title: Inhibiting Histone Deacetylase as a Means to Reverse Resistance to Angiogenesis Inhibitors: Phase I Study of Abexinostat Plus Pazopanib in Advanced Solid Tumor Malignancies.
abstract: Purpose This phase I trial evaluated epigenetic modulation of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor by using a histone deacetylase abexinostat in combination with pazopanib to enhance response and reverse resistance. Patients and Methods Pazopanib was administered once a day on days 1 to 28 and abexinostat was administered orally twice a day on days 1 to 5, 8 to 12, and 15 to 19 (schedule A) or on days 1 to 4, 8 to 11, and 15 to 18 (schedule B). Dose escalation (3 + 3 design) in all solid tumors was followed by dose expansion in renal cell carcinoma (RCC). Results Fifty-one patients with RCC (N = 22) were enrolled, including 30 (59%) with one or more lines of prior VEGF-targeting therapy. Five dose-limiting toxicities, including fatigue (n = 2), thrombocytopenia (n = 2), and elevated AST/ALT (n = 1), were observed with schedule A; one dose-limiting toxicity was observed (elevated AST/ALT) was observed with schedule B. Grade ≥ 3 related adverse events included fatigue (16%), thrombocytopenia (16%), and neutropenia (10%). The recommended phase II dose was established as abexinostat 45 mg/m2twice a day administered per schedule B plus pazopanib 800 mg/d. Objective response rate was 21% overall and 27% in the RCC subset. Median duration of response was 9.1 months (1.2 to > 49 months). Eight patients (16%) had durable control of disease for > 12 months. Durable tumor regressions were observed in seven (70%) of 10 patients with pazopanib-refractory disease, including one patients with RCC with ongoing response > 3.5 years. Peripheral blood histone acetylation and HDAC2 gene expression were associated with durable response to treatment. Conclusion Abexinostat is well tolerated in combination with pazopanib, allowing prolonged exposure and promising durable responses in pazopanib- and other VEGF inhibitor-refractory tumors, which supports epigenetically mediated reversal of treatment resistance.
authors.affiliation: All authors: University of California, San Francisco, San Francisco, CA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Aggarwal
authors.affiliation: All authors: University of California, San Francisco, San Francisco, CA.
authors.forename: Scott
authors.initials: S
authors.lastname: Thomas
authors.affiliation: All authors: University of California, San Francisco, San Francisco, CA.
authors.forename: Nela
authors.initials: N
authors.lastname: Pawlowska
authors.affiliation: All authors: University of California, San Francisco, San Francisco, CA.
authors.forename: Imke
authors.initials: I
authors.lastname: Bartelink
authors.affiliation: All authors: University of California, San Francisco, San Francisco, CA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Grabowsky
authors.affiliation: All authors: University of California, San Francisco, San Francisco, CA.
authors.forename: Thierry
authors.initials: T
authors.lastname: Jahan
authors.affiliation: All authors: University of California, San Francisco, San Francisco, CA.
authors.forename: Amy
authors.initials: A
authors.lastname: Cripps
authors.affiliation: All authors: University of California, San Francisco, San Francisco, CA.
authors.forename: Armand
authors.initials: A
authors.lastname: Harb
authors.affiliation: All authors: University of California, San Francisco, San Francisco, CA.
authors.forename: Jim
authors.initials: J
authors.lastname: Leng
authors.affiliation: All authors: University of California, San Francisco, San Francisco, CA.
authors.forename: Anne
authors.initials: A
authors.lastname: Reinert
authors.affiliation: All authors: University of California, San Francisco, San Francisco, CA.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Mastroserio
authors.affiliation: All authors: University of California, San Francisco, San Francisco, CA.
authors.forename: Thach-Giao
authors.initials: TG
authors.lastname: Truong
authors.affiliation: All authors: University of California, San Francisco, San Francisco, CA.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Ryan
authors.affiliation: All authors: University of California, San Francisco, San Francisco, CA.
authors.forename: Pamela N
authors.initials: PN
authors.lastname: Munster
mesh_terms: D000107:Acetylation; D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects*; D001219:Aspartate Aminotransferases / Q000097:blood; D001572:Benzofurans / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics; D018450:Disease Progression; D018572:Disease-Free Survival; D004351:Drug Resistance; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D044127:Epigenesis, Genetic; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D015870:Gene Expression; D056464:Histone Deacetylase 2 / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D007191:Indazoles; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D011743:Pyrimidines / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000235:genetics; D055815:Young Adult
chemical_list: D020533:Angiogenesis Inhibitors; D001572:Benzofurans; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; C516667:pazopanib; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D056464:Histone Deacetylase 2; C512352:abexinostat