A phase I trial of the histone deacetylase inhibitor panobinostat (LBH589) and epirubicin in patients with solid tumor malignancies.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3058-3058
Author(s):  
Amy Patricia Moore ◽  
Thach-Giao Truong ◽  
Kenneth Ted Thurn ◽  
Scott Thomas ◽  
Charles J. Ryan ◽  
...  
Keyword(s):  
Phase I ◽  
Histone Acetylation ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Phase I Trial ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Deacetylase Inhibitor ◽  
Grade 3

3058 Background: Preclinical and clinical data suggest pre-exposure of cancer cells to a histone deacetylase inhibitor (HDACi) potentiates topoisomerase inhibitors. HDACi-induced histone acetylation and chromatin modulation facilitates DNA access and target recruitment for topo II inhibitors. In vitro data further suggest effective inhibition of HDAC2 is necessary for enhanced epirubicin-induced apoptosis. Methods: This phase I trial explores the safety, tolerability, and maximum tolerated dose (MTD) of escalating doses of panobinostat given orally on days 1, 3, and 5 followed by epirubicin administered intravenously at 75 mg/m2 on day 5 in 21-day cycles. Histone acetylation and HDAC2 expression are evaluated in pre- and post-treatment peripheral blood mononuclear cells (PBMCs) in all patients and in tumor cells of 16 patients treated at the MTD. Results: 36 patients have enrolled [10M/26F, median age 47 years (22-80)] in 5 panobinostat cohorts: 20, 30, 40, 50, 60 mg. Tumor types include melanoma (n=6), breast (n=6), sarcoma (n=16), ovarian (n=2), lung (n=2), and one each of neuroblastoma, pancreatic, testicular, and colon cancer. Prior to enrollment, patients received a median of 3 (0-8) prior chemotherapy regimens and 40% had anthracyclines. Dose-limiting toxicities (DLTs) included 1/3 grade 3 fatigue and 1/3 grade 4 thrombocytopenia at 60 mg of panobinostat, 1/6 patient experienced grade 3 atrial fibrillation at 50 mg, defining 50 mg panobinostat as the MTD. Non-dose–limiting grade 3/4 hematological toxicities include neutropenia (n=19, 53%), febrile neutropenia (n=6, 17%), thrombocytopenia (n=6, 17%), and anemia (n=4, 11%). Of 34 evaluable patients, 5 had partial responses and 14 had stable disease in anthracycline-refractory sarcomas (4) and Her2neu positive breast cancer (2), and small cell lung cancer. Correlative studies demonstrate increased H4 acetylation in PBMCs on day 3 and 5 suggesting sufficient histone deacetylase inhibition. Conclusions: Sequence-specific combination of panobinostat and epirubicin shows early activity without potentiating epirubicin toxicity. Dose expansion in anthracycline-pretreated sarcoma patients is ongoing.

Phase I trial of a sequence-specific combination of the HDAC inhibitor, vorinostat (SAHA) followed by doxorubicin in advanced solid tumor malignancies

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3502-3502 ◽  
Author(s):  
A. Daud ◽  
M. Schmitt ◽  
D. Marchion ◽  
E. Bicaku ◽  
S. Minton ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patient ◽  
Phase I ◽  
Histone Acetylation ◽  
Phase I Trial ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells ◽  
Grade 3 ◽  
Topo Ii

3502 Background: Preclinical cell culture and xenograft studies suggest that pre-exposure of cancer cells to a histone deacetylase inhibitor (HDACi) may potentiate topoisomerase (topo) inhibitors. The HDACi-induced histone acetylation and chromatin modulation facilitates DNA access and target recruitment for topo II inhibitors. Methods: This Phase I trial explores the safety, tolerability and maximum tolerated dose (MTD) of a weekly schedule of escalating vorinostat doses (twice daily days 1–3) followed by doxorubicin (20 mg/m2) on day 3 (3 out of 4 weeks). Histone acetylation and topo II expression are evaluated in pre-and post-vorinostat peripheral blood mononuclear cells and in tumor cells of the 30 patients treated at the MTD. Results: To date, 15 patients [median age 54 (38–73)] have been treated in 4 vorinostat cohorts: 200, 300, 400, 500 mg bid. Tumor types included: breast (3), melanoma (3), pancreatic (2) and one each of SCLC, sarcoma, endometrial, colon, prostate, renal cell and bladder cancer. Dose-limiting toxicities included a grade 3 thrombocytopenia (1/6) at the 400 mg bid dose. Non-dose limiting Grade 3 and 4 toxicities include neutropenia, thrombocytopenia, fatigue, pulmonary embolus, and anemia (1 pt each). Currently, vorinostat doses of 500 mg bid are being evaluated. One confirmed partial response in a breast cancer patient, as well as minor responses in a melanoma and a prostate cancer patient were seen in 10 evaluable patients. Patients received a median number of 2 (1–9+) treatment cycles. Doxorubicin is stopped after 6 cycles and patients continue on vorinostat alone. H3 and H4 histone acetylation and topo II expression will be correlated with vorinostat dose, plasma concentration and response. Conclusion: A sequence-specific combination of vorinostat and doxorubicin is active without exacerbation of doxorubicin toxicity. The tolerated vorinostat dose exceeds the proposed single agent dose for vorinostat derived from patients with hematological malignancies. Histone hyperacetylation occurs in peripheral blood mononuclear cells at all levels. The anti-tumor activity in breast cancer and melanoma will be further explored. No significant financial relationships to disclose.

Histone deacetylase inhibitor FR901228 enhances adenovirus infection of hematopoietic cells

Blood ◽  
2002 ◽  
Vol 99 (6) ◽  
pp. 2248-2251 ◽  
Author(s):  
Masaki Kitazono ◽  
Vemulkonda Koneti Rao ◽  
Rob Robey ◽  
Takashi Aikou ◽  
Susan Bates ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Peripheral Blood ◽  
Histone Deacetylase Inhibitor ◽  
Mononuclear Cells ◽  
Histone H3 ◽  
Hematopoietic Cells ◽  
Adenovirus Infection ◽  
Peripheral Blood Stem Cells ◽  
Peripheral Blood Mononuclear ◽  
Deacetylase Inhibitor

Abstract Adenovirus infection of hematopoietic cells frequently requires high virus concentrations and long incubation times to obtain moderate infection levels because these cells have low levels of Coxsackie and adenovirus receptor (CAR) and αv integrin. The effect of treatment with FR901228 (depsipeptide), a histone deacetylase inhibitor in phase 2 clinical trials, was studied in K562 cells, granulocyte–colony-stimulating factor–mobilized peripheral blood mononuclear cells (PBMCs), and CD34+ peripheral blood stem cells (PBSCs). FR901228 increased CAR and αvintegrin RNA levels and histone H3 acetylation. FR901228 treatment before adenovirus infection was associated with at least a 10-fold increase in transgene expression from a β-galactosidase–expressing adenoviral vector. More than 80% of the PBMCs or CD34+ PBSCs from 7 different donors were β-galactosidase–positive after adenovirus infection with a multiplicity of infection of 10 for 60 minutes. Increased CAR, αv integrin, and acetylated histone H3 levels were observed in PBMCs from a patient treated with FR901228. These studies suggest that FR901228 can increase the efficiency of adenoviral infection in hematopoietic cells.

Phase I trial of the oral histone deacetylase inhibitor MS-275 administered with food

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13036-13036 ◽  
Author(s):  
E. A. Donovan ◽  
A. Sparreboom ◽  
W. Figg ◽  
J. Trepel ◽  
K. Maynard ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Mononuclear Cells ◽  
Interindividual Variability ◽  
Protein Acetylation ◽  
Hdac Inhibition ◽  
Peripheral Blood Mononuclear ◽  
Advanced Malignancy ◽  
Grade 3

13036 Background: The histone deacetylase (HDAC) inhibitor MS-275, a synthetic benzamide derivative, has demonstrated antitumor activity in vitro & in vivo. After determining maximum tolerable dose (MTD = 2 mg/m2) & dose limiting toxicity (DLT) for MS-275 given to fasting patients (pts) weekly ×4 q6 weeks, we explored toxicity profile, MTD, & pharmacokinetics (PK) of MS-275 when given po on the same schedule with food. Methods: MS-275 at 2, 4, or 6 mg/m2 was administered to pts with advanced malignancy & PS ≤2, LFTs ≤2.5 × normal, adequate hematopoietic & renal function, & normal resting MUGA. PK samples were analyzed by LC-MS. Data for pts in the fed state were compared to data obtained in previous cohorts of pts treated in the fasting state. Protein acetylation assessed by a novel flow cytometric assay & HDAC enzymatic activity were measured in peripheral blood mononuclear cells (PBMC). Results: 16 pts received a median of 2 cycles (1–5) of MS-275 2–6 mg/m2 with food. No DLT occurred on 2 or 6 mg/m2 (n = 3 each), while 1 pt on 4 mg/m2 (n = 10) had a DLT: grade 3 hypophosphatemia. For 2–6 mg/m2 other grade 3 toxicities were neutropenia & lymphopenia. Grade 1–2 toxicities in >1 pt were leucopenia, anemia, thrombocytopenia, fatigue, nausea, vomiting, headache, hypoalbuminemia, hypophosphatemia, hyponatremia, & hypocalcemia. MTD has not been reached; current dose level is 8 mg/m2. Comparing PK for fasting & fed pts on 2–4 mg/m2, there was no difference in Tmax (0.5h); average Cmax & AUC were 35% & 25% lower, respectively, in fed pts; this difference is not statistically significant. Interindividual variability in exposure to MS-275 increased from 52% in fasting pts to 100% in fed pts. PBMC protein acetylation & HDAC inhibition were seen at all dose levels (2–6 mg/m2) in fed pts. Of 9 pts evaluable for response (2–4 mg/m2), 2 of 6 pts on 4 mg/m2 had stable disease. Conclusions: MTD has not yet been established for MS-275 given with food on this schedule but is ≥4 mg/m2 weekly x4 q6 weeks. Interindividual variability in exposure increases with food. Whether intestinal absorption is decreased when MS-275 is given with food requires further evaluation with additional patients. Drug-related protein hyperacetylation & HDAC inhibition were observed. [Table: see text]

Combination of 5-azacytidine (5-AZA) and valproic acid (VPA) in advanced solid cancers: A phase I study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3547-3547 ◽  
Author(s):  
A. O. Soriano ◽  
F. Braiteh ◽  
G. Garcia-Manero ◽  
L. H. Camacho ◽  
D. Hong ◽  
...  
Keyword(s):  
Phase I ◽  
Histone Acetylation ◽  
Phase I Study ◽  
Mononuclear Cells ◽  
Neutropenic Fever ◽  
Dna Hypomethylation ◽  
Peripheral Blood Mononuclear ◽  
Western Blots

3547 Background: 5-AZA is a DNA hypomethylating agent. VPA is a histone deacetylase inhibitor (HDACI). The combination of hypomethylating agents and HDACI has synergistic anticancer activity in vitro and in vivo. Based on this, we conducted a phase I study of the combination of 5-AZA and VPA in patients with advanced solid cancers. Methods: 5-AZA was administered SQ daily for 10 days. VPA was given orally daily titrated to 75–100 mcg/ml. Cycles were 28 days long. 5-AZA was started at 20 mg/m2 and escalated using an adaptive algorithm based on toxicity in the prior cohort. Each cohort included 6 patients (pts). Global DNA methylation was estimated with the LINE pyrosequencing assay in peripheral blood mononuclear cells on days 1 and 10 of each cycle. Histone H3 and H4 acetylation was assessed with western blots. Results: Forty seven patients were evaluable. Median age was 60 years (15–77). 5- AZA dose levels included 20, 25, 37.5, 47, 59, 75 and 94 mg/m2. One DLT occurred at 37.5 (Neutropenic fever (NF)). At 75 mg/m2, 1 grade 3 NF and at 94 mg/m2, 3 DLTs (2 NF and 1 thrombocytopenia) were observed. The MTD was 75 mg/m2 SQ daily for 10 days. Other toxicities included drowsiness (N=6), tremor (N=6), hypomagnesemia (N=1), anemia (N=2) and vomiting (N=1). Stable disease (SD) was observed in 16 pts (34%). One pt with rapidly progressive renal cell carcinoma had SD for 6 months (mos). Two pts with leiomyosarcoma of the uterus had SD for 8 and 6 mos. One pt with melanoma and two pts with uveal melanoma had SD for 4 mos. One pt with sinus adenoid cystic carcinoma and 1 with thymic carcinoma had SD for 4 mos. SD was also observed in pts with colon (N=3), sarcoma (N=2), papillary thyroid (N=2) and breast cancer (N=1). Global DNA hypomethylation was demonstrated in all of the doses of 5- AZA. Median LINE methylation pretreatment was 65% (59–70%), it declined to 61% (53–63%) by day 10 (p=0.001) and returned to baseline by day 0 of the next cycle. Histone acetylation was observed in 53% of the pts. Conclusions: The combination of 5-AZA and VPA in patients with advanced solid tumors is safe. The MTD of 5-AZA in combination with VPA was 75 mg/m2 SQ daily for 10 days. DLTs were neutropenic fever and thrombocytopenia. Clinical benefit (SD) was observed in 16 pts (34%). Transient global hypomethylation and histone acetylation were demonstrated. No significant financial relationships to disclose.

scholarly journals Potential efficacy of the oral histone deacetylase inhibitor vorinostat in a phase I trial in follicular and mantle cell lymphoma

2010 ◽  
Vol 101 (1) ◽  
pp. 196-200 ◽  
Author(s):  
Takashi Watanabe ◽  
Harumi Kato ◽  
Yukio Kobayashi ◽  
Satoshi Yamasaki ◽  
Yuriko Morita-Hoshi ◽  
...  
Keyword(s):  
Phase I ◽  
Mantle Cell Lymphoma ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Phase I Trial ◽  
Cell Lymphoma ◽  
Potential Efficacy ◽  
Deacetylase Inhibitor ◽  
Mantle Cell

Final Results of a Phase I Study of the Histone Deacetylase Inhibitor Vorinostat (Suberoyanilide Hydroxamic Acid, SAHA), in Patients with Leukemia and Myelodysplastic Syndrome.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2801-2801 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Hui Yang ◽  
Blanca Sanchez-Gonzalez ◽  
Srdan Verstovsek ◽  
Alessandra Ferrajoli ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Phase I ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Phase I Study ◽  
Hydroxamic Acid ◽  
Significant Activity ◽  
Deacetylase Inhibitor ◽  
Objective Evidence ◽  
Grade 3

Abstract Vorinostat, formerly known as suberoyl anilide hydroxamic acid, (SAHA) is a histone deacetylase inhibitor with potent in vitro antileukemia activity. We conducted a phase I study of two dose schedules of vorinostat: oral three times a day (TID) x 14 days every 21 days; or oral twice a day (BID) x 14 days every 21 days. Patients with relapsed or refractory chronic and acute leukemia or myelodysplastic syndrome (MDS), with adequate renal, hepatic functions and performance status were eligible. Older patients with untreated AML/MDS were also eligible. Forty-one patients were registered and dosed. Median age was 54 years (range 18 to 90), 31 (76%) had AML, 4 (10%) CLL, 3 (7%) MDS, 2 (5%) ALL and 1 (2%) CML. The median number of prior therapies was 2 (range 0–7). The starting dose of the oral TID schedule was 100 mg po TID and it was increased in 50 mg po steps using a 3+3 design. As these patients were thrombocytopenic at baseline due to their underlying disease, thrombocytopenia was not considered to be a dose-limiting toxicity. A dose of 300 mg po TID was considered above the maximally tolerated dose (MTD) with 2 out of 3 patients developing grade 3 toxicity (nausea, vomiting and diarrhea). Subsequently, 7 patients were treated at a dose of 300 mg po BID x 14 days every 21 days. Two patients developed gastrointestinal toxicity (typhlitis) in the setting of profound neutropenia, and the dose was reduced in the next 6 patients to 200 mg po BID x 14 days. No excess toxicity was observed at that dose level. Subsequently, 6 more patients were treated at a dose of 200 mg po TID x 14 days (The MTD of 250 mg po TID X 14 days could not be further evaluated as the 50 mg capsule was no longer available). Only one out 6 patients developed grade 3 toxicity (fatigue). More frequently observed toxicities, regardless of causality, were nausea, vomiting, diarrhea, anorexia, headache, fatigue, typhlitis, and dyspepsia that resolved upon cessation of therapy. Laboratory abnormalities included pancytopenia, hyperglycemia, hypokalemia, hypocalcemia and hypophosphatemia. Overall 9 patients (21%) had objective evidence of response: 1 CR, 2 CRp (CR criteria but no recovery of platelet counts), 1 partial response and 5 complete marrow responses (blasts less than 5%). All responses were observed in patients with AML, and 5 (41%) of these responses were observed at a dose of 200 mg po tid. Histone acetylation was observed in all patients at all dose levels. In summary, the MTD of oral vorinostat is either 200 mg po TID or 200 mg po BID x 14 days every 21 days in patients with leukemia. Significant activity was observed at a dose of 200 mg po TID x 14 days in patients with AML. This single agent activity warrants additional investigation of the role of vorinostat in the therapy of AML and may be guided by the development of informative biomarkers.

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