Panobinostat Dose Research Articles

Pre-Clinical Study of Panobinostat in Xenograft and Genetically Engineered Murine Diffuse Intrinsic Pontine Glioma Models.

BackgroundDiffuse intrinsic pontine glioma (DIPG), or high-grade brainstem glioma (BSG), is one of the major causes of brain tumor-related deaths in children. Its prognosis has remained poor despite numerous efforts to improve survival. Panobinostat, a histone deacetylase inhibitor, is a targeted agent that has recently shown pre-clinical efficacy and entered a phase I clinical trial for the treatment of children with recurrent or progressive DIPG.MethodsA collaborative pre-clinical study was conducted using both a genetic BSG mouse model driven by PDGF-B signaling, p53 loss, and ectopic H3.3-K27M or H3.3-WT expression and an H3.3-K27M orthotopic DIPG xenograft model to confirm and extend previously published findings regarding the efficacy of panobinostat in vitro and in vivo.ResultsIn vitro, panobinostat potently inhibited cell proliferation, viability, and clonogenicity and induced apoptosis of human and murine DIPG cells. In vivo analyses of tissue after short-term systemic administration of panobinostat to genetically engineered tumor-bearing mice indicated that the drug reached brainstem tumor tissue to a greater extent than normal brain tissue, reduced proliferation of tumor cells and increased levels of H3 acetylation, demonstrating target inhibition. Extended consecutive daily treatment of both genetic and orthotopic xenograft models with 10 or 20 mg/kg panobinostat consistently led to significant toxicity. Reduced, well-tolerated doses of panobinostat, however, did not prolong overall survival compared to vehicle-treated mice.ConclusionOur collaborative pre-clinical study confirms that panobinostat is an effective targeted agent against DIPG human and murine tumor cells in vitro and in short-term in vivo efficacy studies in mice but does not significantly impact survival of mice bearing H3.3-K27M-mutant tumors. We suggest this may be due to toxicity associated with systemic administration of panobinostat that necessitated dose de-escalation.

Synergistic Anti-Tumor Effect of KPT-8602, a Second Generation Selective Inhibitor of Nuclear Export (SINE) Compound, and Panobinostat, a Pan-Histone Deacetylase (HDAC) Inhibitor in Multiple Myeloma

Background: XPO1 (Exportin-1/CRM1) is the non-redundant nuclear exporter of over 200 cargos including the major tumor suppressor proteins. Deregulated nuclear export by changes in XPO1 expression is a common characteristic for a broad range of cancers and may aid in the evasion of anti-neoplastic mechanisms. As a result, inhibition of XPO1 has emerged as a promising area of cancer treatment. The Selective Inhibitor of Nuclear Export (SINE) compounds, selinexor, as well as a second generation, KPT-8602, bind to the XPO1 cargo binding pocket and disrupt XPO1-mediated nuclear export, resulting in cancer specific cell death. Although selinexor has been evaluated in >1,500 patients and has manageable tolerability, KPT-8602 may have improved tolerability and efficacy based on decreased brain penetration in animal models allowing more frequent dosing. Currently, the safety, tolerability and efficacy of KPT-8602 is being evaluated in a phase 1 trial of patients with relapsed/refractory multiple myeloma (MM; NCT02649790). Since selinexor synergizes with a broad array of anti-MM agents in patients, KPT-8602 is an excellent candidate for combination therapies. In this study, we investigated the use and mechanism of combining KPT-8602 with the pan-histone deacetylase (HDAC) inhibitor, panobinostat, in MM cell lines and in a xenograft mouse model of MM.Methods: MM.1S cells were treated with single agent KPT-8602, panobinostat or a combination of both. The effects of KPT-8602 and/or panobinostat on cell viability were examined using standard viability assays after 72 hours of treatment. Total RNA or protein levels were examined after 24 hours using quantitative PCR or immunoblots, respectively. Immune compromised mice were injected subcutaneously with MM.1S cells. Tumors were allowed to grow to ~150 mm3before treatment. The mice were treated with vehicle, sub-therapeutic doses of KPT-8602 (5 mg/kg PO QDx5) or panobinostat (5 mg/kg IP QDx5) alone or in combination. Tumor growth and animal weights was monitored to determine tumor growth inhibition (TGI), tumor regression, and tolerability to treatment. The tumors were then harvested for immunohistochemical (IHC) analysis.Results: The combination of KPT-8602 and panobinostat was highly effective against MM.1S cell viability. A synergistic anti-cancer effect was observed against MM.1S cells grown in culture and in mice. In cells, the MTT IC50of KPT-8602 was shifted from 50 to 23 nM by the addition of sub cytotoxic concentrations of panobinostat. In mice, single agent treatment with KPT-8602 led to 96.5% tumor growth inhibition whereas panobinostat resulted in 69.4% tumor growth inhibition within 22 days. Remarkably, in the combination of KPT-8602 and panobinostat, 3 out of 8 tumors totally disappeared and the overall tumor regression was 95%, (Figure 1). Both drugs, as single agents and in combination were well tolerated and no significant changes in weight were observed. Gene and protein expression studies revealed that although both compounds target independent proteins (e.g. HDACs or XPO1), the combination significantly enhances markers of cell death (cleavage of PARP-1, caspase-3, etc.). Curiously, KPT-8602 enhances the inhibitory effect panobinostat has on deacetylation as evidenced by histone acetylation. Moreover, DNA damage, as indicated by ϒ-H2AX, significantly increases in the presence of both compounds.Conclusion: KPT-8602 and panobinostat are dissimilar drugs with unique mechanisms of action, and individually affect a broad range of cellular processes. Here we show that the combination of these drugs can dramatically increase the already potent anti-cancer properties of these compounds in MM cell lines. In addition, KPT-8602 enhances the inhibitory effect exerted by panobinostat on histone deacetylation, which coincides with an increase induction of DNA damage. It should be noted that both panobinostat and SINE compounds have been shown to downregulate checkpoint and DNA damage response (DDR) proteins (e.g. RAD51 and Chk1). We hypothesize that the combination of KPT-8602 and panobinostat promotes significant chromatin remodeling in the presence of a compromised DDR pathway, which destabilizes genomic integrity in MM cells and leads to a synergistic effect on cell viability. Together, these data provide rational support for the study of KPT-8602 and panobinostat in clinical trials. [Display omitted] DisclosuresArgueta:Karyopharm Therapeutics: Employment, Equity Ownership. Chang:Karyopharm Therapeutics: Employment, Equity Ownership. Kashyap:Karyopharm Therapeutics: Employment, Equity Ownership. Elloul:Rubius Therapeutics: Employment. Friedlander:Karyopharm Therapeutics: Employment. Lee:Karyopharm Therapeutics: Employment, Equity Ownership. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Senapedis:Karyopharm Therapeutics: Employment, Equity Ownership. Baloglu:Karyopharm Therapeutics: Employment, Equity Ownership.

Improved Safety with the Use of Subcutaneous Bortezomib in Combination with Panobinostat and Dexamethasone: Preliminary Data from a Panobinostat Global Expanded Treatment Protocol

Introduction:Panobinostat (PAN) is a potent pan-deacetylase inhibitor that targets multiple myeloma (MM) cells via its epigenetic effects as well as its effect on the aggresome. In the PANORAMA 1 phase 3 trial, the combination of PAN, bortezomib (BTZ), and dexamethasone (Dex; PAN+BTZ+Dex) significantly increased progression-free survival compared with placebo plus BTZ and Dex, leading to approval in Europe of the combination for the treatment of patients with MM who have received ≥ 2 prior regimens, including BTZ and an immunomodulatory agent. The purpose of this expanded treatment protocol (ETP) is to further evaluate safety and to provide panobinostat prior to commercial availability to patients with relapsed/refractory MM who have received ≥ 2 prior lines of therapy but for whom satisfactory treatment alternatives are not available.Methods:Panobinostat-ETP is a multicenter, open-label, ETP study of PAN+BTZ+Dex in adult patients with MM relapsed and/or refractory to ≥ 2 prior lines of therapy. During treatment phase (TP) 1 of the study, patients received oral PAN 20 mg (days 1, 3, 5, 8, 10, and 12) plus intravenous or subcutaneous BTZ 1.3 mg/m2 (days 1, 4, 8, and 11) for eight 21-day cycles. Patients with ≥ stable disease proceeded to TP2, with maintained PAN and less frequent BTZ dosing (days 1 and 8) for an additional 8 cycles. In both phases, oral Dex 20 mg was administered on the days of and after BTZ treatment. Reduction to once-weekly BTZ was allowed prior to TP2 as a dose reduction strategy.Results:A total of 49 patients with a median age of 67 years (range, 45-85 years) were enrolled in the study. Patients were heavily pretreated; 73.5% received ≥ 3 prior lines of therapy. Most patients (n = 43 [87.8%]) received subcutaneous BTZ, while 3 (6.1%) received intravenous BTZ, and another 3 (6.1%) received both. The median duration of treatment with PAN+BTZ+Dex was 67 days (range, 12-305 days). The most common grade 3/4 hematologic laboratory abnormalities were thrombocytopenia (51.0%), anemia (12.2%), and neutropenia (10.2%). The most common nonhematologic grade 3/4 treatment-emergent adverse events (AEs) were diarrhea (14.3%), fatigue (8.2%), infection (6.1%), and nausea (6.1%). Common gastrointestinal treatment-emergent AEs of any grade included diarrhea (51.0%), constipation (16.3%), and nausea (16.3%). Interestingly, in the patients receiving subcutaneous BTZ, the rates of grade 3/4 diarrhea (11.6%), thrombocytopenia (48.8%), anemia (14.0%), and neutropenia (11.6%) were lower than those seen with intravenous BTZ administration in the phase 3 PANORAMA 1 trial (25%, 57%, 16.8%, and 24.1%, respectively). Two patients died while on treatment; one due to disease progression and the other due to infection. Common serious AEs included diarrhea (12.2%) and thrombocytopenia, atrial fibrillation, infection, pneumonia, and syncope (all 6.1%); serious AEs of atrial fibrillation and syncope were higher than in PANORAMA 1 (1.0% and 1.3%, respectively). AEs led to PAN, BTZ, and Dex dose adjustment in 36.7%, 42.9%, and 16.3% of patients, respectively; the most common AE leading to dose adjustment or temporary interruption was thrombocytopenia (all-grade, 30.6%; grade 3/4, 28.6%). Efficacy data will be reported after sufficient follow-up.Conclusions:Overall, the safety results from panobinostat-ETP, albeit in an older population of patients with more advanced MM, support those generated in PANORAMA 1, with only a slight increase in atrial fibrillation, potentially because of the older population. In the subgroup of patients receiving subcutaneous BTZ, rates of diarrhea and hematologic toxicities, AEs of interest with PAN+BTZ+Dex therapy, appear to be reduced compared with PANORAMA 1 data with intravenous BTZ administration; however, because of the small size of this study, these results should be interpreted with caution. Further clinical experience with the use of subcutaneous BTZ in this combination will help to determine the potential impact of the route of BTZ administration on tolerability. DisclosuresGuenther:Takeda: Consultancy, Honoraria; Celgene: Honoraria; Novartis: Consultancy, Honoraria. Mügge:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Cilag: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Bristol Myers-Suibb: Honoraria. Schjesvold:Janssen: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Lechner:Novartis: Honoraria. Gisslinger:Novartis: Consultancy, Honoraria; AOP Orphan: Consultancy, Honoraria; Baxalta: Consultancy, Honoraria. Greil:Novartis: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding. Gunsilius:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees. Weisel:Amgen: Consultancy, Honoraria; Bristol Myer-Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Munder:Janssen: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria; Takeda: Honoraria. Kiani:Novartis: Consultancy, Honoraria, Speakers Bureau. Campello-Iddison:Novartis: Employment, Equity Ownership. Einsele:Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau.

Panobinostat Induces Upregulation of CD38 and Augments the Anti-Myeloma Efficacy of Daratumumab in Pre-Clinical Models

Background:Immunotherapy with monoclonal antibodies (mAbs) has recently entered the clinical arena in multiple myeloma, including Daratumumab that targets CD38 on malignant plasma cells. The efficacy of mAbs depends on antigen density and expression of accessory ligands on target cells to initiate cell- and complement-dependent effector mechanisms. Here, we investigate the use of the histone deacetylase inhibitor (HDACi) Panobinostat to modulate target antigen expression and ligand profile on myeloma in favor of potent mAb-mediated recognition and destruction. We show that Panobinostat augments CD38 expression specifically on myeloma cells and demonstrate powerful synergy with anti-CD38 mAb Daratumumab in pre-clinical models.Methods:The myeloma cell line MM1.S and primary myeloma cells were treated with titrated doses of Panobinostat (0, 10, 25 nM) and expression of CD38 and a panel of additional target molecules including B-cell maturation antigen (BCMA) and SLAMF7, as well as accessory ligands analyzed by flow cytometry at 24, 48 and 72 hours. Antibody-dependent cellular cytotoxicity (ADCC) against Panobinostat treated and untreated myeloma cells was analyzed at 4 and 20 hours after addition of PBMC at an effector to target ratio of 25:1 in the presence of Daratumumab (1, 10, 50 ug/mL) or an isotype control antibody.Results:We first treated the myeloma cell line MM1.S with Panobinostat and analyzed its direct cytotoxic anti-myeloma effect. Consistent with previous work, the percentage of live MM1.S myeloma cells had decreased to 85% and 50% after 48 hours of exposure to 10 and 25 nM respectively. We analyzed expression of CD38 on residual live, i.e. 7-AAD negative MM1.S cells by flow cytometry and observed a 1.5 (10 nM) and 2-fold (25 nM) increase of CD38 expression by mean fluorescence intensity (MFI) compared to baseline levels and untreated control cells. The increase in CD38 expression was already detectable after 24 hours and plateaued between 48 and 72 hours. We confirmed our observation in primary myeloma cells from multiple donors (n=4) and detected an even stronger increase to 2 (10 nM) and 4-fold (25 nM) higher CD38 expression compared to untreated cells at 48 hours. Interestingly, expression of BCMA and SLAMF7 was not increased after Panobinostat treatment at all tested concentrations and time points in both MM1.S and primary myeloma. We confirmed that Panobinostat-induced upregulation of CD38 specifically occurred in myeloma, and neither observed this phenomenon in a panel of leukemia and lymphoma cell lines including Raji (Burkitt) and JeKo-1 (mantle cell), nor on resting/activated primary CD8+ and CD4+ T cells that we isolated from peripheral blood of several donors (n=3).Next, we were interested in determining whether the increase in CD38 expression enabled superior anti-myeloma activity of the anti-CD38 mAb Daratumumab. Panobinostat pre-treatment was done for 48 hours at 10 nM as this is a clinically achievable serum level with currently approved regimens. Indeed, significantly higher ADCC was mediated by Daratumumab at all tested concentrations (1, 10 and 50 ug/mL) against MM1.S that we had exposed to Panobinostat. At 4 hours, ADCC was 45% and 25% in Panobinostat-treated and untreated MM1.S respectively, and at 20 hours, near-complete, >90% ADCC of Panobinostat-pre-treated MM1.S had occurred, whereas only 65% of MM1.S were eliminated by Daratumumab without Panobinostat pre-treatment. These data were confirmed in multiple experiments with MM1.S and PBMC from different donors, and with primary myeloma cells. Experiments to evaluate synergy of Panobinostat and Daratumumab therapy in a xenograft model (NSG/MM1.S) are ongoing.Conclusions:Our data demonstrate that the HDACi Panobinostat induces upregulation of CD38 on myeloma and a subsequent dramatic increase of Daratumumab-mediated ADCC in pre-clinical models. These data suggest that Panobinostat could be used synergistically with Daratumumab in a clinical setting to increase response rates and extend duration of responses to Daratumumab. Panobinostat has a known ability to modulate the transcriptional profile of myeloma cells and our data demonstrate for the first time that this ability can be utilized to augment the therapeutic index of antibody-based immunotherapy in multiple myeloma. DisclosuresPallaud:Novartis: Employment. Lehmann:Novartis: Employment. Hudecek:Novartis: Research Funding.

Bortezomib, thalidomide, dexamethasone, and panobinostat for patients with relapsed multiple myeloma (MUK-six): a multicentre, open-label, phase 1/2 trial

Panobinostat (a pan histone deacetylase inhibitor) is approved in combination with bortezomib and dexamethasone for patients with relapsed multiple myeloma who have received two or more previous lines of therapy. We aimed to improve the safety of this combination and investigate efficacy by incorporating low-dose thalidomide, using sub-cutaneous weekly bortezomib, and determining the maximum tolerated dose of panobinostat in this regimen. We did a phase 1/2, multicentre, open-label trial (MUK six) at four hospitals in the UK, enrolling patients with relapsed, or relapsed and refractory, multiple myeloma aged at least 18 years, with an Eastern Cooperative Oncology Group performance status of 2 or less who had previously received 1-4 lines of therapy. Exclusion criteria included any antimyeloma treatment within 28 days of study drugs (except dexamethasone 160 mg >48 h before treatment). We used a rolling six escalation design to determine the maximum tolerated dose of panobinostat, and allocated patients to receive subcutaneous bortezomib 1·3 mg/m2, and oral thalidomide 100 mg, dexamethasone 20 mg, and panobinostat 10, 15, or 20 mg (escalated to 20 mg according to the escalation schedule). Treatment was given during a 21-day cycle (bortezomib on days 1 and 8; thalidomide every day; dexamethasone on days 1, 2, 8, and 9; and panobinostat on days 1, 3, 5, 8, 10, and 12) for 16 cycles in the absence of disease progression or unacceptable toxicity. Patients were permitted to come off study for autologous stem cell transplantation. The primary objective was to determine the maximum tolerated dose and recommended dose of panobinostat, and to estimate the proportion of patients with an overall response that was equal to a partial response or greater within 16 cycles of treatment at the recommended panobinostat dose in the modified intention-to-treat population. We assessed safety in all patients who received a trial drug (ie, bortezomib, thalidomide, dexamethasone, or panobinostat). This trial is registered at ClinicalTrials.gov, number NCT02145715, and with the ISRCTN registry, number ISRCTN59395590 and is closed to recruitment. Between Jan 31, 2013, and Oct 30, 2014, we enrolled 57 eligible patients who received at least one dose of trial medication or any drug. One dose-limiting toxicity was reported (grade 3 hyponatremia at the 20 mg dose), therefore the maximum tolerated dose was not reached, and 20 mg was deemed to be the recommended dose. 46 patients were treated with panobinostat 20 mg (the intention-to-treat population). 42 patients (91%, 80% CI 83·4-96·2) of 46 achieved the primary endpoint of an overall response that was equal to a partial response or greater. Most adverse events were grade 1-2 with few occurrences of grade 3-4 diarrhoea or fatigue. The most common adverse events of grade 3 or worse in the safety population (n=57) were reduced neutrophil count (15 [26%]), hypophosphatemia (11 [19%]), and decreased platelet count (8 [14%]). 46 serious adverse events were reported in 27 patients; of 14 suspected to be related to the trial medication, seven (50%) were gastrointestinal disorders. Panobinostat 20 mg in combination with bortezomib, thalidomide, and dexamethasone is an efficacious and well tolerated regimen for patients with relapsed multiple myeloma. Novartis and Myeloma UK.

Abstract 4720: Synergistic antitumor effect of selinexor, a selective inhibitor of nuclear export (SINE) compound and panobinostat in a mouse model of multiple myeloma

Abstract Introduction: Selinexor is an oral, first-in-class SINE compound that binds to the primary nuclear exporter XPO1/CRM1. XPO1 exports over 200 cargos, including major tumor suppressor proteins (TSPs) leading to their inactivation. Inhibition of XPO1 results in nuclear retention of TSPs and restores their normal functions. XPO1 also mediates the export of key signaling molecules in multiple myeloma (MM) including c-MYC mRNA and NF-κB. Selinexor is currently being investigated in phase 2 clinical trials in MM in combination with dexamethasone, pomalidamide, lenalidomide, bortezomib and carfilzomib. In preclinical studies selinexor has been shown to synergize broadly with these anti-MM drugs making it an excellent candidate partner for combination therapies in MM. To identify additional synergistic pairings, we investigated the use of selinexor in combination with panobinostat, a pan-histone deacetylase inhibitor (HDAC) recently approved by the FDA in combination with bortezomib for 3rd line treatment of MM, as a potential treatment for MM both in-vitro and in-vivo. Methods: The effects of selinexor and panobinostat alone or in combination on cell viability were tested on MM1.S and NCI-H929 cell lines using MTT assays. Total RNA and whole protein cell lysates were extracted and analyzed by qPCR and by immunoblots. In-vivo, MM.1S cells were used to derive a xenograft mouse model. Mice were treated with sub-therapeutic doses of selinexor and panobinostat alone or in combination and with the therapeutic dose of selinexor. Tumor growth was monitored for 17 days and% Tumor Growth Inhibition (%TGI) was determined. Xenografts were harvested and analyzed microscopically and by immunohistochemestry (IHC). Results: Selinexor-panobinostat combination was highly effective both in-vitro and in-vivo. In MTT assays, both selinexor and panobinostat demonstrated low IC50 values (nanomolar) and when combined, they synergistically/ additively inhibit proliferation. Gene expression and western blot analyses showed that the combination treatment leads to a synergistic reduction in c-MYC mRNA and protein levels. In addition, an overall reduction in expression of anti-apoptotic signaling molecules including NF-κB and p21 and an increase of expression of pro-apoptotic molecules including cleaved caspase 3 and BAX were observed. Importantly, in-vivo, while%TGI of sub-therapeutic doses of selinexor and panobinostat measured 58% and 52% respectively, the combination showed a synergistic effect, measuring 93%. Importantly this high%TGI exceeded the effect of the therapeutic dose of selinexor alone 79%. Conclusion: Selinexor-panobinostat combination synergizes to induce apoptosis in MM cells and amplifies anti-tumor effect in a MM xenograft model. These data provide rational support for study of selinexor/ panobinostat combination in clinical trials. Citation Format: Sivan Elloul, Hua Chang, Boris Klebanov, Trinayan Kashyap, Maxwell Werman, Margaret Lee, Yosef Landesman, Sharon Shacham, Michael Kauffman, Sharon Y. Friedlander. Synergistic antitumor effect of selinexor, a selective inhibitor of nuclear export (SINE) compound and panobinostat in a mouse model of multiple myeloma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4720.

Bortezomib (Velcade), Thalidomide, Dexamethasone and Panobinostat (VTD-P) Is a Safe, Well Tolerated and Efficacious Regimen for Patients with Relapsed Multiple Myeloma: Preliminary Results of the Muk-Six Trial

Introduction: VTD is an effective regimen for patients with multiple myeloma and forms a backbone for the addition of novel agents. The MUK-six trial aimed to improve the efficacy by adding Panobinostat, a now FDA approved pan-histone deacetylase inhibitor that demonstrated synergy with proteasome inhibition and immunomodulatory agents in pre-clinical models. We have previously reported the phase 1 dose finding part which determined the MTD of panobinostat with VTD to be 20mg. Here we present the efficacy results from the recommended dose (RD) expansion phase (primary end point) and safety, tolerability data for all patients during the induction phase of the study.Methods: MUK-six was a multi-centre UK Phase I/IIa trial for patients with relapsed and relapsed/ refractory myeloma who had received between 1 and 4 prior lines of therapy. Subjects received VTD-P (bortezomib 1.3mg/2sc days 1 and 8, thalidomide 100mg daily (50mg if pre-existing neuropathy), dexamethasone 20mg days 1, 2, 8, 9 and panobinostat 20mg days 1, 3, 5, 8, 10, 12) every 3 weeks for up to 16 cycles (induction) followed by 1 year of panobinostat maintenance. Those planned for autologous stem cell transplantation (ASCT) received a minimum of 6 cycles of VTD-P. All patients treated with VTD-P received venous thrombosis prophylaxis as per institutional practice. Responses were assessed using modified IWG uniform response criteria and toxicity graded by CTCAE V4.0.Results: 46 patients were treated at the RD and were of a median age of 60 years (41-76). 80.4% had received one prior line of therapy (range 1-4), 71.7% had prior bortezomib and 39.2% prior thalidomide. Most patients were ISS 1 (60.9%), 45.7% had adverse FISH lesions at baseline, 8.7% had 17p deletion. 6 patients remain on treatment at the time of this abstract. 51.3% of patients came off study to proceed to ASCT.The overall response rate (≥PR) for patients receiving at least one dose of panobinostat was 91.3%, ≥VGPR 45.7% (CR 6.5%, VGPR 39.1%, PR 45.7%). The ≥VGPR rate for those with standard FISH was 52.1% vs 42.9% for adverse FISH. Those treated at first relapse had higher overall responses to those treated later in their disease course (≥PR 94.6% vs 77.8%). Responses were independent of prior bortezomib exposure (≥PR 90.9%, ≥VGPR 45.5% vs PR≥92.3%, ≥VGPR 46.2%).Treatment was generally well tolerated, with a mean panobinostat dose of 17.4mg (86.8% of the RD) delivered across all cycles. 32.1% of those starting at 50mg thalidomide stopped the drug due to toxicity, and 52.6% of those starting at 100mg required dose reductions/stopping. 46 serious adverse events were reported in 27 patients which were mainly infections (17/46, 37.0%). The commonest grade 3-4 toxicities reported for all 57 patients were: neutropenia (14, 24.6%), hypophosphatemia (11, 19.3%), thrombocytopenia (8, 14.1%) and diarrhoea (6, 10.5%). Of note there were no reports of ≥ grade 3 neuropathy. The most frequent grade 1-2 toxicities were fatigue (50, 87.7%), neuropathy (43, 75.5%), constipation (35, 61.4%), diarrhoea (35, 61.4%), bone pain (33, 57.9%), and nausea (27, 47.4%). 2 patients withdrew consent due to toxicity.Conclusions: This study demonstrated that panobinostat can be safely given in combination with VTD and appears highly effective with a response rate of 91.3%, ≥VGPR 45.6% despite 72% having previous bortezomib. This regimen was well tolerated, in particular the incidence of diarrhoea, neuropathy and asthenia/fatigue appeared lower than that observed in the PANORAMA 2 trial (San Miguel et al., 2014). It is possible that the incorporation of a low intensity subcutaneous bortezomib schedule (2 doses every 3 weeks) contributed to the lesser toxicity.Acknowledgments: This trial was part of the Myeloma UK Clinical Trial Network, ISRCTN: 59395590. DisclosuresPopat:Janssen: Honoraria. Off Label Use: Panobinostat: use outside of FDA licence, not yet EU approved. Kishore:Celgene: Other: Conference Sponsorship; Jazz pharma: Other: Conference Sponsorship. Oakervee:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Yong:Janssen: Honoraria; Autolous: Consultancy; Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Novartis: Consultancy. Cook:Sanofi: Consultancy, Honoraria, Speakers Bureau; Jazz Pharma: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Chugai: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cavenagh:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

A Phase I/II Study of the Combination of Panobinostat (PAN) and Carfilzomib (CFZ) in Patients (pts) with Relapsed or Relapsed/Refractory Multiple Myeloma (MM): Comparison of Two Expansion Cohorts

Background: Proteasome inhibitors (PI) such as bortezomib (BTZ) and carfilzomib (CFZ) have improved the treatment (tx) of MM; however, resistance invariably develops and MM remains an incurable disease. Changes in histone modification are commonly found in human cancers including MM, and several histone deacetylase inhibitors (HDACi) are in clinical development. Panobinostat (PAN) is an oral pan-HDACi which has shown synergy with PIs through inhibition of the proteasome and aggresome pathways. It was recently approved by the FDA in combination with BTZ and dexamethasone based on the results of the PANORAMA1 study demonstrating efficacy, but significant G3 diarrhea (Lancet Oncol 2014;15:1195-206). We have previously reported the combination of CFZ and PAN in pts with relapsed and relapsed/refractory MM with encouraging results (Haematologica 2015;100:670-6). The maximum tolerated dose (MTD) of CFZ and PAN was never reached and we extended our original study to investigate higher dose levels. Here we present a comparison of the initial dose expansion (DL 4) and the subsequent dose expansion (DL 6). Methods: Ps with MM who had relapsed after ≥ 1 prior tx were enrolled. PAN was administered orally on days 1, 3, 5, 15, 17, 19 of each 28-day cycle. CFZ was administered IV over 30 min on days 1, 2, 8, 9, 15, and 16. In the initial dose escalation portion of the study a standard 3+3 design was used to determine the maximum tolerated dose (MTD) of an initial 4 planned dose levels of the combination of CFZ and PAN. The 4 dose levels tested were DL 1 (20 mg PAN and 20/27 mg/m2 CFZ); DL 2 (20 mg PAN and 20/36 mg/m2 CFZ); DL 3 (20 mg PAN and 20/45 mg/m2 CFZ), and DL 4 (30 mg PAN and 20/45 mg/m2 CFZ). MTD was not reached and the maximum planned dose DL 4 was expanded. We then revised the study in order to escalate to DL 5 (30 mg PAN plus 20/56 mg/m2 CFZ). Due to numerous PAN dose reductions resulting in a delivered PAN dose closer to 20 mg, we explored DL 6 (PAN 20 mg and CFZ 20/56 mg/m2). Tx continued until PD or intolerable toxicity. The primary efficacy endpoint was the overall response rate (ORR) (≥ PR). Secondary end points were time to progression (TTP), progression-free survival (PFS) and overall survival (OS), calculated using Kaplan-Meier methods. AEs were assessed according to CTCAE Version 4 and responses were assessed using IMWG criteria (plus MRs as per the EBMT criteria). Results: 80 pts were enrolled (50% male, median age 65 (range 41-91), 58% poor risk, and median of 4.5 prior therapies (1-9)). Prior PI or IMiD exposure and refractory status for all pts and expansion cohorts are shown in Table 1. 34 pts were in the 1st dose expansion (DL 4) and 33 in the 2nd (DL6). 13 (16%) pts remain on active tx overall, 6% of pts on DL 4 and 30% of pts on DL6. The most common all grade toxicities were thrombocytopenia (73%), nausea (69%), diarrhea (64%), and fatigue (51%). There were no significant differences in types or grades of toxicities between the 2 expansion cohorts except for decreased all grade diarrhea favoring DL 6 (71% v 49%). There was 1 tx related death due to heart failure in a pt with a prior history of hypertension and hyperlipidemia. The ORR was 75% (32% ≥ VGPR, 43% PR) for all pts, 72% (37% ≥ VGPR, 34% PR) for DL4 and 84% (34% ≥ VGPR, 50% PR) for DL 6 pts. With a median follow up (FU) of 14.5 mos for all pts, median PFS and TTP were 13.5 and 18.7 mos, respectively. Median OS was not reached. DL4 pts had a median FU of 24.3 mos, median PFS of 17.8 mo, median TTP of 19.5 mo, and median OS of 28.2 mo. The PFS and OS data of DL 6 pts is immature. Conclusions: The PAN/CFZ combination is effective with an acceptable safety profile in this heavily pretreated and highly refractory population. The results of this study compare favorably with the results of the PANORAMA-1 study in both efficacy and toxicity. An increase in CFZ from 45 to 56 mg/m2 did not appear to increase cardiopulmonary toxicity while a decrease in PAN from 30 to 20 mg appeared to have decreased the incidence of diarrhea. Both expansion dose levels tested were highly efficacious and well tolerated. Further evaluation of this combination in this schedule is warranted. Disclosures Berdeja:Acetylon: Research Funding; MEI: Research Funding; Array: Research Funding; Onyx: Research Funding; Takeda: Research Funding; Curis: Research Funding; Janssen: Research Funding; Celgene: Research Funding; BMS: Research Funding; Abbvie: Research Funding; Novartis: Research Funding. Gregory:Novartis: Speakers Bureau. Hart:Onyx: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Mace:Spectrum Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Bayer: Honoraria, Speakers Bureau; Pfizer: Speakers Bureau. Flinn:Celgene Corporation: Research Funding.

Panobinostat Plus Azacitidine in Adult Patients with MDS, CMML, or AML: Results of a Phase 2b Study

Panobinostat Plus Azacitidine in Adult Patients with MDS, CMML, or AML: Results of a Phase 2b Study

Phase I/II Study of the Deacetylase Inhibitor Panobinostat As Maintenance Therapy after an Allogeneic Stem Cell Transplantation in Patients with High-Risk MDS or AML: The Panobest-Trial

Phase I/II Study of the Deacetylase Inhibitor Panobinostat As Maintenance Therapy after an Allogeneic Stem Cell Transplantation in Patients with High-Risk MDS or AML: The Panobest-Trial

Final Analysis of Overall Survival from the Phase 3 Panorama 1 Trial of Panobinostat Plus Bortezomib and Dexamethasone Versus Placebo Plus Bortezomib and Dexamethasone in Patients with Relapsed or Relapsed and Refractory Multiple Myeloma

Final Analysis of Overall Survival from the Phase 3 Panorama 1 Trial of Panobinostat Plus Bortezomib and Dexamethasone Versus Placebo Plus Bortezomib and Dexamethasone in Patients with Relapsed or Relapsed and Refractory Multiple Myeloma

A Phase 1b Study of Panobinostat in Combination with Idarubicin and Ara-C in Patients with High-Risk Acute Myeloid Leukemia

A Phase 1b Study of Panobinostat in Combination with Idarubicin and Ara-C in Patients with High-Risk Acute Myeloid Leukemia

An Expanded Treatment Protocol of Panobinostat Plus Bortezomib and Dexamethasone in Patients with Previously Treated Myeloma

Introduction: Panobinostat (PAN) is a potent pan-deacetylase inhibitor that targets multiple myeloma (MM) cells via its effects on epigenetics and protein metabolism. In the PANORAMA 1 phase 3 trial, the combination of PAN, bortezomib (BTZ), and dexamethasone (Dex; PAN-BTZ-Dex) significantly increased progression-free survival compared with placebo plus BTZ and Dex, leading to US Food and Drug Administration approval of the combination for the treatment of patients with MM who have received ≥ 2 prior regimens including BTZ and an immunomodulatory agent. The "PANobinostat EXpansion treatment protocol" (PANEX) study was developed to provide access to PAN and gather additional safety data on the PAN-BTZ-Dex combination until PAN became commercially available.Methods: PANEX is a multicenter, open-label, expanded treatment protocol study of PAN-BTZ-Dex in adult patients with MM relapsed and/or refractory to ≥ 1 prior line of therapy. During treatment phase (TP) 1 of the study, patients received oral PAN (20 mg; days 1, 3, 5, 8, 10, and 12) plus intravenous (IV) or subcutaneous (SC) BTZ (1.3 mg/m2; days 1, 4, 8, and 11) for eight 21-day cycles. Patients with at least stable disease proceeded to TP2, with maintained PAN and less frequent BTZ dosing (days 1 and 8) for an additional 8 cycles. In both phases, oral Dex (20 mg) was administered on the days of and after BTZ treatment. Reduction to once-weekly BTZ was allowed before TP2 as a dose reduction strategy. Response assessments were completed per modified European Group for Blood and Marrow Transplantation criteria.Results: A total of 39 patients, with a median age of 70 years (range, 44-88 years), were enrolled in the study. Patients were heavily pretreated, with a median of 3 prior lines of therapy (range, 1-12; 21% ≥ 7 prior therapies), with nearly half of the patients (48.7%) having progressed on their most recent therapy. Most patients received SC BTZ (87.2% [n = 34] vs 12.8% [n = 5] IV BTZ), with a median treatment duration of 9.4 weeks (range, 2-34). A total of 21 patients achieved a partial response, leading to an overall response rate of 53.8%; an additional 17.9% achieved a minimal response, for a clinical benefit rate (≥ minimal response) of 71.8%, with 25.6% having stable disease. Notably, no patients in the current trial had a best response of progressive disease. The most common grade 3/4 hematologic laboratory abnormalities were thrombocytopenia (53.8%), anemia (17.9%), and neutropenia (17.9%). The most common nonhematologic grade 3/4 treatment-emergent adverse events (AEs) were dehydration (28.2%), fatigue (28.2%), diarrhea (17.9%), asthenia (10.3%), and pneumonia (10.3%). Common gastrointestinal treatment-emergent AEs of any grade included diarrhea (48.7%), nausea (25.6%), and vomiting (12.8%), and nearly all cases of dehydration were associated with these gastrointestinal events. Interestingly, in the patients receiving SC BTZ (n = 34), the rate of grade 3/4 diarrhea was 11.8%, approximately half the rate seen with IV BTZ administration in the phase 3 PANORAMA 1 trial (25%). Common serious AEs included dehydration (15.4%), diarrhea (12.8%), and pneumonia (10.3%). AEs led to PAN, BTZ, and Dex dose reductions in 59.0%, 59.0%, and 46.2% of patients, respectively.Conclusions: Overall, the results from PANEX, albeit in an older population of patients with more advanced MM, support those generated in PANORAMA 1. In the subgroup of patients receiving SC BTZ, the rate of diarrhea, an AE of interest with PAN-BTZ-Dex therapy, appeared to be reduced when compared with PANORAMA 1 data with IV BTZ administration. Further clinical experience with the use of SC BTZ in this combination will help to determine the potential impact of route of BTZ administration on tolerability. DisclosuresElkins:Pharmacyclics/Janssen: Speakers Bureau; Onyx Pharmaceuticals: Speakers Bureau. Letzer:Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau. Levy:Takeda: Consultancy. Seneviratne:Novartis: Honoraria, Speakers Bureau. Rine:Novartis: Employment. White:Novartis: Employment. Kuriakose:Novartis: Employment, Equity Ownership.

Velcade, Thalidomide, Dexamethasone and Panobinostat (VTD-P) for Patients with Relapsed and Relapsed/ Refractory Myeloma: Preliminary Results of the Muk-Six Phase I/IIa Trial

Introduction: Bortezomib (velcade), thalidomide and dexamethasone (VTD) is a standard of care regimen for patients with newly diagnosed and relapsed myeloma. The in vitro synergistic cytotoxicity between histone deacetylase and proteasome inhibitors has recently been confirmed by the PANORAMA 1 trial of panobinostat, bortezomib and dexamethasone. MUK-Six (ISRCTN: 59395590) is a multi-centre UK phase I/ IIa trial designed to determine the recommended dose (RD) of the pan-deacetylase inhibitor panobinostat in combination with VTD and to estimate the response rate at the RD within 16 cycles (primary endpoint). Here we report preliminary results of the dose escalation phase and ongoing patients treated at the RD.Methods: Patients with relapsed and relapsed/ refractory myeloma that had between 1 and 4 prior lines of therapy received VTD-P (bortezomib 1.3mg/2sc days 1 and 8, thalidomide 100mg/ daily (50mg if pre-existing neuropathy), dexamethasone 20mg days 1, 2, 8, 9 and panobinostat days 1, 3, 5, 8, 10, 12) every 3 weeks. A rolling six dose escalation design was used to determine the maximum tolerated dose (MTD) and RD of panobinostat using protocol specified dose-limiting toxicity (DLT) criteria. The following panobinostat dose levels were used: cohort 1: 10mg; cohort 2: 15mg; cohort 3: 20mg. Those planned for autologous stem cell transplantation (ASCT) received a minimum of 6 cycles (maximal response plus 2 cycles) whereas those not suitable for ASCT could continue for up to 16 cycles of VTD-P followed by 1 year of panobinostat maintenance (days 1, 3, 5, 8, 10 and 12 of a 21 day cycle dosed at the RD). All patients treated with VTD-P received venous thrombosis prophylaxis as per institutional practice. Responses were assessed using modified IWG uniform response criteria and toxicity graded by CTCAE V4.0.Results: Between January 2013 and July 2014 a total of 55 patients were registered, 19 to the dose escalation phase and 36 to the dose expansion phase. 7 were ineligible to start treatment and 9 were non-evaluable for efficacy analysis due to dose omissions during cycle 1. Patients were of a median of 62 years (41-76) and had received a median of 1 prior line of therapy (range 1-4). 29/48 (60.4%) had received prior bortezomib and 29/48 (60.4%) prior ASCT. Most patients were ISS I (26/48, 54.2%) with 10.4% (5/48) being ISS III. As of 28thJuly 2014, all patients in the dose escalation phase treated at the non-RD had completed treatment having received a median of 15 cycles (range 2-16). Only 1 DLT was observed during the dose escalation phase (cohort 3: hyponatremia ≥ grade 3) and as the criteria for MTD was not met, 20mg was declared to be the RD for dose expansion. Of the 9 patients treated at the non-RD, 8 (89%) achieved ≥ partial response.33 patients treated at the RD were ongoing with treatment and have completed a median of 3 cycles (0-14). Of these, 24 are evaluable for response (out of a target 42 evaluable patients to be recruited). At this stage in an intent-to-treat analysis 15 of the 24 (62.5%, 80% confidence interval [47.4%-75.9%]) had achieved ≥ partial response, although 5 did not yet have response data available. The recruitment target of 42 patients at the RD is expected to be completed by the time of presentation and responses updated accordingly.The VTD-P combination was generally well tolerated with no treatment discontinuations due to toxicity. Grade 3-4 toxicities included (number, %): hypophosphatemia (8, 16.7%), neutropenia (7, 14.6%), abnormal liver tests (3, 6.3%) (none observed at the non-RD); thrombocytopenia (3, 6.3%), peripheral neuropathy (1, 2.1%), diarrhoea (1, 2.1%) and hyperglycemia (1, 2.1%). The predominant grade 1-2 toxicities were: fatigue (31, 64.5%), neuropathy (28, 58.3%), constipation (22, 45.8%) and diarrhoea (17, 35.4%). 19 serious adverse events (SAEs) were reported by 12 patients at the RD, of which 4 were treatment related and predominantly gastrointestinal (GI).Conclusions: This preliminary data demonstrates that VTD-P is a safe, well tolerated and potentially active regimen for patients with relapsed myeloma. The incidence of grade 3-4 GI and neurotoxicity was low and there were no discontinuations for toxicity. The RD of panobinostat was 20mg and enrolment to this expansion phase is currently ongoing. .Acknowledgments: On behalf of the Myeloma UK Clinical Trial Network DisclosuresPopat:Janssen: Honoraria. Off Label Use: Use of Panobinostat in relapsed myeloma. Cavenagh:Janssen: Honoraria; Celgene: Honoraria.

A Phase I/II Trial Evaluating the Use of a Histone Deacetylase Inhibitor Panobinostat (LBH589) in Addition to Glucocorticoids in Patients with Acute Graft-Versus-Host Disease

Graft-versus-host disease (GVHD) remains the principal obstacle to successful outcomes in allogeneic hematopoietic stem cell transplant (HCT). Glucocorticoids are the current standard initial treatment for acute GVHD with variable complete responses rates (30% to 60%). New immunosuppressive strategies are required to improve survival and to decrease immunosuppressive toxicities. Vorinostast, a histone deacetylase inhibitor (HDACi), have shown efficacy for acute GVHD prevention in MRD HCT. Panobinostat is a potent inhibitor of deacetylases and HSP90 belonging to a structurally novel class of the cinnamic hydroxamic acid class and is one of most potent pan-HDACi. This protocol tested the safety and efficacy of Panobinostat (LBH589) as initial adjunct treatment for acute GVHD, administered within 72 hours of the first high dose glucocorticoid (methylprednisolone 0.8 mg/Kg/day IV or equivalent PO for 14 days and then taper per MD discretion). We have enrolled 19 subjects, median age 53 years (range, 34-76), male (n=12)/female (n=7), white(n=14)/hispanic(n=5); with diagnosis of CLL (n=2), MDS (n=2), Myeloma (n=1), Follicular NHL (n=1), CML(n=1), Myelofibrois (n=3), AML (n=5), MDS/CMML (n=3) or ALL(n=1). Conditioning regimens included Busulfan(BU)/fludarabine(FLU) AUC 5300 (n=10) or AUC 3500 (n=3), FLU/Melphalan (n=4) or Pentostatin/BU (n=2); and GVHD prophylaxis for MUD 8/8 (n=11) or MRD (n=5) HCT with TAC/MTX (n=6), TAC/rapamycin(n=7), TAC/MMF(n=3) and for mismatched transplants with either TAC/RAPA/ATG (n=2) or TAC/MTX/ATG (n=1). Median day of acute GVHD (n=16) onset was day + 37 post HCT (26 -109 days) with overall grade GVHD II (n=13) or III (n=6); and median day of acute symptoms in overlap GVHD patients (n=3) was day + 712 (528-981). All Patients were treated with voriconazole (n=15) or micafungin (n=4) for fungal prophylaxis. For the first four patients Panobinostat was administered intravenously (IV) weekly x 4 at 2.5MG/M2 (n=3) or 5MG/M2 IV (n=1) with all 4 achieving either CR (n=3) or PR (n=1) GVHD responses by day +15 of Panobinostat. Due to manufacturer discontinuation of IV formulation, the protocol was amended to use PO Panobinostat. Using 10mg PO TIW 3 doses q week x 4 weeks, we treated 2 subjects which were both discontinued from study drug due to presumed GHVD progression within 7 days of Panobinostat (after 3-4 doses). First subject had grade II GVHD (skin stage 3, gut stage 1 and liver stage 0) that progress in gut and skin; second subject with grade II GVHD (skin stage 3, gut stage 1, liver stage 1) with LFTs worsening ultimately evolving into VOD. Due to safety concerns next subjects were treated with 5 mg PO TIW 3 doses q week x 4 weeks, dose that was determined to be the maximal tolerated dose (MTD) after 6 patients completed therapy in phase I. Currently we are enrolling in phase II portion (n=7). GVHD response rate among MTD treated was complete in 85% (n=11), partial in 7.6% (n=1) or progressive in 7.6% (n=1) by day +36 after Panobinostat with majority achieving responses by day +21. Chronic GVHD at day +365 in evaluable patients (n=6) was none (n=3) or mild (n=3) and steroid was discontinued at a median of 3 months (3-6). Hematological toxicities in evaluable patients (n=13) were mild with worsening of prior thrombocytopenia (n=7/10), anemia (n=3/10) and leukopenia (n=3/10) and returned to baseline within 1-2 weeks; LFTs deterioration (n=1) within 1 week of Panobinostat in a GVHD stages 3 liver/3 skin patient; pericarditis/cardiogenic shock CTCAE 5 of unclear etiology (n=1); worsening thyroid function (n=1) and hypercholesterolemia (n=1). Preliminary correlative studies in MTD treated patients showed that CD4 and CD8 numbers remained stable during treatment. T regulatory cells numbers decreased at day +8 after Panobinostat and recovered by days +15 and +29 of treatment. Level of T regs inducing cytokines (TGFB and IL-10) increased, possibly contributing to an immune-modulatory environment. There is evidence of an increased in acetylation of histone 3 in CD4, CD8 and monocytes subsets over time. We are encouraged with tolerability of level -1 Panobinostat dose and the high GVHD response rate of 85% which may compare favorably to the historical GVHD response rate. These results suggest a potential role for Panobinostat as a tool to improve success of glucocorticoids for acute GVHD treatment. DisclosuresNo relevant conflicts of interest to declare.

A Phase I/II Trial of the Histone Deacetylase (HDAC) Inhibitor, Panobinostat, in Combination with Lenalidomide in Patients with Relapsed/Refractory Hodgkin’s Lymphoma (HL)

Introduction: Phase 2 single agent trials with lenalidomide and panobinostat in patients with relapsed or refractory HL have demonstrated overall response rates (ORR) of 19% (Fehniger et al., Blood 118:5119-5125, 2011) and 27% (Younes et al., JCO 30:2197-2203, 2012), respectively. We conducted a phase I/II trial to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD), and overall response rate (ORR) with combined lenalidomide and panobinostat in patients with relapsed HL.Methods: Patients with relapsed or refractory classical HL (cHL) or lymphocyte predominant HL (LP HL) after at least one prior therapy were eligible. Measurable disease > 1 cm, ejection fraction ≥ 45%, ECOG PS 0-2, QTc ≤ 450 msec, ANC ≥ 1200/mm3, platelets ≥ 100,000/mm3, AST/ALT ≤ 2.5 x the upper limit of normal (ULN), bilirubin ≤ 1.5 x ULN, and creatinine clearance 60 ≥ ml/min were also required. In the phase I trial, escalating doses of panobinostat (15 or 20 mg) days 1, 3, and 5 weekly were combined with lenalidomide 25 mg days 1-21 utilizing a 3+3 standard dose escalation design. DLT was defined during cycle 1 as grade 4 neutropenia or thrombocytopenia, grade 4 infection, grade 3 infection for > 7 days, treatment delays > 14 days, or other grade 3-4 non-hematologic toxicity. Twenty-eight days defined a cycle and patients could remain on therapy until disease progression. Response was assessed after cycles 2, 6, and every 4 cycles thereafter by International Harmonization Criteria (Cheson, JCO 25:579-586, 2007).Results: From Feb 2012 through June 2014, 22 patients (16 males) with cHL (n=21) and LP HL (n=1) and a median age of 45 (range 22-72) have been enrolled. Patients had received a median of 4 prior therapies (range 2-13), 9 patients were refractory to their most recent therapy, and 91% had stage III-IV disease at study entry. Ten patients had a prior autologous SCT, 1 patient had received prior allogeneic EBV-directed cytotoxic T-cells, 1 patient had a prior syngeneic transplant, and 1 patient had both prior autologous and allogeneic transplants. Eleven patients were enrolled in the phase 1 study at dose level (DL) 1 (25 mg lenalidomide + 15 mg panobinostat, n=6) and at DL 2 (25 mg lenalidomide + 20 mg panobinostat, n=5). Although there were no DLTs observed in cycle 1, 2 patients treated at DL 2 experienced grade 4 neutropenia and thrombocytopenia for > 14 days in cycle 2 and 3 of 5 patients were dose reduced to DL 1 in cycles 2 or 3. Therefore, DL 1 was expanded to 6 patients to ensure patient safety at this dose level and the phase 2 study was conducted at DL 1. Eleven patients have been treated in the phase 2 study. In all 22 patients, the median number of cycles completed on study was 4 (range 1-22). Grade 3-4 toxicities in all patients included neutropenia (59%), thrombocytopenia (41%), lymphopenia (27%), febrile neutropenia (27%), hypophosphatemia (9%), hypocalcemia (5%), QTc prolongation (5%), fatigue (5%), nausea/vomiting (5%), erythema nodosum (5%), transaminitis (5%), and unexplained altered mental status after administration of study medications (5%). Dose reductions were required in 10 patients (45%, 5 in the phase 2 study and 3 patients with multiple dose reductions) for febrile neutropenia, grade 3-4 neutropenia/thrombocytopenia, erythema nodosum, and transaminitis. Twenty-one patients have discontinued protocol therapy for PD (n=15), adverse events (n=5, including grade 4 neutropenia/thrombocytopenia or unexplained altered mental status after drug dosing), and to undergo elective CABG (n=1). ORR is 14% (2 CR and 1 PR) in 21 evaluable patients with complete responses in 1 patient with cHL and 1 patient with LP HL of 6 and 25 months duration, respectively.Conclusions: Combined panobinostat and lenalidomide appears to be well tolerated in patients with relapsed/refractory HL. Due to myelosuppression at higher doses, the recommended phase 2 dose of the combination is 25 mg lenalidomide days 1-21 with 15 mg panobinostat days 1, 3, and 5 weekly on a 28-day cycle. Accrual continues to the two-stage phase 2 trial, but based on preliminary data in the first 22 patients, the efficacy of combined lenalidomide and panobinostat appears similar to that previously reported with these drugs as single agents. DisclosuresChristian:Celgene: Research Funding. Fehniger:Celgene: Research Funding. Wagner-Johnston:Celgene: Research Funding. Bartlett:Celgene: Research Funding; Novartis: Research Funding. Blum:Celgene: Research Funding; Novartis: Research Funding. Off Label Use: Panobinostat and lenalidomide are not approved for the treatment of Hodgkin’s lymphoma.

AT-51 * PHASE I STUDY OF PANOBINOSTAT AND FRACTIONATED STEREOTACTIC RE-IRRADIATION THERAPY (FSRT) FOR RECURRENT HIGH GRADE GLIOMAS

PURPOSE: To perform a phase I study to evaluate the safety, and tolerability of panobinostat, an HDAC inhibitor, when combined with fractionated stereotactic re-irradiation therapy (FSRT) for recurrent gliomas. METHODS: Patients with recurrent gliomas (WHO grade II-IV) were eligible for this trial. FSRT was prescribed to 30-35 Gy delivered in 10 daily fractions. Panobinostat was administrated orally once daily every Monday, Wednesday, and Friday concurrently with radiation treatment. The panobinostat dose was escalated from 10 to 30 mg using a 3 + 3 trial design. RESULTS: A total of 16 patients were enrolled on the trial. Four patients were excluded. There were no treatment related grade 3 or higher toxicities in the 10 mg or 20 mg cohort. In the 30 mg panobinostat cohort, one patient developed grade 3 leukopenia and grade 4 neutropenia which was possibly related to the treatment. The minimum follow up of the living patients is 8.5 m. The 4-m progression survival (PFS) of all the evaluable patients is 87%, and 6-m PFS of 56%. The medial overall survival is 9.5 m. There is a suggestion of dose response to the panobinostat. The 4-m PFS is 100%, 100%, and 67% for 30 mg, 20 mg, and 10 mg cohort respectively. The 6-m PFS is 83%, 33%, and 67% for 30 mg, 20 mg, and 10 mg cohort respectively. The overall survival for the 30 mg cohort is not reached with a median follow up of 11.5 m. CONCLUSIONS: Panobinostat administrated with FSRT is well tolerated at a 30 mg dose. There is a suggestion of a dose response with panobinostat. The median overall survival is not reached with a median follow up of 11.5 m for the 30 mg cohort. A phase II trial is warranted to confirm the efficacy of combining panobinostat with FSRT for recurrent gliomas.

Phase I study of panobinostat and imatinib in patients with treatment-refractory metastatic gastrointestinal stromal tumors

Background:Panobinostat, a pan-deacetylase inhibitor, overcomes imatinib resistance in preclinical models of gastrointestinal stromal tumours (GIST). Here we determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of panobinostat in combination with imatinib (IM) for treatment of patients with refractory GIST.Methods:Following a 7-day run-in phase of IM (400 mg per day), escalating doses of panobinostat were added following a ‘3 plus 3' design. Twelve heavily pretreated GIST patients were enrolled in two dose levels.Results:Most common adverse events were thrombocytopenia, anaemia, fatigue, creatinine elevation, nausea, emesis and diarrhoea. Twenty micrograms of panobinostat and 400 mg IM were declared the MTD. Pharmacologically active concentrations of panobinostat and IM were achieved as evidenced by histone H3 acetylation in blood mononuclear cells in vivo and inhibition of the IM-resistant KIT (D816) mutation in vitro. In FDG-PET-CT scans after IM run-in and following 3 weeks panobinostat treatment, 1 out of 11 evaluable patients showed a metabolic partial response, 7 patients were metabolically stable and 3 patients progressed. Longest treatment duration was 17 weeks (median 6).Conclusion:Panobinostat and IM can be administered at doses achieving target inhibition in vivo. Further clinical exploration of patients with treatment-refractory GIST is warranted. Correlative studies in this trial may help to optimise dosing schedules in GIST.

Post-Transplant Maintenance With The Deacetylase Inhibitor Panobinostat In Patients With High-Risk AML Or MDS: Results Of The Phase I Part Of The Panobest Trial

Inhibitors of class I/II histone deacetylases (HDACi) possess anti-leukemic activity and have been reported to modulate the function of immune effector cells. Thus, they could provide specific clinical benefit in the allogeneic hematopoietic stem cell transplantation (HSCT) setting. Panobinostat (PAN) is a potent, orally available pan-HDACi reported to either suppress or stimulate regulatory T cells (T reg), depending on the administered dose (Shen L & Pili R, OncoImmunology 1;7:948, 2012). The feasibility and efficacy of PAN treatment following HSCT for patients (pts) with high risk acute myeloid leukemia (AML) has not been established. We report clinical and translational results of the dose-escalation phase of the PANOBEST study with PAN as post-HSCT maintenance.Primary objectives were, based on dose-limiting toxicity (DLT), determining the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D) of PAN in patients with high risk AML or myelodysplastic syndromes (MDS) in complete remission (CR) after reduced-intensity conditioning HSCT. Secondary objectives were the evaluation of safety, tolerability and immunoregulatory properties of PAN, and overall (OS) and disease-free survival (DFS) of treated patients.PAN was started at 10 mg p.o. three times a week (TIW) and escalated to 20 and 30 mg TIW using a 3+3 design. Treatment was initiated 60-150 days after HSCT and continued for up to one year. Eligibility criteria included: recovery of peripheral blood counts, adequate organ function and no severe graft versus host disease (GvHD). All pts gave written informed consent. DLT was defined as prolonged grade 4 hematologic or grade 3/4 non-hematologic toxicity within 28 days of the first PAN dose. Immunophenoytyping of lymphocyte subsets was performed pre-treatment and on days 3, 8, 30, 90, 180 and 360.12 pts (11 AML, 1 MDS), median age of 52 years (21-62) were enrolled. PAN was started within a median of 73 days (60-126) after HSCT, which was performed with active disease (n=11) or in CR2 (n=1). The RP2D was determined to be 20 mg TIW based on one DLT (fatigue grade 3) at 20 mg and two DLTs (nausea/emesis and colitis grade 3 each) at 30 mg. Grade 2-4 adverse events (AEs) were reported in 10 out of the 12 pts (83%). Grade 3/4 AEs included hematologic toxicity (50% of pts), laboratory alterations (33%), gastrointestinal symptoms (25%), fatigue, pulmonary infection (17% each), sepsis, herpes stomatitis, diabetes, syncope, deep vein thrombosis and pulmonary embolism (8% each). Toxicity was reversible and required at least one PAN dose reduction in 3 pts. Acute GvHD grade 2 (1 pt) and 3 (2 pts) was responsive to steroids in 2 pts or salvage therapy in 1 pt. Four pts developed mild (n=3) or moderate (n=1) chronic GvHD. To date, 5 pts have completed one year of PAN and 2 pts remain on treatment (days 238, 290). Five pts discontinued treatment prematurely after 10-217 days due to grade 3 toxicities (n=4) or AML relapse (n=1). With a median follow up of 579 days (129-911), 11/12 pts are alive and 10/12 in continuous CR after HSCT. Seven pts received prophylactic donor lymphocyte infusions (DLIs, 1-5 doses of 0.1-20x106 CD3+ cells/kg). Immunophenotyping revealed no impact of PAN on absolute T reg numbers (9 pts), but a significantly reduced proportion of CD4+CD25++CD127dim/- T reg to CD3+CD4+ T helper (Th) cells by day 8 after 3 doses of PAN (mean±SEM: 14.6±2.6 vs. 9.6±1.2%, p value of t test =0.03). While Treg/Th proportion continuously decreased in pts with ongoing CR, it again increased after PAN discontinuation or remained stable under PAN treatment in both relapsing patients. Outcome of the study population was compared with a historical cohort of 29 consecutive pts with active AML transplanted in Frankfurt in 2000-2009. Both cohorts were similar in age, gender, disease stage or BM blasts at time of HSCT, donor type and use of DLIs. In a landmark analysis including all pts who were in CR and without severe GvHD on day 73 after HSCT, probabilities for DFS and OS at 18 months after HSCT were 83±11% vs. 55±9% (p=0.145, log-rank test) and 92±8% vs.66±9% (p=0.085) in the PANOBEST vs. historical cohort (Fig 1). [Display omitted] PAN is well tolerated after HSCT at a RP2D of 20 mg TIW. Comparison with a historical control cohort of pts transplanted with active AML shows a low relapse rate, which appears to be associated with a PAN-induced modulation of the T reg/Th proportion. Disclosures:Bug:Novartis: Honoraria, Travel grants, support for the clinical study Other. Ottmann:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

A Phase I Study Of Panobinostat In Combination With ICE (Ifosfamide, Carboplatin and Etoposide) In Patients With Relapsed Or Refractory Classical Hodgkin Lymphoma (cHL)

▪The standard approach to patients with refractory or recurrent cHL is treatment with an effective salvage chemotherapy followed by stem cell transplantation. The best outcome from the transplant is expected in patients who achieve complete response (CR) after the salvage chemotherapy. The commonly used regimen, ICE produces CR rate ranging from 26% (response evaluation by CT, Moskowitz CH et al. Blood 2001) to 61% (by augmented ICE, response evaluation by PET, Moskowitz CH et al. Blood 2012). Panobinostat is a potent oral pan-deacetylase inhibitor that has shown activity against refractory or recurrent cHL after transplant with acceptable toxicity profile with a dose limiting toxicity of reversible thrombocytopenia (Younes A et al. JCO 2012). We conducted a phase I study of oral panobinostat in combination with standard ICE for patients who had recurrent or refractory disease after ABVD based chemotherapy. The treatment consisted of oral panobinostat on Monday/Wednesday/Friday starting from 1 week before first ICE, and to be continued during ICE through the second cycle. Third cycle was administered without panobinostat concerning the potential adverse impact on stem cell collection. The starting dose of panobinostat was 20mg, and the target dose was 30mg based on 3+3 design, with planned expansion at the highest dose. As the time of data cut off (July 2013), a total of 23 patients were registered and 21 were assessable for toxicity and response. The median age of patients were 31 (range 19-60), male/female 14/7 patients, primary refractory disease in 9 patients. At 20mg, dose limiting toxicity (DLT, febrile neutropenia) was observed in one of the 6 patients. At 30mg, 3 patients were enrolled without DLT. Thus, we expanded the cohort at 30mg in two different schedules (A: panobinostat to be started one week before first ICE, then 1st and 2nd week of ICE [n=10], B: panobinostat to be started one week before ICE, then only 1st week of ICE of each cycle [n=2, ongoing]). Overall, there was no grade 3/4 non-hematologic toxicity observed. The common non-hematologic toxicity of grade 1/2 (>10%) was fatigue (43%), nausea (43%), and vomit (29%). Hematologic toxicity included anemia (grade 1/2 in 24%, grade 3 in 5%), neutropenia (grade 1/2 in 5%, grade 3 in 10%, grade 4 in 57%), thrombocytopenia (grade 1/2 in 5%, grade 2 in 10%, grade 4 in 81%) and febrile neutropenia (grade 3 in 10%). All 21 patients were assessed for response and overall response rate was 86%, with complete response rate of 71%. All responding patients (86%) proceeded to autologous stem cell transplant after this regimen. Patients who did not have a stem cell collection after 3rd cycle of ICE received stem cell mobilizing chemotherapy. There were no issues with stem cell harvest and engraftment in any of patients. In conclusion, panobinostat plus ICE is an effective first salvage regimen for recurrent or refractory cHL. We are currently evaluating schedule B, which is with shorter treatment with panobinostat, in an expansion cohort in this phase I study. Disclosures:Oki:Novartis: Research Funding. Fowler:pharmacyclics: Research Funding, Scientific advisory board Other; Jannsen: Scientific advisory board, Scientific advisory board Other; Roche: Honoraria, Research Funding, Scientific advisory board, Scientific advisory board Other; Celgene: Research Funding, Scientific advisory board, Scientific advisory board Other; gillead: Research Funding, Scientific advisory board Other, Scietific advisory board. Younes:Novartis: Research Funding.