/5/17/entrez SP - 1036 EP - 1049 JF - Cancer discovery JO - Cancer Discov VL - 9 IS - 8 N2 - RNA polymerase I (Pol I) transcription of ribosomal RNA genes (rDNA) is tightly regulated downstream of oncogenic pathways, and its dysregulation is a common feature in cancer. We evaluated CX-5461, the first-in-class selective rDNA transcription inhibitor, in a first-in-human, phase I dose-escalation study in advanced hematologic cancers. Administration of CX-5461 intravenously once every 3 weeks to 5 cohorts determined an MTD of 170 mg/m2, with a predictable pharmacokinetic profile. The dose-limiting toxicity was palmar-plantar erythrodysesthesia; photosensitivity was a dose-independent adverse event (AE), manageable by preventive measures. CX-5461 induced rapid on-target inhibition of rDNA transcription, with p53 activation detected in tumor cells from one patient achieving a clinical response. One patient with anaplastic large cell lymphoma attained a prolonged partial response and 5 patients with myeloma and diffuse large B-cell lymphoma achieved stable disease as best response. CX-5461 is safe at doses associated with clinical benefit and dermatologic AEs are manageable. SIGNIFICANCE: CX-5461 is a first-in-class selective inhibitor of rDNA transcription. This first-in-human study establishes the feasibility of targeting this process, demonstrating single-agent antitumor activity against advanced hematologic cancers with predictable pharmacokinetics and a safety profile allowing prolonged dosing. Consistent with preclinical data, antitumor activity was observed in TP53 wild-type and mutant malignancies.This article is highlighted in the In This Issue feature, p. 983. SN - 2159-8290 UR - https://www.unboundmedicine.com/medline/citation/31092402/First_in_Human_RNA_Polymerase_I_Transcription_Inhibitor_CX_5461_in_Patients_with_Advanced_Hematologic_Cancers:_Results_of_a_Phase_I_Dose_Escalation_Study_ L2 - http://cancerdiscovery.aacrjournals.org/cgi/pmidlookup?view=long&pmid=31092402 DB - PRIME DP - Unbound Medicine ER -