First-in-Class ERK1/2 Inhibitor Ulixertinib (BVD-523) in Patients with MAPK Mutant Advanced Solid Tumors: Results of a Phase I Dose-Escalation and Expansion Study
Ulixertinib (BVD-523) is an ERK1/2 kinase inhibitor with potent preclinical activity in BRAF- and RAS-mutant cell lines. In this multicenter phase I trial (NCT01781429), 135 patients were enrolled to an accelerated 3 + 3 dose-escalation cohort and six distinct dose-expansion cohorts. Dose escalation...
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| Published in: | Cancer discovery Vol. 8; no. 2; p. 184 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
United States
01.02.2018
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| Subjects: | |
| ISSN: | 2159-8290, 2159-8290 |
| Online Access: | Get more information |
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| Abstract | Ulixertinib (BVD-523) is an ERK1/2 kinase inhibitor with potent preclinical activity in BRAF- and RAS-mutant cell lines. In this multicenter phase I trial (NCT01781429), 135 patients were enrolled to an accelerated 3 + 3 dose-escalation cohort and six distinct dose-expansion cohorts. Dose escalation included 27 patients, dosed from 10 to 900 mg twice daily and established the recommended phase II dose (RP2D) of 600 mg twice daily. Ulixertinib exposure was dose proportional to the RP2D, which provided near-complete inhibition of ERK activity in whole blood. In the 108-patient expansion cohort, 32% of patients required dose reduction. The most common treatment-related adverse events were diarrhea (48%), fatigue (42%), nausea (41%), and dermatitis acneiform (31%). Partial responses were seen in 3 of 18 (17%) patients dosed at or above maximum tolerated dose and in 11 of 81 (14%) evaluable patients in dose expansion. Responses occurred in patients with
-,
V600-, and non-V600
-mutant solid tumors.
Here, we describe the first-in-human dose-escalation study of an ERK1/2 inhibitor for the treatment of patients with advanced solid tumors. Ulixertinib has an acceptable safety profile with favorable pharmacokinetics and has shown early evidence of clinical activity in
- and
V600- and non-V600-mutant solid-tumor malignancies.
. |
|---|---|
| AbstractList | Ulixertinib (BVD-523) is an ERK1/2 kinase inhibitor with potent preclinical activity in BRAF- and RAS-mutant cell lines. In this multicenter phase I trial (NCT01781429), 135 patients were enrolled to an accelerated 3 + 3 dose-escalation cohort and six distinct dose-expansion cohorts. Dose escalation included 27 patients, dosed from 10 to 900 mg twice daily and established the recommended phase II dose (RP2D) of 600 mg twice daily. Ulixertinib exposure was dose proportional to the RP2D, which provided near-complete inhibition of ERK activity in whole blood. In the 108-patient expansion cohort, 32% of patients required dose reduction. The most common treatment-related adverse events were diarrhea (48%), fatigue (42%), nausea (41%), and dermatitis acneiform (31%). Partial responses were seen in 3 of 18 (17%) patients dosed at or above maximum tolerated dose and in 11 of 81 (14%) evaluable patients in dose expansion. Responses occurred in patients with
-,
V600-, and non-V600
-mutant solid tumors.
Here, we describe the first-in-human dose-escalation study of an ERK1/2 inhibitor for the treatment of patients with advanced solid tumors. Ulixertinib has an acceptable safety profile with favorable pharmacokinetics and has shown early evidence of clinical activity in
- and
V600- and non-V600-mutant solid-tumor malignancies.
. Ulixertinib (BVD-523) is an ERK1/2 kinase inhibitor with potent preclinical activity in BRAF- and RAS-mutant cell lines. In this multicenter phase I trial (NCT01781429), 135 patients were enrolled to an accelerated 3 + 3 dose-escalation cohort and six distinct dose-expansion cohorts. Dose escalation included 27 patients, dosed from 10 to 900 mg twice daily and established the recommended phase II dose (RP2D) of 600 mg twice daily. Ulixertinib exposure was dose proportional to the RP2D, which provided near-complete inhibition of ERK activity in whole blood. In the 108-patient expansion cohort, 32% of patients required dose reduction. The most common treatment-related adverse events were diarrhea (48%), fatigue (42%), nausea (41%), and dermatitis acneiform (31%). Partial responses were seen in 3 of 18 (17%) patients dosed at or above maximum tolerated dose and in 11 of 81 (14%) evaluable patients in dose expansion. Responses occurred in patients with NRAS-, BRAF V600-, and non-V600 BRAF-mutant solid tumors.Significance: Here, we describe the first-in-human dose-escalation study of an ERK1/2 inhibitor for the treatment of patients with advanced solid tumors. Ulixertinib has an acceptable safety profile with favorable pharmacokinetics and has shown early evidence of clinical activity in NRAS- and BRAF V600- and non-V600-mutant solid-tumor malignancies. Cancer Discov; 8(2); 184-95. ©2017 AACR.See related commentary by Smalley and Smalley, p. 140This article is highlighted in the In This Issue feature, p. 127.Ulixertinib (BVD-523) is an ERK1/2 kinase inhibitor with potent preclinical activity in BRAF- and RAS-mutant cell lines. In this multicenter phase I trial (NCT01781429), 135 patients were enrolled to an accelerated 3 + 3 dose-escalation cohort and six distinct dose-expansion cohorts. Dose escalation included 27 patients, dosed from 10 to 900 mg twice daily and established the recommended phase II dose (RP2D) of 600 mg twice daily. Ulixertinib exposure was dose proportional to the RP2D, which provided near-complete inhibition of ERK activity in whole blood. In the 108-patient expansion cohort, 32% of patients required dose reduction. The most common treatment-related adverse events were diarrhea (48%), fatigue (42%), nausea (41%), and dermatitis acneiform (31%). Partial responses were seen in 3 of 18 (17%) patients dosed at or above maximum tolerated dose and in 11 of 81 (14%) evaluable patients in dose expansion. Responses occurred in patients with NRAS-, BRAF V600-, and non-V600 BRAF-mutant solid tumors.Significance: Here, we describe the first-in-human dose-escalation study of an ERK1/2 inhibitor for the treatment of patients with advanced solid tumors. Ulixertinib has an acceptable safety profile with favorable pharmacokinetics and has shown early evidence of clinical activity in NRAS- and BRAF V600- and non-V600-mutant solid-tumor malignancies. Cancer Discov; 8(2); 184-95. ©2017 AACR.See related commentary by Smalley and Smalley, p. 140This article is highlighted in the In This Issue feature, p. 127. |
| Author | Saha, Saurabh Groover, Anna L Ribas, Antoni Hyman, David M Carvajal, Richard D Lacouture, Mario E Varterasian, Mary Shapiro, Geoffrey I Janku, Filip Keedy, Vicki Buchbinder, Elizabeth Varghese, Anna M Infante, Jeffrey R Patel, Sapna P Sosman, Jeffrey A Sullivan, Ryan J Wong, Deborah Jean Lee Sznol, Mario Flaherty, Keith Tolcher, Anthony W Welsch, Dean J Patel, Manish R Wang-Gillam, Andrea DeCrescenzo, Gary A Li, Bob T Emery, Caroline M Mier, James W |
| Author_xml | – sequence: 1 givenname: Ryan J surname: Sullivan fullname: Sullivan, Ryan J email: rsullivan7@mgh.harvard.edu, lib1@mskcc.org organization: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts. rsullivan7@mgh.harvard.edu lib1@mskcc.org – sequence: 2 givenname: Jeffrey R surname: Infante fullname: Infante, Jeffrey R organization: Sarah Cannon Research Institute, Tennessee Oncology, Nashville, Tennessee – sequence: 3 givenname: Filip surname: Janku fullname: Janku, Filip organization: The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 4 givenname: Deborah Jean Lee surname: Wong fullname: Wong, Deborah Jean Lee organization: University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, California – sequence: 5 givenname: Jeffrey A surname: Sosman fullname: Sosman, Jeffrey A organization: Vanderbilt University Medical Center, Nashville, Tennessee – sequence: 6 givenname: Vicki surname: Keedy fullname: Keedy, Vicki organization: Vanderbilt University Medical Center, Nashville, Tennessee – sequence: 7 givenname: Manish R surname: Patel fullname: Patel, Manish R organization: Sarah Cannon Research Institute, Florida Cancer Specialists, Sarasota, Florida – sequence: 8 givenname: Geoffrey I surname: Shapiro fullname: Shapiro, Geoffrey I organization: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts – sequence: 9 givenname: James W surname: Mier fullname: Mier, James W organization: Beth-Israel Deaconess Medical Center, Boston, Massachusetts – sequence: 10 givenname: Anthony W surname: Tolcher fullname: Tolcher, Anthony W organization: South Texas Accelerated Research Therapeutics, San Antonio, Texas – sequence: 11 givenname: Andrea surname: Wang-Gillam fullname: Wang-Gillam, Andrea organization: Washington University in St. Louis, St. Louis, Missouri – sequence: 12 givenname: Mario surname: Sznol fullname: Sznol, Mario organization: Yale University, New Haven, Connecticut – sequence: 13 givenname: Keith surname: Flaherty fullname: Flaherty, Keith organization: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts – sequence: 14 givenname: Elizabeth surname: Buchbinder fullname: Buchbinder, Elizabeth organization: Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts – sequence: 15 givenname: Richard D surname: Carvajal fullname: Carvajal, Richard D organization: Memorial Sloan Kettering Cancer Center, New York, New York – sequence: 16 givenname: Anna M surname: Varghese fullname: Varghese, Anna M organization: Memorial Sloan Kettering Cancer Center, New York, New York – sequence: 17 givenname: Mario E surname: Lacouture fullname: Lacouture, Mario E organization: Memorial Sloan Kettering Cancer Center, New York, New York – sequence: 18 givenname: Antoni surname: Ribas fullname: Ribas, Antoni organization: University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, California – sequence: 19 givenname: Sapna P surname: Patel fullname: Patel, Sapna P organization: The University of Texas MD Anderson Cancer Center, Houston, Texas – sequence: 20 givenname: Gary A surname: DeCrescenzo fullname: DeCrescenzo, Gary A organization: BioMed Valley Discoveries, Inc., Kansas City, Missouri – sequence: 21 givenname: Caroline M surname: Emery fullname: Emery, Caroline M organization: BioMed Valley Discoveries, Inc., Kansas City, Missouri – sequence: 22 givenname: Anna L surname: Groover fullname: Groover, Anna L organization: BioMed Valley Discoveries, Inc., Kansas City, Missouri – sequence: 23 givenname: Saurabh surname: Saha fullname: Saha, Saurabh organization: BioMed Valley Discoveries, Inc., Kansas City, Missouri – sequence: 24 givenname: Mary surname: Varterasian fullname: Varterasian, Mary organization: BioMed Valley Discoveries, Inc., Kansas City, Missouri – sequence: 25 givenname: Dean J surname: Welsch fullname: Welsch, Dean J organization: BioMed Valley Discoveries, Inc., Kansas City, Missouri – sequence: 26 givenname: David M surname: Hyman fullname: Hyman, David M organization: Memorial Sloan Kettering Cancer Center, New York, New York – sequence: 27 givenname: Bob T surname: Li fullname: Li, Bob T email: rsullivan7@mgh.harvard.edu, lib1@mskcc.org organization: Memorial Sloan Kettering Cancer Center, New York, New York. rsullivan7@mgh.harvard.edu lib1@mskcc.org |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/29247021$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Copyright | 2017 American Association for Cancer Research. |
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| Snippet | Ulixertinib (BVD-523) is an ERK1/2 kinase inhibitor with potent preclinical activity in BRAF- and RAS-mutant cell lines. In this multicenter phase I trial... |
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| SubjectTerms | Adult Aged Aged, 80 and over Aminopyridines - pharmacology Aminopyridines - therapeutic use Female Humans Magnetic Resonance Imaging Male Middle Aged Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors Mitogen-Activated Protein Kinases - genetics Mitogen-Activated Protein Kinases - metabolism Mutation Neoplasm Staging Neoplasms - diagnosis Neoplasms - drug therapy Neoplasms - genetics Neoplasms - metabolism Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - therapeutic use Pyrroles - pharmacology Pyrroles - therapeutic use Tomography, X-Ray Computed Treatment Outcome Young Adult |
| Title | First-in-Class ERK1/2 Inhibitor Ulixertinib (BVD-523) in Patients with MAPK Mutant Advanced Solid Tumors: Results of a Phase I Dose-Escalation and Expansion Study |
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