Yale School of Medicine, New Haven, CT
Edward Samuel James , Gina G. Chung , Michael DiGiovanna , Tara Beth Sanft , Erin Wysong Hofstatter , Noelle Sowers , Mary Beth Clark , Rebecca Lilian , Susan Chmael , Michelle Cappiello , Gineesha Abraham , Gary M Israel , Lajos Pusztai , Lyndsay Harris , Maysa M. Abu-Khalaf
Background: Synergy between histone deacetylase inhibitors and 5-fluorouracil is thought to be due to down regulation of thymidylate synthase. Study objectives are to assess maximum tolerated dose (MTD), dose limiting toxicities (DLT) and objective response rate of vorinostat (V) in combination with capecitabine (C). Secondary aims are pharmacodynamics of V. Methods: Cohorts of 3-6 patients (pts) were enrolled on a 3+3 dose-escalation phase to assess MTD of escalating doses of oral C (1500/1800/2000mg) with V 200 mg BID on days 1-7 and 15-21 of a 28 d cycle. 10 pts enrolled on dose expansion phase and treated at MTD. Pts received a “run in” treatment of V for 5 d and pre/post V biopsy (bx) collected when feasible. DLT was defined as ≥ grade 3 non hematological toxicity, grade 4 thrombocytopenia, grade 4 neutropenia > 5 d, grade 4 febrile neutropenia requiring hospitalization, QTc >500ms,or treatment delay > 2 weeks from toxicity. Microarray analysis was performed using Illumina HT-12 gene arrays on pre/post bx from 4 pts. Results: 23 ptswith median age 51 (range 33-69) were treated: 8 pts at 1500/200mg, 5 pts at 1800/200mg, and 10 pts treated on dose expansion phase at 1500/200mg. Median # of prior lines of chemotherapy was 2 (range 0-7). 3 pts are still on study. Median # of cycles on study were 2 (range 1-42). Cycle 1 DLT was grade 3 fatigue in 2 pts treated on 1800/200mg, and in 1 pt treated on 1500/200mg. Other grade 3/4 toxicities are summarized in the Table. 14 pts are evaluable for response (12 pts at 1500/200mg and 2 pts at 1800/200mg). No objective responses were seen, 3 pts had stable disease > 6 months (1 pt completed 42 cycles). Changes in pathways involved in extracellular matrix and TGFb pathway were noted. Conclusions: DLT of C concomitant with V was fatigue. MTD was 1500 mg C combined with 200 mg V BID. Combination has modest clinical activity. Consistent modulation of pathways involved in extracellular matrix and TGFb pathway, suggesting biomarkers of response to V. Clinical trial information: NCT00719875.
Adverse events | Grade 3 # pts | Grade 4 # pts |
---|---|---|
Thrombocytopenia | 2 | 1 |
Leukopenia | 3 | 0 |
Anemia | 3 | 1 |
Mucositis | 1 | 0 |
Hand-foot syndrome | 2 | 0 |
Nausea/vomiting | 2 | 0 |
Hypokalemia | 1 | 1 |
Hyponatremia | 1 | 0 |
Hypoalbuminemia | 1 | 0 |
Syncope | 1 | 0 |
Ataxia | 1 | 0 |
Dyspnea | 0 | 1 |
Bone pain | 1 | 0 |
Infection | 1 | 0 |
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Abstract Disclosures
2013 Breast Cancer Symposium
First Author: Edward Samuel James
2024 ASCO Annual Meeting
First Author: Feifei Sun
2024 ASCO Annual Meeting
First Author: yuqin xi
2011 ASCO Annual Meeting
First Author: M. M. Abu-Khalaf