A Phase I Study of LBH589, a Novel Histone Deacetylase Inhibitor in Patients with Primary Myelofibrosis (PMF) and Post-Polycythemia/Essential Thrombocythemia Myelofibrosis (Post-PV/ET MF).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 308-308 ◽  
Author(s):  
John Mascarenhas ◽  
Xiaoli Wang ◽  
Amelyn Rodriguez ◽  
Mingjiang Xu ◽  
Elaine Gorman ◽  
...  
Keyword(s):  
Platelet Count ◽  
Phase I ◽  
Histone Deacetylase ◽  
Peripheral Blood ◽  
Histone Deacetylase Inhibitor ◽  
Cxcr4 Expression ◽  
Cd34 Cells ◽  
Deacetylase Inhibitor ◽  
Grade 3 ◽  
Jak2v617f Allele Burden

Abstract Abstract 308 Background: Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by progressive constitutional symptoms, cytopenias, splenomegaly and constitutive mobilization of CD34+ cells. The JAK2V617F mutation is present in approximately 50% of MF patients and the mutational burden has been used as a surrogate marker of disease burden and treatment response. LBH589 (Panobinostat), is a novel histone deacetylase inhibitor (HDACi) with potent inhibitory activity against HDAC and HSP90. CXCR4 has previously shown to be down-regulated in PMF CD34+ cells but can be up-regulated by in vitro treatment with sequential chromatin modifying agents (CMA). In addition, the number of JAK2V617F + progenitor cells (PC) can be reduced by treatment of MF CD34+ cells with CMA. (Shi et al, Cancer Research 67: 6417, 2007) Our working hypothesis is that restoration of CXCR4 expression by PMF CD34+ cells would redirect these cells to the bone marrow niche and reduce extramedullary hematopoiesis and promote elimination of MF PC. In order to test this hypothesis, a series of preclinical studies with purified CD34+ cells isolated from peripheral blood of untreated PMF patients were performed. Cells were cultured with SCF, IL-3, FLT3 and TPO ± LBH589 for 2 days and assayed for total number of cells, CD34+ cells, and % CD34+ cells expressing CXCR4. Both total and CD34+ cell numbers were reduced following LBH589 treatment. CXCR4 expression by cultured CD34+ PMF cells was up-regulated in the presence of LBH589. Cells were placed in semi-solid culture and hematopoietic colonies were enumerated, plucked and genotyped for JAK2V617F. CD34+ cells from 2 of 4 PMF patients treated with LBH589 had a decrease in the number of JAK2V617F homozygous colonies. Based on these data, we are presently conducting an ongoing investigator initiated phase I/II study of LBH589 in patients with MF at our institution. Methods: Patients with Lille class I/II PMF, post-ET/PV MF, collectively referred to as MF were eligible if they had an ANC >1000 and platelet count > 60,000. The primary endpoint of the study is to assess the safety and tolerability of LBH589. Secondary endpoints include measurement of clinical response as assessed by IWG-MRT criteria and assessment of change in JAK2V617F burden, histone acetylation, peripheral blood CD34+ cell number and cytogenetics. DLT was defined as an AE that occurred in the first 28 days on study and judged unrelated to disease progression, intercurrent illness or concomitant medications. AEs were graded by CTCAEv3.0 criteria. LBH589 was given to patients in the first cohort at an oral dose of 20mg TIW and the second cohort at 30mg TIW for 28 days and were eligible to receive additional cycles if no DLT was seen. Results: A total of 12 patients (6 in cohort 1 and 6 in cohort 2) have been enrolled and 8 patients (6 in cohort 1 and 2 in cohort 2) are evaluable to date. Thrombocytopenia is the only DLT observed as of yet and was seen in 2 patients. Grade 3 soft tissue hemorrhage requiring platelet and red blood cell transfusion occurred in a single patient in the first cohort who developed worsening thrombocytopenia from a baseline count of 61,000. In the second cohort at a 30mg TIW dose, Grade 3 thrombocytopenia occurred in 1 patient with a baseline normal platelet count after only 3 doses and resolved within 1 week off the drug. Grade 3 anemia is the only other hematologic AE seen in subsequent cycles in 25% of patients (2/8; a patient in both cohorts). The most common non-hematologic AEs noted were grade 1 nausea, fatigue, diarrhea and musculoskeletal pain. Two patients in cohort 1 have had a greater than 50% reduction in spleen size. One of these patients has also had a significant reduction in RBC transfusion requirements and has complete resolution of splenomegaly at 7 months. By IWG consensus criteria for treatment response, 2 patients (1 JAK2V617F + and 1 -) experienced clinical improvement and 4 patients had stable disease. Conclusion: Treatment of MF patients with LBH589 is associated with acceptable hematologic and non-hematologic toxicity and can result in clinical improvement in patients with advanced MF. Based on these observations, LBH589, an oral HDACi, appears to be a promising new agent for the treatment of both JAK2V617F positive and negative MF. Accrual continues in the phase I portion of this study and data on the effects of LBH589 on a variety of biomarkers including JAK2V617F allele burden, will be presented at the meeting. Disclosures: Off Label Use: LBH589, panobinostat, is a novel oral histone deacetylase inhibitor that is being investigated in myelofibrosis to reverse the splenomegaly and improve cytopenias as well to modulate the JAK2V617F allele burden and potentially change the natural history of the disease. .

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.

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.

Histone Deacetylase Inhibitor Valproic Acid Has Differential Effects on Trafficking of Normal Hematopoietic Stem/Progenitor Cells and Leukemic Blasts.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1417-1417
Author(s):  
Hilal Gul ◽  
Leah A. Marquez-Curtis ◽  
Ashraf Kharrat ◽  
Jencet Montano ◽  
A. Robert Turner ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Progenitor Cells ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Chemotherapeutic Agents ◽  
Cxcr4 Expression ◽  
The Other ◽  
Hematopoietic Stem ◽  
Cd34 Cells ◽  
Deacetylase Inhibitor

Abstract Stromal-cell derived factor (SDF)-1α (CXCL12) is a potent chemoattractant for hematopoietic stem/progenitor cells (HSPC) whose chemotactic effect is mediated through the G protein-coupled receptor CXCR4. The expression level of CXCR4 on leukemic blasts is known to be a major prognostic factor in acute myeloid leukemia (AML) because it increases cell retention, survival and growth within the bone marrow (BM) microenvironment, resulting in resistance to conventional chemotherapy. Modulation of CXCR4 expression would be relevant not only in the trafficking of normal HSPC and leukemic cells but also in the response of the latter to chemotherapeutic agents. Previously, we demonstrated that valproic acid (VPA), an effective histone deacetylase inhibitor (HDI) known to induce differentiation in leukemic blasts, increases proliferation, self-renewal and engraftment of normal murine HSPC (Cancer Res.2005:65;2537), and increases the response of AML cells to chemotherapeutic agents (Blood2003:102). Because of this differential effect we hypothesized that VPA enhances homing/engraftment of normal human HSPC by increasing the cell surface expression of CXCR4 but induces the release of AML blasts from BM by decreasing it, making the AML blasts more susceptible to chemotherapy. Thus, we examined the effect of VPA on CXCR4 expression (by FACS analysis and real-time RT-PCR) and on functional response towards an SDF-1α gradient (by chemotaxis assay) of normal HSPC (CD34+ cells from cord blood (CB)) and AML cells (KG-1 and HL-60 cell lines and primary AML cells). Cells were incubated for 24 h and 48 h in IMDM supplemented with 20% FCS in the presence of 1 mM VPA. We found that VPA increases by about 2-fold the percentage of CXCR4-expressing CB CD34+ and KG-1 cells after 24 h incubation, but did not increase the percentage of CXCR4-expressing HL-60 or primary AML cells. Surprisingly, after 48 h incubation we found that VPA decreases (up to 3-fold) the percentage of CXCR4-expressing HL-60 and primary AML cells. These effects were also confirmed at the mRNA level in KG-1 cells (8-fold upregulation) and in HL-60 cells (2.5-fold downregulation). Consistent with these findings, VPA was also found to increase (1.8-fold for normal CD34+ cells and 1.6-fold for KG-1 cells) chemotaxis towards SDF-1α (20 ng/mL), which was inhibited in KG-1 cells by AMD3100, a potent antagonist of CXCR4. On the other hand, chemotaxis was decreased in VPA-treated HL-60 cells (4-fold) and AML primary cells (2.5-fold). Our present data support previous findings that there is a relationship between the differentiation status of cells and their response to HDI such as VPA. We propose that very immature cells (CD34+ cells) respond to VPA by upregulation of CXCR4 (thereby enhancing homing responses towards an SDF-1α gradient); whereas more differentiated cells (AML blasts) downregulate CXCR4 resulting in their egress from the BM. Hence, we suggest that ex vivo priming of HSPC with HDI may improve their marrow engraftment. On the other hand, HDI may mobilize AML cells from the protective stromal microenvironment and render them more susceptible to chemotherapy.

A Phase I Study of Oral Melphalan Combined with LBH589 for Patients with Relapsed or Refractory Multiple Myeloma (MM).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1855-1855 ◽  
Author(s):  
James R. Berenson ◽  
Ori Yellin ◽  
Ralph V. Boccia ◽  
Youram Nassir ◽  
Shellie Rothstein ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Phase I ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitor ◽  
Chemotherapeutic Agents ◽  
Treatment Schedule ◽  
Deacetylase Inhibitor ◽  
Previously Treated ◽  
Grade 3

Abstract Abstract 1855 Poster Board I-881 We and others have shown that LBH589, a potent histone deacetylase inhibitor (HDACi), significantly inhibits the growth of MM cells in vitro and enhances the cytotoxicity triggered by chemotherapeutic agents. Using our SCID-hu models of MM, we have also shown a striking inhibition of MM cell growth in vivo when LBH589 was combined with low doses of melphalan compared to treatment with either drug alone. Thus, these preclinical studies provided the rationale for evaluating the combination of oral melphalan with oral LBH589 for the treatment of MM patients with relapsed or refractory disease. We present the results of an ongoing phase I, open-label, multicenter, dose-escalation study. The initial treatment schedule involved administering patients oral LBH589 every Monday, Wednesday and Friday (MWF) combined with oral melphalan on days 1–5 of a 28-day cycle. Patients were to be treated to maximum response plus 2 additional cycles or complete 8 cycles of therapy without disease progression. To date, 15 patients have been enrolled. At study entry, eleven patients (73%) had International Staging System II or III MM. Fourteen patients were previously treated with melphalan. Three subjects were enrolled into the first cohort (oral LBH589 10 mg; melphalan 0.05 mg/kg) and all experienced significant hematological adverse events. During cycle 1, 2 of 3 subjects had grade 3 thrombocytopenia and all 3 patients developed grade 3 neutropenia. As a result, the melphalan dosing schedule was changed from being administered on days 1-5 to only on days 1, 3 and 5. Three subjects were enrolled into this modified first cohort using the same doses of both drugs. One subject in this cohort experienced both a grade 3 neutropenia and thrombocytopenia. However, there were no DLTs in this cohort and so enrollment into the next cohort (LBH589 at 20 mg and melphalan at 0.05 mg/kg) was initiated. In this cohort, one subject experienced a DLT (grade 4 thrombocytopenia) while the other two developed grade 3 thrombocytopenia. One patient achieved a immunofixation (IF)+ CR but withdrew consent due to intolerable fatigue. As a result, three additional patients were evaluated at this dose level, and two patients have responded including one active patient who is now in PR and another one also achieved a PR but had to be taken off study due to persistent grade 3 neutropenia. Based on the ongoing significant fatigue among patients treated with LBH89 throughout the treatment cycle, the protocol was revised so that the HDACi was administered only during the first two weeks (days 1, 3, 5, 8, 10, and 12) of the 28-day schedule. To date, 3 patients have recently started treatment with this modified schedule of LBH589 at 20 mg and melphalan at 0.05 mg/kg again administered on days 1, 3 and 5 of each 28-day cycle but are not yet evaluable for response. Thus, 12 patients are currently evaluable for response and 4 (33 %) who had previously received melphalan at higher doses have achieved a response including 1 complete response (IF+ CR) and 3 partial responses. Another 4 patients showed stable disease so that disease control was achieved overall in 8 (67%) patients. Overall, the most common ≥ grade 3 adverse events included reversible neutropenia and thrombocytopenia. Specifically, there were 6 cases of grade 3 neutropenia, 6 with grade 3 thrombocytopenia and 1 with grade 4 thrombocytopenia. All of these cytopenias were reversible. Because of the encouraging response rate (33%) that has already been observed in this relapsed and refractory population of heavily pretreated MM patients previously treated with melphalan, an expanded Phase II trial will be conducted using this combination once the MTD has been determined and schedule of dosing has been optimized. Disclosures: Berenson: Novartis Pharmaceuticals Corporation: Consultancy, Research Funding, Speakers Bureau. Off Label Use: LBH589 is a histone deacetylase inhibitor that is used for the treament of multiple myeloma. Rothstein:Novartis Pharmaceuticals Corporation: Employment.

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