Oral Panobinostat Research Articles

A Phase III Randomized, Double Blind, Placebo Controlled Multi-Center Study Of Panobinostat For Maintenance Of Response In Patients With Hodgkin Lymphoma Who Are At Risk For Relapse After High Dose Chemotherapy and Autologous Stem Cell Transplant: Final Results After Early Trial Discontinuation

Introduction High dose chemotherapy with autologous stem cell transplant (ASCT) is the treatment of choice for Hodgkin Lymphoma (HL) patients suffering from relapse or progression after first line therapy. However, patients with recurrence after ASCT have a very poor prognosis. Thus, the oral deacetylase inhibitor panobinostat was evaluated as maintenance therapy for patients at risk for relapse after ASCT to prevent recurrences. Methods HL patients after ASCT with at least one of the risk factors: primary refractory disease, early relapse (<12 months), multiple relapses, stage III/IV disease or hemoglobin <10,5 g/dl at relapse prior to transplant were randomized to receive oral panobinostat (45mg three times a week, every other week, QOW) or placebo (2:1 randomization) in this phase III randomized, double blind, placebo controlled multi-center trial. As per the original protocol, disease-free survival (DFS) was the primary endpoint. However, the trial was terminated prematurely due to slow recruitment and the new primary objective was the provision of drug to ongoing patients randomized to panobinostat in an open label phase and to the evaluation of safety in the whole patient population. Results The study was closed to enrollment and data were unblinded with only a total of 41 patients out of the planned 367 patients enrolled; 27 patients in the panobinostat arm and 14 patients in the placebo arm. Three patients (1 from the panobinostat arm and 2 from the placebo arm) never received treatment. Data are reported for patients treated during the randomized phase and no formal statistical analyses were conducted. The median duration of treatment was longer in the placebo arm (217 days) than in the panobinostat arm (176 days, randomized phase). The majority of patients in both treatment arms had an exposure of ≥ 24 weeks (53.8% in the panobinostat arm, 75% in the placebo arm). In the panobinostat arm, the most common reasons that patients discontinued were due to withdrawal of consent (29.8%) and adverse events (22.2%), whereas in the placebo arm, patients most commonly discontinued due to disease progression (28.6%). Most adverse events (AEs) occurred more frequently in the panobinostat arm (randomized phase). The most frequently reported AEs as compared to the placebo arm included: diarrhea (88.5%/25%), nausea (57.7%/8.3%), vomiting (46.2%/25%), fatigue (34.6%/25%), neutropenia (26.9%/33.3%), thrombocytopenia (26.9%/8.3%), oropharyngeal pain (26.9%/0%), headache (23.1%/0%), nasopharyngitis (19.2%/0%), upper respiratory infection (19.2%/8.3%), decreased appetite (15.4%/16.7%), pyrexia (15.4%/8.3%), influenza like illness (15.4%/0%) and sinusitis (15.4%/8.3%). Overall, the incidence of grade 3/4 AEs was 65.4% in the panobinostat arm during the randomized phase and 41.7% in the placebo arm. In the panobinostat arm, the most frequently reported grade 3/4 AEs were neutropenia (26.9%), thrombocytopenia (15.4%), and diarrhea, vomiting and fatigue (all 11.5%). In the placebo arm, the most frequently reported grade 3/4 AEs were neutropenia (33.3%), leukopenia (16.7%) and herpes zoster (16.7%). Although efficacy could not be formally evaluated due to the small number of patients in this trial, it is interesting to note that more patients from the placebo arm discontinued from the study due to disease progression (28.6% vs. 14.8% panobinostat patients). Conclusion The safety observations from this study were consistent with the general safety profile known for panobinostat. The use of panobinostat in a maintenance setting in a QOW schedule appeared to have acceptable tolerability in a population of patients with HL who are at risk for relapse after high dose chemotherapy and ASCT. Disclosures: von Tresckow: Takeda: Honoraria, Reimbursement of congress, travel, and accommodation costs , Reimbursement of congress, travel, and accommodation costs Other; Novartis: Consultancy, Honoraria. Szer:Novartis: Membership on an entity’s Board of Directors or advisory committees. Sureda:Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Engert:Seattle Genetics, Inc.: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Takeda: Honoraria.

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.

Time To Event Analyses in PANORAMA 2: A Phase 2 Study Of Panobinostat, Bortezomib, and Dexamethasone In Patients With Relapsed and Bortezomib-Refractory Multiple Myeloma

Time To Event Analyses in PANORAMA 2: A Phase 2 Study Of Panobinostat, Bortezomib, and Dexamethasone In Patients With Relapsed and Bortezomib-Refractory Multiple Myeloma

A phase 1/2 study of oral panobinostat combined with melphalan for patients with relapsed or refractory multiple myeloma

Panobinostat is a histone deacetylase inhibitor that has shown synergistic preclinical anti-myeloma activity when combined with other agents, recently exhibiting synergy with the alkylating agent melphalan (Sanchez et al., Leuk Res 35(3):373-379, 2011). This phase 1/2 trial investigated the safety and efficacy of panobinostat in combination with melphalan for relapsed/refractory multiple myeloma patients. There were four different trial treatment schedules due to tolerability issues, with the final treatment schedule (treatment schedule D) consisting of panobinostat (15 or 20 mg) and melphalan (0.05 or 0.10 mg/kg), both administered on days 1, 3, and 5 of a 28-day cycle. A total of 40 patients were enrolled; 3 in treatment schedule A, 9 in schedule B, 7 in schedule C, and finally 21 schedule D. Patients had been treated with a median of four regimens (range, 1-16) and two prior bortezomib-containing regimens (range, 0-9). Maximum-tolerated dose was established at 20 mg panobinostat and 0.05 mg/kg melphalan in treatment schedule D. Overall, 3 patients (7.5 %) achieved ≥partial response (two very good PRs and one PR) while 23 exhibited stable disease and 14 showed progressive disease. All three responders were enrolled in cohort 2 of treatment schedule B (panobinostat 20 mg thrice weekly continuously with melphalan 0.05 mg/kg on days 1, 3, and 5). Neutropenia and thrombocytopenia were common, with 30.8 and 23.1 % of patients exhibiting ≥grade 3, respectively. Panobinostat + melphalan appears to have tolerability issues in a dosing regimen capable of producing a response. Care must be taken to balance tolerability and efficacy with this combination.

Interim analysis of a phase I/II study of panobinostat in combination with bevacizumab for recurrent glioblastoma.

2013 Background: Bevacizumab is frequently used to treat recurrent GBM, but responses are generally not durable. Panobinostat is a histone deacetylase inhibitor with anti-neoplastic and anti-angiogenic effects in GBM and may work synergistically with bevacizumab. We conducted a multicenter phase I/II trial of panobinostat in combination with bevacizumab in patients with recurrent GBM. Methods: In the phase II trial, patients with recurrent GBM were treated with oral panobinostat 30 mg three times per week, every other week, in combination with bevacizumab 10 mg/kg every other week. The primary endpoint was 6-month progression-free survival (PFS6) and the study was powered to discriminate between a 35% and 55% PFS6 rate (85% power at an alpha level of 0.07). A planned interim analysis specified suspension of accrual and careful data review if 12 or more of the first 21 patients accrued to the study progress within 6 months of initiating treatment. Patients with recurrent GBM enrolled in the phase I study at the maximum tolerated dose (which is the phase II dose) were eligible for inclusion in the interim analysis. Results: Thirteen of the first 21 patients accrued to the GBM arm of the study had progressed within 6 months of initiating study treatment. The study was closed to further accrual and a planned interim analysis was performed. Median age was 53 (range 22-66) and median KPS was 80% (60%-100%). PFS6 rate was 33.9% [95% CI 12.8, 56.5), median was PFS 5 months [95% CI 3 months, NR], and median OS was 342 days [95% CI 203 days, NR]. Five patients (23.8%) achieved partial responses. Conclusions: Although reasonably well-tolerated, this phase I/II study of panobinostat and bevacizumab in recurrent GBM did not meet criteria for continued accrual and the study was closed. Updated outcome and safety data will be presented at the meeting. Study Supported by: Novartis and Genentech Clinical trial information: NCT00859222.

Phase Ia/II, two-arm, open-label, dose-escalation study of oral panobinostat administered via two dosing schedules in patients with advanced hematologic malignancies

Panobinostat is a potent oral pandeacetylase inhibitor that leads to acetylation of intracellular proteins, inhibits cellular proliferation and induces apoptosis in leukemic cell lines. A phase Ia/II study was designed to determine the maximum-tolerated dose (MTD) of daily panobinostat, administered on two schedules: three times a week every week or every other week on a 28-day treatment cycle in patients with advanced hematologic malignancies. The criteria for hematologic dose-limiting toxicities differed between patients with indications associated with severe cytopenias at baseline (leukemia and myeloid disorders) and those less commonly associated with baseline cytopenias (lymphoma and myeloma). In patients with leukemia and myeloid disorders, 60 mg was the MTD for weekly as well as biweekly panobinostat. In patients with lymphoma and myeloma, 40 mg was the recommended dose for phase II evaluation (formal MTD not determined) of weekly panobinostat, and 60 mg was the MTD for biweekly panobinostat. Overall, panobinostat-related grade 3-4 adverse events included thrombocytopenia (41.5%), fatigue (21%) and neutropenia (21%). Single-agent activity was observed in several indications, including Hodgkin lymphoma and myelofibrosis. This phase Ia/II study provided a broad analysis of the safety profile and efficacy of single-agent panobinostat in patients with hematologic malignancies.

Initial Results of the Phase I/II Panobidara Study of Panobinostat in Combination with Idarubicin and Cytarabine in Patients Aged 65 Years or Older with Newly Diagnosed Acute Myeloblastic Leukaemia (AML)

AbstractAbstract 1512 Introduction:Acute Myeloblastic Leukemia (AML) in elderly patients remains an unmet medical need with a long term survival rate inferior to 10% despite the use of novel drugs. Therefore, there is a need for new agents that could induce higher CR rates and, most importantly, that could prolong the relapse free survival (RFS) and the overall survival (OS) of these poor-prognosis patients. Agents targeting epigenetics such as the hypomethylating drug 5-Azacitidine, have emerged as a promising strategy for elderly patients with AML or MDS. A second group of drugs targeting the epigenome are deacetylase inhibitors. Panobinostat is a pan-deacetylase inhibitor, with clear in vitro activity in AML and which is synergistic with anthracyclines (Maiso et al. Leukemia 2009). Based on these data we designed a phase I/II trial of panobinostat in combination with idarubicine and cytarabine followed by panobinostat maintenance in newly diagnosed AML patients older than 65 years. Methods:The initial schema included one or two induction cycles with idarubicine (8 mg/m2 days 1–3) + cytarabine (100 mg/m2 days 1–7) followed by escalating doses of panobinostat three days per week, per 3 weeks starting at 20 mg. Patients achieving CR/CRi received a consolidation cycle with the same schema. Those patients remaining in CR/CRi started a maintenance phase with 40 mg oral panobinostat in monotherapy three days per week, for 3 weeks in 28-days cycles. This schedule was amended after the six first patients, to reduce the weeks of administration of panobinostat to two weeks in the cycles in combination and to every other week in the maintenance phase. Initially a dose-escalating phase I with the classical 3+3 schema was carried out to define the maximum tolerated dose (MTD) of panobinostat in this combination; and then a phase 2 expansion phase was started to determine the efficacy of this combination in terms of CR rate and RFS. Results:21 patients have been included after the amendment. Median age was 71 (range 66–83). Median % blasts was 40 (20–93). 35% of patients had AML with dysplastic features while adverse cytogenetics were present in 24%.Two out of 6 evaluable patients in the first cohort developed DLTs with panobinostat 20 mg (G3 hyperbilirrubinaemia in both, and one of them also G3 oedema), accordingly the dose of panobinostat was reduced to 10 mg. No DLTs were observed at this dose level, so 10 mg panobinostat was defined as the MTD in this combination. Treatment was well tolerated in the intensive cycles with the toxicity proper of standard induction chemotherapy. The most common non-hematologic toxicities (occurring in ≥20% of patients) included: fever (90%), infections (62%), mucositis (52%), diarrhoea (62%), constipation (43%), vomiting (57%), skin rash (38%), hepatotoxicity (38%) and hypokalaemia (24%). Grade 3/4 AEs were fever, infection, diarrhoea and hepatotoxicity in 2 patients each (10%) and hypokalaemia in 5 (24%). The median duration of the aplasia was 32 days (range 26–51). Regarding the maintenance phase with panobinostat monotherapy, the most frequent AEs were gastrointestinal: diarrhoea (62%), vomiting (62%) or abdominal pain (25%); as well as asthenia (50%. One of them being G3) and hyporexia (25%).In terms of efficacy, 11 patients (52%) achieved CR plus 2 more (10%) achieving CR with incomplete blood recovery (CRi) (overall 62%). There were 2 deaths in induction (10%), one due to a tumoral lysis syndrome before starting panobinostat and the other secondary to a respiratory infection. From the remaining 6 patients, 2 achieved partial response (10%) and 4 showed refractory disease (19%). With a median follow up of 6 months (range 2–14), among the 11 patients that achieved CR, 10 of them remain in CR and only 1 has progressed (in the 9th maintenance cycle). Both patients that achieved CRi have progressed in the 2nd and 6thmaintenance cycles. The median overall survival for the whole population is 13 months (2.3–23.6), and has not been reached for patients achieving CR. Conclusion:To the best of our knowledge, this is the first report of the use of a histone deacetylase inhibitor with chemotherapy in elderly AML patients. This combination was shown to be safe at the MTD. Although preliminary results are encouraging, particularly for the potential benefit of the maintenance phase, longer follow up is needed to evaluate if panobinostat maintenance is able to prolong RFS and subsequently OS in this poor prognostic population. Disclosures:Ocio:Novartis: Consultancy, Research Funding. Off Label Use: Panobinostat in newly diagnosed AML. Aliseda:Novartis: Employment. Winiger:Novartis: Employment. Hardikar:Novartis: Employment. Mateos:Novartis: Consultancy. San-Miguel:Novartis: Consultancy, Research Funding.

Bortezomib (BTZ) and Panobinostat (PAN) Combination Is Effective in Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma (PTCL) or NK/T-Cell Lymphoma (NKL) and Maintenance Treatment May Be Essential for Sustained Response

AbstractAbstract 3669 Background:Relapsed/refractory PTCL and NKL after conventional chemotherapy carry a poor prognosis and there is currently no proven salvage treatment available. Numerous preclinical studies have demonstrated synergistic interactions between proteasome and histone deacetylase (HDAC) inhibitors. Inhibition of HDAC6 by PAN abrogates BTZ-induced protective aggreosome formation and accentuates BTZ induced endoplasmic reticulum stress, leading to further apoptosis. Primary end point of this ongoing phase II multi-center open-label clinical study (NCT00901147) is the objective response rate (ORR) according to the Revised Response Criteria (2007) among eligible patients (pts) treated with this novel combination of BTZ and PAN. Secondary end points include the evaluation of the progression-free survival (PFS) and the assessment of the safety and tolerability of the combination. Methods:Pts with histologically confirmed PTCL or NKL who failed or were refractory to 1 prior systemic therapy, and had measurable disease and ECOG performance status 0–2 were eligible. Pts were accrued according to a 2-stage Gehan design. Pts receive thrice weekly oral PAN (20 mg) and twice weekly BTZ (IV 1.3 mg/m2), both for 2 of 3 weeks for up to 8 cycles. Preliminary response data were available for all 11 pts recruited for stage 1 of the study. A response rate of >25% will allow the study to proceed to stage 2. Results:Among pts enrolled, histologies included: angioimmunoblastic T-cell lymphoma (AITL) n=4, PTCL (unspecified) n=4, ALK+ Anaplastic large cell lymphoma n=1 and NKL, nasal type n=2. The median age was 52 (35–72) years, and 70% were male. The ORR was 54.5% with 18% attaining a complete response. Four pts (36%) had a partial response, and stable disease was noted in 2 (18%). Pts received a median of 2 prior therapies (range 1–3); 27% received an autogous stem cell transplantation (SCT). Common treatment-related grade 3/4 adverse events included thrombocytopenia (36%), neutropenia (27%), diarrhoea (18%) and fatigue (9%). Peripheral neuropathy of any grade was observed in 35%. Among pts who responded or had stable disease, the median PFS was 6 months and disease progression occurred at a median of 2.5 months after stopping trial drugs. Two deaths have occurred: 1 due to progressive disease and 1 associated with an unrelated cardiac event. 3 pts successfully underwent subsequent allogeneic SCT. Conclusions:The study regimen shows activity across T/NK-cell lymphomas and ORR greatly exceeds the predefined threshold of 25% allowing, together with early tolerability data, continuation of study enrolment in stage 2. The early progression of the disease after stopping trial drugs albeit the high initial ORR suggests that the novel combination provides a tonic suppression of tumor proliferation and ongoing treatment will be beneficial for pts without option for subsequent alternative treatment like SCT. An extended phase of maintenance treatment will be incorporated into stage 2 of the study to allow pts to optimally benefit from the combination. Our interim findings may have implications on the design of future studies seeking proteasome and HDAC inhibition in PTCL or NKL. Ongoing correlative studies are designed to determine if the study regimen is more active in diseases with up-regulation of NF-kappa B activity or transcription factors/co-regulators known to be modified by acetylation. Disclosures:Tan:Novartis: Research Funding; Janssen: Equity Ownership, Honoraria, Research Funding. Goh:Novartis: Honoraria, Research Funding; Jansen: Honoraria, Research Funding.

PANORAMA 2: Panobinostat Combined with Bortezomib and Dexamethasone in Patients with Relapsed and Bortezomib-Refractory Multiple Myeloma

Abstract Abstract 1852 Background: There are limited treatment options for patients (pts) with multiple myeloma (MM) whose disease is refractory to bortezomib (BTZ) and are relapsed and/or refractory, intolerant or ineligible to receive an immunomodulatory (IMiD) drug. These pts have a poor prognosis with a response rate for subsequent BTZ-containing regimens of 20% and median event-free survival of 5 months (Kumar S, et al. Leukemia. 2011). Panobinostat (PAN) is an oral pan-deacetylase inhibitor (pan-DACi) that has low nanomolar activity against all class I, II, and IV histone deacetylase enzymes, including those implicated as potential targets in MM. PAN synergizes with BTZ to inhibit both the aggresome and proteasome pathways in preclinical studies. Phase 1 results with PAN + BTZ demonstrated clinical responses in pts with BTZ-refractory disease. PANORAMA 2 expands upon these results and evaluates whether PAN can recapture responses in BTZ-refractory MM pts. Methods: Pts with relapsed and BTZ-refractory MM (≥2 prior lines of therapy including an IMiD and who had progressed on or within 60 days of the last BTZ-based therapy) were treated in this single-arm, phase 2 study with PAN + BTZ + dexamethasone (Dex) in 2 phases. Treatment phase 1 (TP1) consisted of 8 three-week cycles of oral PAN (20 mg) + intravenous BTZ (1.3 mg/m2) + oral Dex (20 mg). Pts demonstrating clinical benefit (≥stable disease [SD]) could proceed to treatment phase 2 (TP2), which consisted of 6-week cycles until disease progression. The primary endpoint was overall response rate (≥partial response [PR]), as defined by the European Group of Blood and Marrow Transplantation (EBMT) 1998 criteria, in TP1. Secondary efficacy endpoints included minimal response (MR), time to response (TTR), duration of response (DOR), progression-free survival (PFS), time to progression (TTP), and overall survival (OS). Secondary safety endpoints included safety and tolerability. Results: Fifty-five pts with BTZ-refractory MM were enrolled (median age, 61 years [range, 41–88 years]). Pts were heavily pretreated with a median of 4 prior regimens (range, 2–11), and a median of 2 prior BTZ-containing regimens (range, 1–6). All pts (100%) were previously treated with BTZ, Dex, and at least 1 IMiD (lenalidomide [98%], thalidomide [69%]). The majority of pts received prior autologous stem cell transplant (64%). Forty-five pts (82%) received Dex with their last BTZ-containing regimen. In the most recent prior line of therapy, 27 pts (49%) had BTZ. As of the February 20, 2012, cutoff, all pts had completed TP1 or stopped treatment, and 7 of the 18 pts who entered TP2 were ongoing. The overall response rate was 35% (1 near complete response [nCR] and 18 PR or better, with 3 pts [5%] achieving a very good partial response [VGPR; Table]). An additional 10 pts achieved MR, for a clinical benefit rate of 53%. The median duration of exposure was 4.6 months (range, < 1–14.8 months). The median PFS and TTP were 4.9 months. The PFS rates for pts whose disease progressed on BTZ (n = 39) and within 60 days of BTZ (n = 16) were 4.2 and 7.6 months, respectively. In pts who achieved a response, the mean TTR was 1.7 months (range, 0.1–3.9), and the median DOR was 6.0 months. With a median follow-up time of 8.1 months, the median OS has not been reached. Common adverse events (AEs) of any grade regardless of study drug relationship included diarrhea (71%), fatigue (69%), thrombocytopenia (65%), nausea (60%), anemia (47%), dyspnea (44%), decreased appetite (42%), and peripheral edema (40%). Common grade 3/4 AEs regardless of study drug relationship included thrombocytopenia (64%), fatigue (20%), diarrhea (20%), anemia (15%), pneumonia (15%), and neutropenia (15%). Only 1 pt (2%) experienced grade 3 peripheral neuropathy. Conclusions: PAN, when combined with BTZ and Dex can recapture responses in heavily pretreated, BTZ- and Dex-refractory MM pts. The regimen was tolerable with manageable toxicities, with 33% of pts on therapy for > 8 cycles. The combination of PAN, BTZ and Dex is therefore an important potential therapeutic option for relapsed and refractory MM pts, including those with BTZ, Dex, and IMiD resistance. Disclosures: Richardson: Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Alsina:Millenium: Consultancy, Research Funding. Weber:Novartis: Research Funding. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Onyx: Consultancy; Merck: Consultancy. Gasparetto:Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mukhopadhyay:Novartis: Employment. Ondovik:Novartis: Employment, Equity Ownership. Khan:Novartis: Employment. Paley:Novartis: Employment, Equity Ownership. Schlossman:Celgene: Membership on an entity's Board of Directors or advisory committees.

A phase I trial of oral administration of panobinostat in combination with paclitaxel and carboplatin in patients with solid tumors

To determine the maximum tolerated doses and dose-limiting toxicities of oral panobinostat in combination with paclitaxel and carboplatin when administered to patients with advanced solid tumors. Patients initially received panobinostat twice weekly. Following amendment #1, patients received panobinostat three times weekly. Paclitaxel and carboplatin were administered intravenously on day 1 of each 21-day treatment cycle. Dose escalation continued until the maximum tolerated dose was determined. A total of 10 patients were treated at the recommended phase II dose to further assess safety. Twenty-one patients were enrolled across four different dose levels. The dose-limiting toxicity of the combination regimen was myelosuppression (neutropenia and thrombocytopenia), which often warranted panobinostat dose omissions or reductions. Nearly two-thirds of the patients experienced grade 4 neutropenia or grade 3 or 4 thrombocytopenia. Non-hematologic toxicities consisted primarily of diarrhea, fatigue, and vomiting, which were mild to moderate in intensity. No QTc prolongation was reported. Three partial responses were confirmed in patients with carcinoma of unknown primary (two patients) and non-small-cell lung cancer (one patient). Eleven additional patients reported stable disease as their best response to treatment. The recommended phase II dose is panobinostat 10 mg orally three times weekly in combination with paclitaxel 175 mg/m(2) and carboplatin AUC 5 administered intravenously on day 1 of every 21-day cycle.

A phase I/II trial of melphalan (MEL) combined with panobinostat (PAN) for patients with relapsed or refractory (R/R) multiple myeloma (MM).

e18558 Background: PAN, a potent histone deacetylase inhibitor, significantly inhibits the growth of MM cells in vitro and enhances the cytotoxicity of standard chemotherapy. Studies with our SCID-hu MM models show an increased inhibition of MM cell growth when PAN was combined with MEL compared to treatment with either drug alone. These preclinical studies provided the rationale for evaluating the combination of oral MEL with oral PAN for the treatment of MM patients with R/R disease. Methods: This was a Phase 1/2, open-label, dose‑escalation study to treat R/R MM patients initially using oral PAN every Monday, Wednesday and Fridayin combination with oral MEL (0.05 mg/kg) on days 1-5 of a 28‑day cycle. Results: Thirty-seven patients were enrolled into the Phase 1 portion of this study. The median number of prior regimens received were 4 (range, 1-17) with 22 patients previously treated with MEL. Following amendments to dose and schedule because of toxicity including cytopenias and fatigue, PAN and MEL were both administered only on days 1, 3 and 5 of a 28-day cycle. The maximum tolerated dose for this combination was defined as PAN at 20 mg and MEL at 0.05 mg/kg both administered on only days 1, 3 and 5. Overall, 4 patients (11%) showed objective responses to this combination with 1 complete (3%) and 3 partial (8%) responses and only occurred among patients receiving PAN throughout the cycle. An additional 18 (49%) patients had stable disease while 15 (41%) progressed while on study. Eighteen patients experienced grade 3 or 4 adverse events (AEs) with 6 of these meeting the definition of a dose-limiting toxicity. These AEs included reversible thrombocytopenia (n=11), reversible neutropenia (n=10), reversible worsening anemia (n=3), and one case each of a forearm rash, fatigue/weakness, pneumonia, hypokalemia and hyponatremia. Three more patients who are not yet evaluable have been enrolled into the Phase 2 portion to complete the planned 40 patients on the trial. Conclusions: The combination of intermittent PAN & low-dose oral MEL shows modest activity in heavily pretreated patients with R/R MM. Continuous doses of PAN with MEL yielded better efficacy but this treatment schedule was not tolerable.

PANORAMA 2: A phase II study of panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory multiple myeloma.

8012 Background: Patients (pts) with multiple myeloma (MM) refractory to bortezomib (BTZ) and an immunomodulatory drug have limited treatment options and a poor prognosis. In a phase I study of pts with relapsed or relapsed/refractory MM treated with panobinostat (PAN) + BTZ, clinical responses were observed overall and in pts with BTZ-refractory disease. We report results in PANORAMA 2, a trial in relapsed and BTZ-refractory pts. Methods: PANORAMA 2 is a single-arm, phase II study of PAN + BTZ + dexamethasone (Dex) in pts with relapsed and BTZ-refractory MM. Treatment phase 1 (TP1) consists of eight 3-week cycles of oral PAN + intravenous BTZ + oral Dex. Pts demonstrating clinical benefit enter treatment phase 2 (TP2) which consists of four 6-week cycles of PAN + BTZ + Dex. The primary endpoint is overall response (≥ partial response [PR]) in TP1. Results: Fifty-five pts with BTZ-refractory MM were enrolled with 10 pts ongoing and 28 in follow-up. The median age was 61 years (range 41-88 years). Pts were heavily pretreated: the median number of prior regimens was 4 (range 2-11), and most pts (64%) received prior autologous stem cell transplant. Twenty-seven (49%) and 36 (65%) pts had BTZ and Dex in their most recent prior line of therapy, respectively. Eighteen pts achieved ≥ PR for an overall response rate of 33% (1 near complete response and 17 PR), and 13 pts achieved MR for a clinical benefit rate of 56%. Three pts achieved a VGPR. Eighteen pts completed TP1 and entered TP2, and 2 have completed ≥ 12 cycles. Common adverse events (AEs) of any grade included thrombocytopenia (66%), fatigue (64%), diarrhea (62%), nausea (58%), dyspnea (40%), anemia (38%), decreased appetite (36%), and dizziness (36%). Common grade 3/4 AEs included thrombocytopenia (58%), fatigue (17%), anemia (15%), pneumonia (15%), neutropenia (13%), and diarrhea (13%). Only 1 pt (2%) experienced grade 3/4 peripheral neuropathy. Conclusions: PAN synergizes with BTZ in recapturing responses in heavily pretreated, BTZ-refractory MM pts. The combination of PAN and BTZ is a promising treatment for pts with BTZ-refractory MM that is generally well tolerated, with several pts receiving therapy long term.

Phase II study of melphalan, thalidomide and prednisone combined with oral panobinostat in patients with relapsed/refractory multiple myeloma

The combination of melphalan, prednisone and thalidomide (MPT) has demonstrated efficacy and acceptable toxicity in newly diagnosed and relapsed/refractory patients with multiple myeloma (MM). Panobinostat is a potent oral pan-deacetylase inhibitor (pan-DACi). In preclinical and clinical studies, panobinostat showed good anti-myeloma activity in combination with several agents. This phase II study evaluated the combination of a fixed dose of MPT with escalating doses of panobinostat (three times weekly for 3 weeks, followed by a 9-day rest period) in relapsed/refractory MM. We used a two-stage design to determine whether the combination was safe and effective. At least a partial response was observed in 38.5% of patients. The maximum tolerated dose of panobinostat in combination with MPT could not be determined due to the high rate of dose-limiting toxicities experienced with panobinostat at doses of 10 and 15 mg. The most common grade 3/4 adverse events were neutropenia (71%) and thrombocytopenia (35.5%). In conclusion, MPT in combination with panobinostat three times weekly for 3 weeks followed by a 9-day rest period is not well tolerated in patients with relapsed/refractory MM. Future studies should evaluate alternative dose schedules of panobinostat.

Determination of a Phase II Dose of Panobinostat in Combination with 5-Azacitidine in Patients with Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Acute Myeloid Leukemia

Abstract 459 BACKGROUND:5-Azacitidine (AZA), a demethylating agent, is approved for treatment of myelodysplastic syndromes (MDS) and provides complete remission (CR) in 17% of patients (pts) and a median overall survival of 24.5 months, thus highlighting an unmet need in this population. Panobinostat, a potent pan-deacetylase inhibitor (pan-DACi), has demonstrated anti-tumor activity in pts with MDS and acute myeloid leukemia (AML). Preclinical studies suggest a combination of AZA and a pan-DACi may, in part through synergistic gene reactivation and apoptosis induction, improve outcomes in pts with MDS, AML, and chronic myelomonocytic leukemia (CMML) and appears to be a promising new approach in this population. AIMS:The primary objective of this phase I, open-label, multicenter, dose-escalation study is to determine maximum tolerated dose (MTD) of panobinostat with a fixed dose of AZA. Secondary objectives are to characterize safety and tolerability, with an exploratory objective to evaluate preliminary anti-leukemic activity of panobinostat in combination with AZA. METHODS:Adult pts (ECOG ≤ 2) with IPSS intermediate-2 or high-risk MDS, CMML, or AML with multi-lineage dysplasia and 20%–30% marrow blasts, not initially eligible for hematopoietic stem-cell transplantation, were treated with oral panobinostat (20 mg/day starting dose and 10-mg dose increments) during a 28-day cycle on days 3, 5, 8, 10, 12, and 15 in combination with a fixed dose of AZA (75 mg/m2 sc) on days 1–7 of each cycle. On the basis of the occurrence of dose-limiting toxicities (DLTs) during the first treatment cycle and an overall assessment of safety and tolerability data from all cycles, a phase II dose was recommended. Safety and tolerability were described as type, duration, frequency, relatedness, and severity of adverse events (AEs) according to CTCAE, v3.0. The adaptive Bayesian logistic regression model was used to guide panobinostat dose escalation with overdose control at all dose levels. Cycle extension, up to day 42, is allowed in cases of toxicity. The minimum exposure criterion for determining MTD was 6 scheduled doses of panobinostat and 7 scheduled doses of AZA during cycle 1. RESULTS:A total of 31 pts, with a median age of 70 years (range 34–81), in 3 cohorts were enrolled. Of these pts, 6 were treated at a dose level of 20 mg, 18 at 30 mg, and 7 at 40 mg of panobinostat; 28 pts were evaluable for MTD. Safety and efficacy data are based on 29 and 16 pts, respectively. One DLT (febrile neutropenia) was observed at 20 mg, 3 DLTs (dehydration/fatigue, colitis, a 1-day echocardiogram T-wave inversion, and an atrial fibrillation/syncope) were seen at 30 mg, and 2 DLTs (hyperbilirubinemia and nausea/vomiting) were reported in the 40-mg cohort. On the basis of the occurrence of DLTs and overall safety and tolerability data in cycle 1, dose levels at and above 40 mg were not further evaluated. Additional pts were enrolled at 30 mg. The most frequent AEs suspected to be related to the study treatment were gastrointestinal issues and fatigue. Grade 3/4 treatment-related AEs included thrombocytopenia (8 [28%]), neutropenia (5 [17%]), and febrile neutropenia (6 [21%]). Other frequent AEs of all grades, regardless of study drug relationship, included nausea (19 [67%]), fatigue (18 [62%]), diarrhea (16 [55%]), vomiting (15 [52%]), thrombocytopenia (13 [45%]), and decreased appetite (12 [41%]). The most common serious AEs (SAEs), regardless of study drug relationship, were febrile neutropenia (8 [28%]) and asthenia (5 [17%]). Based on the DLTs observed in cycle 1 and overall assessment of safety and tolerability, a phase II dose of 30 mg was recommended. Preliminary efficacy data for 8 pts with AML and 8 with MDS/CMML show 4 pts (2 at 30 mg, 2 at 40 mg) achieving CR or morphological CR (CRi) and 6 pts (4 at 30 mg, 2 at 40 mg) showing stable disease (SD). Hematologic improvement was seen in 4 pts, 2 of whom relapsed. CONCLUSIONS:Current data show that oral panobinostat at 30 mg/day on days 1, 3, 5, 8, 10, and 12 of a 28-day cycle can be safely combined with AZA at the registered label dose in pts with intermediate-2 or high-risk MDS, CMML, or AML. Additional pts will be evaluated in an expansion phase to further characterize the safety profile and activity at the 30-mg dose level. To date, preliminary efficacy shows that CR/CRi was achieved in 4 pts, SD was achieved in 6 pts, and HI was observed in 4 pts. Disclosures:Ottmann:Novartis Corporation: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding. DeAngelo:Novartis Corporation: Membership on an entity's Board of Directors or advisory committees. Sekeres:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Zahlten:Novartis AG: Employee of Novartis, Employment. Squier:Novartis Corporation: Employment. Acharyya:Novartis Corporation: Employment. Winiger:Novartis AG: Employment, Equity Ownership, Honoraria. Fenaux:Celgene Corporation: Honoraria, Research Funding; Amgen: Honoraria; Roche: Research Funding; Janssen Cilag: Research Funding.

Determination of the Maximum Tolerated Dose of Panobinostat in Combination with Cytarabine and Mitoxantrone As Salvage Therapy for Relapsed/Refractory Acute Myeloid Leukemia

Abstract 423 BACKGROUND:Relapsed/refractory acute myeloid leukemia (AML) is characterized by poor prognosis, with low complete remission (CR) rates after salvage therapy and low overall survival. A major challenge is to improve the CR rate, thereby increasing allogeneic hematopoietic stem cell transplantation (alloHSCT) rates. Panobinostat is a pan-deacetylase inhibitor that increases acetylation of proteins involved in cancer. Preclinical studies in AML demonstrated that panobinostat potentiates the activity of cytarabine (ara-C) and fludarabine and has synergistic activity in combination with doxorubicin in vitro. Single-agent panobinostat has induced CR in patients (pts) with AML. The addition of panobinostat to an active chemotherapeutic regimen in pts with relapsed/refractory AML has the potential to improve therapeutic outcomes in this setting. AIMS:This phase Ib, multicenter, open-label dose-escalation study was designed to determine the maximum tolerated dose (MTD) of panobinostat in combination with a fixed dose of ara-C and mitoxantrone in pts with relapsed/refractory AML. The secondary objectives were to characterize safety and tolerability during the dose-escalation phase and at the MTD and to evaluate anti-leukemic activity. METHODS:Successive cohorts of at least 3 pts with confirmed relapsed or refractory AML were treated with oral panobinostat (starting with 20 mg, escalated in 10-mg steps) thrice weekly on days 1, 3, 5, 8, 10, and 12, in combination with intravenous ara-C (1 g/m2) on days 1–6 and mitoxantrone (5 mg/m2) on days 1–5 of a 28-day cycle. The MTD was determined on the basis of the observed dose-limiting toxicities (DLTs), safety assessment, and tolerability during the first 28 days after starting panobinostat. A DLT was defined as any adverse event (AE) or abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medications with the following criteria: neutropenia lasting > 28 days after cycle 1 for hematologic DLTs; grade 4 AST/ALT or grade 3 AST/ALT for > 7 days; grade 3/4 bilirubin, vomiting, diarrhea, or any non-hematologic toxicity for non-hematologic DLTs. Safety and tolerability were described as type, duration, frequency, relatedness, and severity of AEs according to CTCAE v3.0. The adaptive Bayesian logistic regression model was used to guide dose escalation with overdose control. RESULTS:Of 5 dose levels, 40 pts (median age, 55 years; range, 19–73 years) were treated at panobinostat dosages of 20 to 60 mg, with 5 pts at 20 mg, 8 at 30 mg, 10 at 40 mg, 11 at 50 mg, and 6 at 60 mg. Of 6 DLTs observed, 1 was at 40 mg (sepsis and tachyarrhythmia), 2 were at 50 mg (vomiting/nausea; diarrhea), and 3 were at 60 mg (neutropenic colitis; 2 hypokalemic events). Frequent AEs of all grades, regardless of causality, included nausea (32 [80%]), diarrhea (31 [78%]), vomiting (26 [65%]), hypokalemia (25 [63%]), thrombocytopenia (24 [60%]), abdominal pain (22 [55%]), decreased appetite, and febrile neutropenia (21 each [53%]). The most frequent grade 3/4 treatment-related AEs were thrombocytopenia (20 [50%]), anemia (9 [23%]), leukopenia, and neutropenia (7 each [18%]). Serious AEs, regardless of causality, were reported in 23 pts, with febrile neutropenia (12 [30%]) being the most common. The MTD was determined to be 50 mg of panobinostat on the basis of observed DLTs and safety and tolerability in cycle 1 of the dose-escalation phase. Clinical responses were observed in 22 pts (55%), including 13 CR, 5 morphological CR, and 4 partial remissions. In pts receiving 40- and 50-mg doses of panobinostat, the preliminary efficacy was promising, with a response in 11 of 21 pts (52%). An alloHSCT was performed in 8 pts after the start of salvage therapy. CONCLUSIONS:The combination of panobinostat, ara-C, and mitoxantrone showed no unexpected toxicities and promising anti-leukemic activity in pts with relapsed/refractory AML. The MTD was determined to be 50 mg of panobinostat; enrollment at this dose is ongoing for the dose-expansion phase to further assess safety, tolerability, and activity. Thrombocytopenia and anemia were the principal treatment-related hematologic AEs. Treatment-related non-hematologic AEs were primarily gastrointestinal toxicities and fatigue. Disclosures:Krauter:Novartis: Consultancy, Honoraria. Winiger:Novartis AG: Employment, Equity Ownership, Honoraria. Squier:Novartis Corporation: Employment. Zahlten:Novartis AG: Employment. Wang:Novartis Corporation: Employment. Ottmann:Novartis Corporation: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding.

Phase II Study of the Pan-Deacetylase Inhibitor Panobinostat in Combination with Bortezomib and Dexamethasone in Relapsed and Bortezomib-Refractory Multiple Myeloma (PANORAMA 2)

Phase II Study of the Pan-Deacetylase Inhibitor Panobinostat in Combination with Bortezomib and Dexamethasone in Relapsed and Bortezomib-Refractory Multiple Myeloma (PANORAMA 2)

Phase II study of the histone deacetylase inhibitor panobinostat (LBH589) in patients with low or intermediate‐1 risk myelodysplastic syndrome

AbstractA phase II non‐randomized single arm trial of oral panobinostat (LBH589) was conducted in patients with low or intermediate‐1 risk myelodysplastic syndrome (MDS). The objective of this study was to determine the clinical efficacy, safety, and tolerability of panobinostat in this patient population. The study would stop early if there was a chance >99% that the average overall response rate was <15%. Thirteen patients were treated: Median age was 70 years (range 47–84), 70% were transfusion dependent, 70% had intermediate‐1 risk MDS. Most patients were diploid but one patient with del(5q), one with trisomy 8, one with complex cytogenetics, and two with deletion of 20q were included. Approximately 40% had previous therapy for MDS. Of the 13 patients, 1 (8%) achieved hematological improvement (HI‐E and HI‐P, duration 3 months) and 6 (46%) had stable disease for a median duration of 6 months (range 1.7–13.6). Treatment was withheld in one patient because of QTc prolongation but no other serious adverse effects were otherwise observed. Panobinostat did not consistently induce histone acetylation as measured with Western blot. This data indicates that panobinostat at the dose and schedule studied here has limited activity in lower risk MDS. Am. J. Hematol., 2012. © 2011 Wiley Periodicals, Inc.

The effect of food on the bioavailability of panobinostat, an orally active pan-histone deacetylase inhibitor, in patients with advanced cancer.

Panobinostat is a novel oral pan-deacetylase inhibitor with promising anti-cancer activity. The study aimed to determine the influence of food on the oral bioavailability of panobinostat. This multicenter study consisted of a randomized, three-way crossover, food-effect study period (cycle 1) followed by single-agent panobinostat continual treatment phase in patients with advanced cancer. Patients received panobinostat 20mg twice weekly, and panobinostat pharmacokinetics was investigated on days 1, 8, and 15 with a randomly assigned sequence of three prandial states (fasting, high-fat, and normal breakfast). Thirty-six patients were assessed for the food effect on pharmacokinetics and safety in cycle 1, after which 29 patients continued treatment, receiving single-agent panobinostat. Safety and antitumor activity were assessed during the extension period. Panobinostat systemic exposure was marginally reduced (14-16%) following food [geometric mean ratio (GMR) of the AUC(0-∞)/high-fat breakfast/fasting, 0.84 (90% confidence interval {CI}, 0.74-0.96); normal breakfast/fasting, 0.86 (90% CI, 0.75-1.00)], and interpatient variability (coefficient of variation, 59%) remained essentially unchanged with or without food. Panobinostat C (max) was reduced by 44% (high-fat) and 36% (normal) with median T (max) prolonged by 1-1.5h following food. Panobinostat was well tolerated, with thrombocytopenia, fatigue, nausea, and vomiting as common adverse events, and demonstrated antitumor activity with one patient with a partial response and six patients with stable disease as best response. Food produced minor changes in oral panobinostat exposure; thus, panobinostat can be given without regard to food intake in future clinical studies.

Phase I study of panobinostat in combination with bevacizumab for recurrent high-grade glioma

Bevacizumab is frequently used to treat patients with recurrent high-grade glioma (HGG), but responses are generally not durable. Panobinostat is a histone deacetylase inhibitor with anti-neoplastic and anti-angiogenic effects and may work synergistically with VEGF inhibitors. We performed a phase I study to evaluate the safety and tolerability of the combination of orally administered panobinostat with bevacizumab in patients with recurrent HGG. Patients with recurrent HGG were treated on a 3 + 3 trial design. Patients received bevacizumab 10 mg/kg every other week in combination with oral panobinostat. The starting dose of panobinostat was 20 mg three times per week, weekly (cohort 1). Due to concerns for thrombocytopenia with the weekly dosing regimen, the protocol was amended to examine an every other week regimen. Cohort 2 received panobinostat 20 mg three times per week, every other week, and cohort 3 received 30 mg three times per week, every other week. Dose-limiting toxicity during the first 30 days was used to determine the maximum-tolerated dose. Twelve patients (median age 50, median KPS 90) with recurrent HGG were enrolled. One dose-limiting toxicity (DLT) (Grade 3 thrombocytopenia) was observed in cohort 1. No DLTs were observed in cohorts 2 and 3. The following grade 3 toxicities were seen in one patient each: thrombocytopenia, hypophosphatemia, esophageal hemorrhage, and deep venous thrombosis. There were no grade 4 or 5 toxicities. There were three patients with partial responses and seven with stable disease. The recommended doses for further study are oral panobinostat 30 mg three times per week, every other week, in combination with bevacizumab 10 mg/kg every other week. A phase II clinical trial in recurrent HGG is underway.

Phase I dose-escalating study of panobinostat (LBH589) Administered intravenously to Japanese patients with advanced solid tumors

Panobinostat (LBH589) is a potent pan-histone deacetylase inhibitor. As a result of promising preclinical data, Phase I and II clinical trials of intravenous and oral panobinostat have been conducted in patients with a wide variety of hematologic and solid tumors. This is the first report of a phase I study to evaluate intravenous panobinostat given on days 1 and 8 of a 21-day cycle in patients with solid tumors. The primary objective was to characterize the safety and tolerability of panobinostat by evaluating the occurrence of dose-limiting toxicity (DLT) and determining the maximum tolerated dose (MTD) in Japanese patients with advanced solid tumors. Secondary objectives included characterizing the pharmacokinetics and assessing antitumor activity. Fourteen patients were assigned to three dose levels (Cohort 1: 10 mg/m(2) [three patients], Cohort 2: 15 mg/m(2) [three patients], Cohort 3: 20 mg/m(2) [eight patients]), according to a standard "3 + 3" design. One patient who received 20 mg/m(2) had a DLT (grade 3 elevation of γ-glutamyl transpeptidase for >7 days). Thrombocytopenia was observed in all patients (grade 3 or 4 in 8), the severity of which was dependent on the dose and platelet count at baseline. The thrombocytopenia rapidly resolved within 8 days. Plasma panobinostat levels increased dose dependently, without clinically significant drug accumulation. Stable disease for ≥4 months was observed in six patients; however, there were no complete or partial responses. It is feasible to conclude that 20 mg/m(2) was the MTD and recommend as the starting dose for phase II clinical trials.