TY - JOUR
T1 - Preclinical development and first-in-human study of KA2507, a selective and potent inhibitor of histone deacetylase 6, for patients with refractory solid tumors
AU - Tsimberidou, Apostolia M.
AU - Beer, Philip A.
AU - Cartwright, Carrie A.
AU - Haymaker, Cara
AU - Vo, Henry H.
AU - Kiany, Simin
AU - Cecil, Alexander R.L.
AU - Dow, James
AU - Haque, Kemal
AU - Silva, Franck A.
AU - Coe, Lucy
AU - Berryman, Helen
AU - Bone, Elisabeth A.
AU - Nogueras-Gonzalez, Graciela M.
AU - Vining, David
AU - McElwaine-Johnn, Hilary
AU - Wistuba, Ignacio I.
N1 - Funding Information:
A.M. Tsimberidou reports grants from Immatics, Parker Institute for Cancer Immunotherapy, OBI Pharma, Bayer, Boston Biomedical, Placon Therapeutics, Karus Therapeutics, Tvardi Therapeutics, Agenus, and Tempus, as well as other support from Covance, Genentech, and Tempus during the conduct of the study. P.A. Beer reports other support from Karus Therapeutics during the conduct of the study. C. Haymaker reports other support from Briacell Therapeutics and Mesothelioma Applied Research Foundation outside the submitted work. A.R.L. Cecil reports other support from Karus Therapeutics outside the submitted work; in
Funding Information:
Preclinical and clinical studies were funded by Karus Therapeutics Ltd. Translational studies were supported by the NIH/NCI award number P30 CA016672 (The University of Texas MD Anderson Cancer Center) and the Translational Molecular Pathology-Immunoprofiling Laboratory (TMP-IL) at the Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center. This work was also in part supported by donor funds from Jamie’s Hope, Mr. and Mrs. Zane W. Arrott, and Mr. and Mrs. Steven McKenzie for Dr. Tsimberidou’s Personalized Medicine Program.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/7/1
Y1 - 2021/7/1
N2 - Purpose: Inhibition of histone deacetylase 6 (HDAC6) is predicted to deliver both direct antitumor activity and modulation of the antitumor immune response. This study describes the development of a novel HDAC6 inhibitor. Patients and Methods: KA2507 was characterized in HDAC biochemical and cellular target engagement assays and in preclinical efficacy models of melanoma and colorectal cancer. In a phase I study, KA2507 was administered orally using a 3+3 dose-escalation design (NCT03008018). Results: KA2507 is a potent and selective inhibitor of HDAC6 (biochemical IC50 = 2.5 nmol/L). Preclinical models demonstrated antitumor efficacy in syngeneic tumor-bearing mice, with translational studies highlighting modulation of the antitumor immune response. Twenty patients were treated in a phase I study. KA2507 was well tolerated; dose-limiting toxicity was not observed up to the maximum dose administered. Pharmacokinetic profiling supported twice-daily oral dosing. Pharmacodynamic analysis demonstrated selective HDAC6 target engagement in peripheral blood cells, free from off-target class I HDAC activity. Stable disease was the best clinical response (7 patients). Three of these patients (adenoid cystic carcinoma, n = 2; rectal adenocarcinoma, n = 1) had prolonged disease stabilization that lasted for 16.4, 12.6, and 9.0 months, respectively. Conclusions: KA2507 is a potent and selective inhibitor of HDAC6 showing antitumor efficacy and immune modulatory effects in preclinical models. In a phase I study, KA2507 showed selective target engagement, no significant toxicities, and prolonged disease stabilization in a subset of patients. Further clinical studies of KA2507 are warranted, as a single agent or, preferably, combined with other immuno-oncology drugs.
AB - Purpose: Inhibition of histone deacetylase 6 (HDAC6) is predicted to deliver both direct antitumor activity and modulation of the antitumor immune response. This study describes the development of a novel HDAC6 inhibitor. Patients and Methods: KA2507 was characterized in HDAC biochemical and cellular target engagement assays and in preclinical efficacy models of melanoma and colorectal cancer. In a phase I study, KA2507 was administered orally using a 3+3 dose-escalation design (NCT03008018). Results: KA2507 is a potent and selective inhibitor of HDAC6 (biochemical IC50 = 2.5 nmol/L). Preclinical models demonstrated antitumor efficacy in syngeneic tumor-bearing mice, with translational studies highlighting modulation of the antitumor immune response. Twenty patients were treated in a phase I study. KA2507 was well tolerated; dose-limiting toxicity was not observed up to the maximum dose administered. Pharmacokinetic profiling supported twice-daily oral dosing. Pharmacodynamic analysis demonstrated selective HDAC6 target engagement in peripheral blood cells, free from off-target class I HDAC activity. Stable disease was the best clinical response (7 patients). Three of these patients (adenoid cystic carcinoma, n = 2; rectal adenocarcinoma, n = 1) had prolonged disease stabilization that lasted for 16.4, 12.6, and 9.0 months, respectively. Conclusions: KA2507 is a potent and selective inhibitor of HDAC6 showing antitumor efficacy and immune modulatory effects in preclinical models. In a phase I study, KA2507 showed selective target engagement, no significant toxicities, and prolonged disease stabilization in a subset of patients. Further clinical studies of KA2507 are warranted, as a single agent or, preferably, combined with other immuno-oncology drugs.
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U2 - 10.1158/1078-0432.CCR-21-0238
DO - 10.1158/1078-0432.CCR-21-0238
M3 - Article
C2 - 33947698
AN - SCOPUS:85109174376
SN - 1078-0432
VL - 27
SP - 3584
EP - 3594
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 13
ER -