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.
Acetylation is a common and reversible post-translational protein modification.1 A recent study identified 1750 proteins as targets for acetylation, and proteins regulated by acetylation are implicated in carcinogenesis.1 This diverse group of proteins is involved in a variety of cellular functions and includes histones, the protein chaperone Hsp90, the tumor suppressor p53, the proangiogenic transcription factor Hif1-α and the cytoskeletal protein α-tubulin.2, 3 Acetylation is regulated by the activity of histone acetyltransferases, whereas deacetylation is mediated by the histone deacetylase (HDAC) class of enzymes.2, 3 There are 11 HDAC enzymes (excluding class III NAD+-dependent sirtuins) across three classes (class I, II and IV), which differ in intracellular localization and target proteins.2, 3 Dysregulation of these enzymes leads to altered acetylation of cellular proteins, and global hypoacetylation of histone proteins has been identified as a hallmark of cancer development.4
Deacetylase inhibitors (DACi) are a novel class of anticancer agents. Currently, two DACi, vorinostat and romidepsin, are approved by the US Food and Drug Administration for the treatment of cutaneous T-cell lymphoma.5, 6 DACi lead to hyperacetylation of target proteins and elicit anticancer activity through induction of cell-cycle arrest, apoptosis, differentiation and targeting of the tumor microenvironment.2 Panobinostat is a potent pan-DACi with greater inhibitory activity of HDACs than currently approved agents.7, 8, 9, 10, 11, 12, 13, 14 Preclinical studies have shown that panobinostat has antitumor activity against hematologic tumors, including Hodgkin lymphoma (HL) and multiple myeloma (MM) cells.14, 15 In patients, panobinostat has been shown to elicit direct epigenetic effects, including induction of fetal hemoglobin.16
On the basis of promising preclinical activity, this phase Ia/II study was designed to determine the maximum-tolerated dose (MTD) of single-agent panobinostat on two different dosing schedules in patients with hematologic malignancies. The study was designed to determine the differences between a weekly schedule, in which the increased frequency had the potential to lead to higher potency, and a biweekly schedule, in which intermittent dosing had the potential to result in a more tolerable safety profile and allow for greater therapy duration. Overall, the trial was conducted to gain insight on the safety, pharmacokinetics (PK) and preliminary activity of panobinostat in hematologic malignancies to better understand the patient population that may benefit.
Materials and Methods
Adult patients with advanced hematologic malignancies whose disease had progressed on or following available standard treatments or for whom no standard therapy existed were eligible. All patients were required to have a World Health Organization performance score ⩽2 and adequate hepatic and renal function. Patients were excluded if they had active central nervous system disease, impaired cardiac function or other severe or uncontrollable medical conditions. Patients who received prior DACi treatment for cancer or who were receiving active treatment with agents with the potential to prolong QT interval were also excluded. This study was conducted according to the guidelines of the Declaration of Helsinki, and written informed consent was obtained from all patients. The study and amendments were reviewed by the independent ethics committee or institutional review board for each center.
Study design and patient enrollment
The primary objective of this two-arm, open-label, multicenter, phase Ia/II study was to determine the MTD of panobinostat on two different schedules. The study design is outlined in Figure 1. In the dose-escalation phase, panobinostat was administered during 28-day treatment cycles according to one of two dosing schedules: once a day three days per week every week (Arm 1) or every other week (Arm 2). The starting doses were 20 mg for Arm 1 and 30 mg for Arm 2. The criteria for hematologic dose-limiting toxicities (DLTs) differed between patients with indications associated with disease-related cytopenias—Group X: acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), myelofibrosis (MF), acute lymphoblastic leukemia, chronic myelomonocytic leukemia, chronic myeloid leukemia (CML), atypical CML, chronic lymphocytic leukemia (CLL) and prolymphocytic leukemia—and patients with indications not typically associated with disease-related cytopenias—Group Y: MM HL, and non-Hodgkin lymphoma (NHL). Dose escalation and determination of the MTD were guided by a three-parameter Bayesian logistic regression model with overdose control similar to that proposed by Babb et al.17 Each arm enrolled independently so that during dose escalation neither subarm 1X/2X nor 1Y/2Y will be >1 treated dose level ahead of the other. In the dose-escalation phase, 53 patients were enrolled in Arm 1 Group X and 26 in Arm 1 Group Y. Of patients enrolled in Arm 2, 33 were enrolled in Group X and 23 in Group Y. Toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (v.3.0). Following MTD determination, an additional 41 patients were evaluated for safety and efficacy in the dose-expansion phase.
Hematologic DLT criteria for Group X indications (myeloid malignancies) were defined as the inability to administer panobinostat for >42 days after the first missed dose because of grade 4 neutropenia or thrombocytopenia that was unrelated to disease. For patients with Group Y indications (lymphoid malignancies), hematologic DLT was defined as grade 4 neutropenia for >7 consecutive days, grade 4 thrombocytopenia or febrile neutropenia (absolute neutrophil count <0.5 × 109/l, fever ⩾38.5 °C). Non-hematologic DLT criteria were identical for both groups and included renal impairment (⩾grade 3 serum creatinine or ⩾2.0 × upper limit of normal for >7 consecutive days), hepatic impairment (⩾grade 3 total bilirubin or ⩾2.0 × upper limit of normal to ⩽3.0 × upper limit of normal for >7 consecutive days; grade 3 aspartate aminotransferase or alanine aminotransferase for >7 consecutive days or grade 4), cardiac abnormalities (⩾grade 3) and neurotoxicity (>1 grade increase). Additional DLTs included grade 3 adverse events (AEs) (excluding grade 3 elevations in alkaline phosphatase) that interfered with the ability to administer panobinostat for >7 consecutive days, grade 4 AEs (excluding grade 4 elevations in alkaline phosphatase), ⩾grade 3 vomiting, grade 3 nausea despite the use of antiemetics, ⩾grade 3 diarrhea despite the use of antidiarrheal medications and any AE that interfered with the ability to administer >7 doses (Arm 1) or >4 doses (Arm 2) of panobinostat within a cycle of treatment. The study further evaluated patients with AML and a group of patients with various hematologic malignancies (acute lymphoblastic leukemia, MDS, MF, chronic myelomonocytic leukemia, atypical CML, CLL, prolymphocytic leukemia, HL and NHL) at the MTD for the weekly dosing schedule.
Safety evaluations included assessment of hematologic parameters, biochemistry panel assessment, urinalysis and thyroid function test. Incidence of AEs was summarized by system organ class, severity, type and relation to study drug. Comprehensive cardiac assessments were performed, including electrocardiograms at baseline, throughout treatment and at the end of treatment, as well as cardiac enzyme assessment at baseline, on day 8 of cycles 1 and 2, as clinically indicated during treatment, and at the end of treatment. A multigated acquisition scan and/or an echocardiogram was also performed at baseline and end of treatment.
For patients with AML, responses were based on the criteria outlined by Cheson et al.18 Assessment of response in patients with MF was based on Tefferi et al,19 including physical examination of spleen size, assessment of constitutional symptoms and complete blood count with differential. The response criteria for HL were based on Cheson et al.20 A computed tomography (CT) scan was performed at baseline and repeated for determination of anatomic response ⩽7 days before the completion of each even-numbered cycle, at the end of treatment and as determined necessary by the investigator. An exploratory analysis of metabolic response using [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) was also performed in patients with HL. A standardized imaging protocol was used per institutional guidelines at each site. FDG-PET data were evaluated using modified European Organization for Research and Treatment of Cancer criteria,21 with thresholds for progression and response set at ±25% change in standardized uptake value versus baseline rather than ±20%. Analysis of response for HL patients was conducted by the investigator and also by central review (VirtualScopics, Inc., Rochester, NY, USA).
PK and pharmacodynamics
The methodology for panobinostat PK and pharmacodynamic analysis of histone acetylation are described in the Supplementary Material.
The MTD determination and toxicity monitoring during the dose-escalation phase of the trial were based on a three-parameter version of a Bayesian logistic regression model with overdose control.17 Separate but identical models were used for each X and Y group and were updated after each cohort of patients had completed enrollment and a first cycle of treatment. Selection of subsequent doses was based on these probabilities along with clinical information.
Patients and treatment
From 6 March 2006 to 2 December 2009, 176 patients were enrolled in the study. There were 119 patients enrolled with Group X indications (myeloid malignancies); 86 patients received panobinostat three times weekly every week (Arm 1), and 33 patients received panobinostat every other week (Arm 2; Table 1). The most common indication in Group X was AML (n=83, 69.7% overall). In all, 57 patients with Group Y indications (lymphoid malignancies) were enrolled in the trial, with 34 patients on Arm 1 and 23 on Arm 2. Patients with HL accounted for 18.2% (n=32) of patients enrolled in the study. The median age of the overall patient population was 63 years, and was higher among Group X patients compared with Group Y patients, which is generally reflective of patients enrolled in these groups (AML vs HL).
Dose escalation and determination of MTD
Because of disease-related cytopenias, hematologic DLT criteria differed between Group X and Group Y (see Methods). For Arm 1 Group X patients, the MTD dose was determined to be 60 mg. The most common DLT observed in Arm 1 Group X was fatigue, which was observed in five patients across doses of 40–80 mg (Table 2). Cardiac-related DLTs were observed at 80 mg in three patients, including two instances of grade 3 QTcF prolongation. Among Group X patients who received panobinostat three times weekly every other week (Arm 2), DLTs were observed at the dose of 80 mg. The most common DLTs included cardiac-related AEs and fatigue (Table 2). Although it was determined that 80 mg exceeded the MTD, further evaluation at the 60-mg biweekly dosing was not conducted because preliminary efficacy was more promising for the weekly dosing schedule. Thus, the sample size was not sufficient for the MTD to be formally determined per protocol, and 60 mg was considered to be the highest safe dose evaluated.
Thrombocytopenia was a DLT in nine Arm 1 Group Y patients treated at the 40- and 60-mg doses. On the basis of DLT information from patients treated at different cohorts in Arm 1 Group Y, Bayesian logistic regression analysis indicated 38 mg of panobinostat to be the highest recommended dose for a new cohort. However, as the smallest capsule strength was 5 mg, and the DLT of thrombocytopenia observed was deemed to be acceptable for this patient population, the investigators decided that 40 mg could be further evaluated. This dose was formally declared to be the recommended phase II dose rather than the MTD. For Arm 2 Group Y patients, DLTs were observed in three patients at the 60-mg dose, and thrombocytopenia occurred in two of three patients (Table 2), 60 mg was declared to be the MTD.
All 176 patients had discontinued at the time of the final data analysis, most commonly due to disease progression (56.3%). An additional 45 patients (25.6%) discontinued because of AEs. A total of 42 deaths occurred while on study treatment or within 28 days of the last panobinostat dose. Death was the reason for discontinuation for eight patients (4.5%). Two of these deaths were suspected to be related to panobinostat and occurred in Arm 1 Group X patients. One death was due to pulmonary hemorrhage secondary to bronchopulmonary aspergillosis at 60 mg, and another was due to multiorgan failure in a patient who experienced acute renal failure and sepsis at 80 mg.
Common AEs suspected to be treatment related are summarized in Table 3. AEs regardless of relation to study drug are summarized in Supplementary Data 1 and 2. Overall, the most common AEs suspected to be treatment related were gastrointestinal and hematologic in nature. Most gastrointestinal AEs were mild (grades 1 and 2). Common hematologic AEs related to study drug included thrombocytopenia, neutropenia and anemia. As observed in other studies with panobinostat,22, 23 thrombocytopenia was the most common grade 3–4 AE and was more common in patients with Group Y indications. Although the incidence of thrombocytopenia was relatively high, discontinuation due to thrombocytopenia was rare (four patients, 2.3%), as thrombocytopenia was reversible and manageable following dose delays and interruptions. The time to onset and duration of grade 3–4 thrombocytopenia analysis was conducted using Kaplan–Meier method on platelet count data (Supplementary Data 3). For Arm 1 the median time to grade 3–4 thrombocytopenia for Groups X and Y was 12 and 15 days, respectively; median duration was 10 and 4 days, respectively. For Arm 2 the median time to grade 3–4 thrombocytopenia for Groups X and Y was 12 and 64 days, respectively; median duration was 38 and 4 days, respectively. Although differences were observed among the arms and groups, the ability to draw conclusions is confounded by the various dose groups within each arm and other factors, including dose reductions and blood transfusions. Fatigue, another common AE related to panobinostat, was observed in 53% of patients overall with a grade 3–4 incidence of 21%. Because of small patient numbers among dose cohorts, no clear relationship between dose and incidence or severity of AEs could be determined.
Plasma concentration following panobinostat dosing on day 1 was available from 140 patients (87 patients in Arm 1 and 53 patients in Arm 2). Panobinostat was rapidly absorbed, with a median Tmax achieved within 2 h (Supplementary Data 4). The Cmax and AUC0−∞ generally increased with dose; however, AUC appeared to increase less than dose proportionally beyond 45 mg. The mean half-life was approximately 16 h. Panobinostat PK parameters were similar following dosing on day 1 and after repeated dosing on day 15 for patients treated on Arm 1 (Supplementary Data 5) with minimal drug accumulation as indicated by the similarity of AUC values observed on days 1 and 15.
To relate exposure levels of panobinostat to its ability to inhibit HDACs in patients, changes in histone acetylation in peripheral blood mononuclear cells following panobinostat administration were assessed. Induction of histone acetylation as detected by western blot was observed in a majority of patients at all dose levels and time points evaluated (Supplementary Data 6). At doses above 20 mg, every sample with adequate protein isolated demonstrated increased histone acetylation; however, because of the lack of dynamic range with the western blot assay, a dose–response curve was not demonstrated.
Efficacy in Hodgkin lymphoma
Intriguing preliminary activity was noted in an earlier report of 13 patients with HL enrolled in this trial.24 The characteristics of all 32 patients with HL are summarized in Table 4. Patients were heavily pretreated with a median of five (range 3–16) prior therapeutic regimens. Patient profile review demonstrated that all patients received prior autologous stem cell transplant, and 13 patients received prior allogeneic stem cell transplantation. Response was evaluated by investigator assessment and central review. Best response for all patients by CT and FDG-PET is presented in Table 5. Activity of panobinostat was demonstrated in these heavily pretreated patients. Anatomic response rate, as determined by central review, was 34.4% (11 partial response (PR)), and metabolic response rate, by FDG-PET central review, was 53.1%. Waterfall plots demonstrating best metabolic and anatomic responses by central review are shown in Figures 2a and b, respectively. Responses to panobinostat in patients with HL were durable. Response data were available for patients assessed by CT according to investigator assessment (n=9). Patient profile review of duration of response demonstrated a median of 283 days (range 1–309; n=7 censored because of missing evaluations, including loss to follow-up, or no documentation of PD), with four patients demonstrating duration of response >150 days. Of four patients who demonstrated long-term responses, two started treatment at the planned dose of 40 mg in Arm 1 (phase 2 recommended dose) and were subsequently dose reduced to 20 mg, the third patient received a starting dose of 60 mg (in Arm 2) and was dose reduced to 20 mg and the fourth patient received a starting dose of 30 mg in Arm 1 with no subsequent dose reductions. These data, combined with low rates of progressive disease (one patient by CT, four patients by FDG-PET), support activity of panobinostat in relapsed HL and suggest that lower doses may be preferred for long-term treatment.
Efficacy in MF
In all, 13 patients with MF were treated on this trial (Table 6). Most patients received >2 cycles of panobinostat. Review of patient profiles demonstrated that median duration of treatment was 117 days (range 1–1188). Clinical improvement (CI), including reductions in spleen size by palpation, was observed in four patients (30.8%), including one treated at 30 mg and three treated at 60 mg in Arm 1. The median time to response was 278 days (range 1–278), and the range of duration of response for the responders was 1–369 days. The patient who received a planned dose of 30 mg panobinostat was subsequently dose reduced to 25 mg after approximately 4 months. This patient received >40 treatment cycles and demonstrated a splenic reduction of 86.2%. Review of the patient profiles demonstrated that the three patients who received a planned dose of 60 mg and demonstrated CI had a JAK2 mutation. These patients demonstrated reductions in spleen size of 57–85% and all three had at least one dose reduction that ranged between 20 and 45 mg during their treatment. Of these three patients, two who received panobinostat long-term (⩾11 cycles) experienced splenic reductions of >80%. There were a total of seven patients (53.8%) who demonstrated stable disease. Three patients who demonstrated best response of stable disease received treatment for ⩾4 cycles, all three of whom were in the 60 mg dose group and had at least one dose reduction during their treatment. These data support single-agent activity in MF with long-term activity observed in patients receiving lower doses (⩽45 mg).
Efficacy in other hematologic malignancies
Overall, patients with AML enrolled on this trial presented with poor prognostic factors (Supplementary Data 7), including patients who presented with high-risk cytogenetic characteristics (Supplementary Data 8). Less than half achieved a complete response (CR) prior to enrollment, and 24% had not responded to any prior therapy. Modest activity was observed in patients with AML. Of the AML patients in Arm 1, two demonstrated a CR and one demonstrated a PR. All received 60 mg panobinostat. Another patient treated in Arm 2 demonstrated a PR at a dose of 60 mg. Of note, one patient who achieved a CR presented with AML with multilineage dysplasia following MDS and had a translocation of MLL and CREB binding protein: t(11;16)(q23;p13.3) in 20 of 21 metaphase cells as determined by cytogenetic analysis.25 This patient maintained a complete cytogenetic response for >12 months. The other patient with AML with multilineage dysplasia following MDS with normal cytogenetics demonstrated a CR for 50 days.
Although patient numbers were limited, activity was observed in other indications. Nine patients with MDS were treated on Arm 1, and two were treated on Arm 2. Modest activity was observed, with one PR observed in an Arm 2 patient with a chromosome 20q deletion treated with 60 mg panobinostat. Stable disease was observed in four patients treated in Arm 1 and one patient in Arm 2. Review of the patient profiles among the other indications demonstrated a PR in one patient with MM, one patient with CLL, two patients with NHL, including one patient with diffuse small lymphocytic B-cell lymphoma and one patient with pleomorphic T-cell lymphoma of the skin.
This phase Ia/II study provided a comprehensive overview of the safety, PK and activity of panobinostat in a wide range of hematologic malignancies. A dose of 60 mg was determined to be the MTD in Group X patients in Arms 1 and 2 and Group Y patients in Arm 2. For Group Y patients treated on the weekly schedule (Arm 1), 60 mg exceeded MTD, and 40 mg of panobinostat was the recommended dose for phase II. Overall, the MTD of panobinostat differed based on the patient indication and schedule of administration. Of note, the 40-mg weekly dose was evaluated in a phase II trial of patients with relapsed/refractory HL, and the phase II/III PANORAMA program in MM is evaluating panobinostat in combination with bortezomib and dexamethasone using a 20-mg dose administered three times weekly for 2 weeks followed by a 1-week treatment holiday.22, 23, 26 As investigation of panobinostat in other hematologic malignancies continues, the dose and schedule will need to be tailored for each indication and combination partner.
Overall, safety data were similar to other studies of DACi, with nausea, diarrhea and fatigue as the most common study drug-related non-hematologic AEs.22, 23, 27, 28 The most common grade 3–4 AEs related to panobinostat were hematologic, and thrombocytopenia was the most common grade 3–4 AE observed. Thrombocytopenia is commonly observed in trials with panobinostat but is rapidly reversible and manageable with dose interruptions or reductions and rarely lead to treatment discontinuations or hemorrhages. Recent preclinical studies demonstrated that panobinostat-related thrombocytopenia is transient and rapidly reversible upon drug removal29 and inhibits platelet budding by leading to increased phosphorylation of the myosin light chains.30
PK parameters, including Cmax, AUC and t1/2, were similar to those observed in other studies of panobinostat.31 Cmax and AUC increased near dose proportionally through 50 mg. In addition, minimal drug accumulation was observed following thrice-weekly dosing, and sustained histone acetylation was observed in a majority of patient blood samples, particularly at doses above 20 mg, suggesting prolonged intracellular effects. Owing to low sensitivity of the western blot assay and limited single-agent efficacy, a clear correlation for acetylation was not observed. Future studies should analyze the correlation between global protein acetylation status with efficacy and/or toxicity.
The antitumor activity of single-agent panobinostat was most apparent in patients with HL. Central review analysis demonstrated a response rate by CT of 34.4% and a response rate by FDG-PET of 53.1%. These data led to further investigation in a phase II trial of panobinostat in patients with HL after autologous stem cell transplant. These recent data confirm the activity observed here, with a 27% overall response rate by CT, including five CRs per investigator assessment.23
CI was noted in four of 13 patients with MF. Mutation of JAK2 was confirmed in three of the four patients demonstrating CI. Although three of the patients demonstrating CI were treated with 60 mg of panobinostat, all of these patients had dose reductions, and preliminary reports from recent studies seem to suggest that a lower dose (<40 mg) may allow for longer therapy duration.32, 33 Clinical trial experience with panobinostat has demonstrated long-term tolerability (ongoing >2 years) and remarkable clinical benefit in patients who received panobinostat at 25–30 mg, three times per week, every other week (Kavita Natrajan, personal communication). Furthermore, a recent study with another pan-DACi, givinostat, demonstrated clinical responses in patients with JAK2V617F-positive myeloproliferative neoplasms, including MF.34 Mechanistically, it has been demonstrated that panobinostat inhibits JAK2V617F signaling and depletes mutant JAK2V617F protein via inhibition of Hsp90 activity.35 Indeed, both panobinostat and the Hsp90 inhibitor AUY922 synergistically activate apoptosis of myeloproliferative neoplastic cells when used in combination with JAK inhibitors.35, 36 On the basis of these findings, a phase I study of combination panobinostat and the JAK1/2 inhibitor ruxolitinib is ongoing in patients with MF.
Although not as striking, some intriguing results were noted in other indications. Cytogenetic analysis identified that one patient who achieved CR had a translocation of MLL and CREB binding protein: t(11;16)(q23;p13.3). MLL is a transcriptional regulator implicated in HDAC-dependent epigenetic pathways, and MLL genetic aberrations, including translocations, have been implicated in leukemogenesis.37, 38 The observation of a CR in a patient with MLL-aberrant leukemia is worth noting as panobinostat targets both epigenetic and non-epigenetic pathways, and further clinical investigation is warranted.25 In addition, a separate report of a patient treated on this study demonstrated laboratory tumor lysis syndrome in a patient with AML with cytogenetically determined trisomy 8 and del(20q). Substantial decreases of white blood cell counts (60 × 109/l to 6 × 109/l) were observed within 24 h of panobinostat administration.39 These data supported the antileukemic activity of panobinostat, and also provide cautionary evidence for the potential of tumor lysis. A PR was also observed in a patient with MDS with del(20q). Further analysis may identify genetic aberrations associated with the activity of panobinostat in patients with AML and MDS, and current trials are evaluating panobinostat in combination with standard-of-care agents that have demonstrated synergy in preclinical models, including anthracylines and demethylating agents.40, 41, 42, 43
Modest activity in MM was demonstrated with one PR observed. Further investigation of panobinostat in MM will most likely be as a combination therapy based on preclinical evidence, demonstrating that dual inhibition of the proteasome and aggresome by bortezomib and panobinostat, respectively, leads to MM cell death.44, 45 Recent results from three separate phase I clinical trials of panobinostat, vorinostat or romidepsin in combination with the proteasome inhibitor bortezomib demonstrated encouraging activity in patients with relapsed and refractory MM, including PR in patients with bortezomib-refractory MM.22, 46, 47 Preliminary reports from phase II and III studies are suggesting that combination therapy with DACi can overcome resistance to bortezomib therapy in patients with relapsed/refractory MM.26, 48, 49, 50
DACi are well known to be effective in patients with cutaneous T-cell lymphoma and peripheral T-cell lymphoma.28, 51, 52, 53 Moreover, a recent trial evaluating vorinostat in patients with NHL demonstrated encouraging activity, including a response rate of 47% (four CR, four PR) among patients with follicular lymphoma.54 In the study reported here, only 13 patients with NHL were enrolled, and two PR were observed in one patient with diffuse small lymphocytic B-cell lymphoma and one patient with pleomorphic T-cell lymphoma of the skin, as determined by patient profile review. On the basis of these observations, future studies should evaluate panobinostat in a larger cohort of patients with NHL subtypes that are associated with response to DACi.
This study represented the first phase I trial that evaluated panobinostat in a broad range of hematologic malignancies and established the efficacy, safety and PK profile for this potent DACi. Promising single-agent activity was noted in patients with relapsed and refractory HL, and MF, and led to the design of phase II trials in these indications.23, 33 Of note, although the MTD was identified, a majority of patients who received long-term panobinostat had at least one dose reduction. These data seem to suggest that doses lower than the MTD may have higher long-term tolerability. Along with elucidation of the safety profile, these data guided the design of subsequent trials in indications, such as MM and MDS, in which panobinostat holds promise as a combination therapy.26, 41, 49 For these studies, panobinostat is administered at doses lower than the MTD identified in this study, and treatment holidays are included in the dosing schedules. Ongoing and future studies will seek to optimize the dose and schedule of panobinostat with combination partners across various hematologic malignancies.
Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 2009; 325: 834–840.
Bolden JE, Peart MJ, Johnstone RW . Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 2006; 5: 769–784.
Minucci S, Pelicci PG . Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 2006; 6: 38–51.
Fraga MF, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet 2005; 37: 391–400.
StatBite FDA oncology drug product approvals in 2009. J Natl Cancer Inst 2010; 102: 219.
Mann BS, Johnson JR, Cohen MH, Justice R, Pazdur R . FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist 2007; 12: 1247–1252.
Gu W, Roeder RG . Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 1997; 90: 595–606.
Qian DZ, Kachhap SK, Collis SJ, Verheul HM, Carducci MA, Atadja P et al. Class II histone deacetylases are associated with VHL-independent regulation of hypoxia-inducible factor 1 alpha. Cancer Res 2006; 66: 8814–8821.
Qian DZ, Kato Y, Shabbeer S, Wei Y, Verheul HM, Salumbides B et al. Targeting tumor angiogenesis with histone deacetylase inhibitors: the hydroxamic acid derivative LBH589. Clin Cancer Res 2006; 12: 634–642.
Yang Y, Rao R, Shen J, Tang Y, Fiskus W, Nechtman J et al. Role of acetylation and extracellular location of heat shock protein 90alpha in tumor cell invasion. Cancer Res 2008; 68: 4833–4842.
Bali P, Pranpat M, Bradner J, Balasis M, Fiskus W, Guo F et al. Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors. J Biol Chem 2005; 280: 26729–26734.
Bishton MJ, Johnstone RW, Dickinson M, Harrison S, Prince HM . Overview of histone deacetylase inhibitors in haematological malignancies. Pharmaceuticals 2010; 3: 2674–2688.
Verheul HM, Salumbides B, Van Erp K, Hammers H, Qian DZ, Sanni T et al. Combination strategy targeting the hypoxia inducible factor-1 alpha with mammalian target of rapamycin and histone deacetylase inhibitors. Clin Cancer Res 2008; 14: 3589–3597.
Atadja P . Development of the pan-DAC inhibitor panobinostat (LBH589): successes and challenges. Cancer Lett 2009; 280: 233–241.
Prince HM, Bishton MJ, Johnstone RW . Panobinostat (LBH589): a potent pan-deacetylase inhibitor with promising activity against hematologic and solid tumors. Fut Oncol 2009; 5: 601–612.
Bradner JE, Mak R, Tanguturi SK, Mazitschek R, Haggarty SJ, Ross K et al. Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease. Proc Natl Acad Sci U S A 2010; 107: 12617–12622.
Babb J, Rogatko A, Zacks S . Cancer phase I clinical trials: efficient dose escalation with overdose control. Stat Med 1998; 17: 1103–1120.
Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 2003; 21: 4642–4649.
Tefferi A, Barosi G, Mesa RA, Cervantes F, Deeg HJ, Reilly JT et al. International Working Group (IWG) consensus criteria for treatment response in myelofibrosis with myeloid metaplasia, for the IWG for Myelofibrosis Research and Treatment (IWG-MRT). Blood 2006; 108: 1497–1503.
Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM et al. Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin Oncol 1999; 17: 1244.
Young H, Baum R, Cremerius U, Herholz K, Hoekstra O, Lammertsma AA et al. Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. Eur J Cancer 1999; 35: 1773–1782.
San-Miguel JF, Richardson PGG, Sezer O, Guenther A, Siegel DSD, Blade J et al. A phase lb study of oral panobinostat and IV bortezomib in relapsed or relapsed and refractory multiple myeloma. J Clin Oncol 2011; 29, (abstract 8075).
Younes A, Sureda A, Ben-Yehuda D, Zinzani PL, Ong TC, Prince HM et al. Panobinostat in patients with relapsed/refractory Hodgkin’s lymphoma after autologous stem-cell transplantation: results of a phase II study. J Clin Oncol 2012; 30: 2197–2203.
Dickinson M, Ritchie D, DeAngelo DJ, Spencer A, Ottmann OG, Fischer T et al. Preliminary evidence of disease response to the pan deacetylase inhibitor panobinostat (LBH589) in refractory Hodgkin lymphoma. Br J Haematol 2009; 147: 97–101.
Burbury KL, Bishton MJ, Johnstone RW, Dickinson MJ, Szer J, Prince HM . MLL-aberrant leukemia: complete cytogenetic remission following treatment with a histone deacetylase inhibitor (HDACi). Ann Hematol 2010; 90: 847–889.
Richardson PG, Alsina M, Weber DM, Coutre SE, Lonial S, Gasparetto C et al. Phase II study of the pan-deacetylase inhibitor panobinostat in combination with bortezomib and dexamethasone in relapsed and bortezomib-refractory multiple myeloma (PANORAMA 2). Blood 2011; 118, (abstract 814).
Whittaker SJ, Demierre MF, Kim EJ, Rook AH, Lerner A, Duvic M et al. Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. J Clin Oncol 2010; 28: 4485–4491.
Duvic M, Talpur R, Ni X, Zhang C, Hazarika P, Kelly C et al. Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood 2007; 109: 31–39.
Giver CR, Jaye DL, Waller EK, Kaufman JL, Lonial S . Rapid recovery from panobinostat (LBH589)-induced thrombocytopenia in mice involves a rebound effect of bone marrow megakaryocytes. Leukemia 2011; 25: 362–365.
Bishton MJ, Harrison SJ, Martin BP, McLaughlin N, James C, Josefsson EC et al. Deciphering the molecular and biological processes that mediate histone deacetylase inhibitor-induced thrombocytopenia. Blood 2011; 117: 3658–3668.
Woo MM, Culver K, Li W, Liu A, Scott J, Parker K et al. Panobinostat (LBH589) pharmacokinetics (PK): implication for clinical safety and efficacy. Ann Oncol 2008; 19, (abstract 487P).
Mascarenhas J, Mercado A, Rodriguez A, Lu M, Kalvin C, Li X et al. Prolonged low dose therapy with a pan-deacetylase inhibtor, panobinostat (LBH589), in patients with myelofibrosis. Blood 2011; 118, (abstract 794).
DeAngelo DJ, Tefferi A, Fiskus W, Mesa RA, Paley CS, Wadleigh M et al. A phase II trial of panobinostat, an orally available deacetylase inhibitor (DACi), in patients with primary myelofibrosis (PMF), post essential thrombocythemia (ET), and post polycythemia vera (PV) myelofibrosis. Blood 2010; 116, (abstract 630).
Rambaldi A, Dellacasa CM, Finazzi G, Carobbio A, Ferrari ML, Guglielmelli P et al. A pilot study of the histone-deacetylase inhibitor givinostat in patients with JAK2V617F positive chronic myeloproliferative neoplasms. Br J Haematol 2010; 150: 446–455.
Wang Y, Fiskus W, Chong DG, Buckley KM, Natarajan K, Rao R et al. Cotreatment with panobinostat and JAK2 inhibitor TG101209 attenuates JAK2V617F levels and signaling and exerts synergistic cytotoxic effects against human myeloproliferative neoplastic cells. Blood 2009; 114: 5024–5033.
Fiskus W, Verstovsek S, Manshouri T, Rao R, Balusu R, Venkannagari S et al. Heat shock protein 90 inhibitor is synergistic with JAK2 inhibitor and overcomes resistance to JAK2-TKI in human myeloproliferative neoplasm cells. Clin Cancer Res 2011; 17: 7347–7358.
Slany RK . The molecular biology of mixed lineage leukemia. Haematologica 2009; 94: 984–993.
Krivtsov AV, Feng Z, Lemieux ME, Faber J, Vempati S, Sinha AU et al. H3K79 methylation profiles define murine and human MLL-AF4 leukemias. Cancer Cell 2008; 14: 355–368.
Kalff A, Shortt J, Farr J, McLennan R, Lui A, Scott J et al. Laboratory tumor lysis syndrome complicating LBH589 therapy in a patient with acute myeloid leukaemia. Haematologica 2008; 93: e16–e17.
Schlenk RF, Krauter J, Schaich M, Bouscary D, Dombret H, Winiger IJ et al. Determination of the maximum tolerated dose of panobinostat in combination with cytarabine and mitoxantrone as salvage therapy for relapsed/refractory acute myeloid leukemia. Blood 2011; 118, (abstract 423).
Ottmann OG, DeAngelo DJ, Garcia-Manero G, Lubbert M, Jillella A, Sekeres MA et al. 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. Blood 2011; 118, (abstract 459).
Maiso P, Colado E, Ocio EM, Garayoa M, Martín J, Atadja P et al. The synergy of panobinostat plus doxorubicin in acute myeloid leukemia suggests a role for HDAC inhibitors in the control of DNA repair. Leukemia 2009; 23: 2265–2274.
Fiskus W, Buckley K, Rao R, Mandawat A, Yang Y, Joshi R et al. Panobinostat treatment depletes EZH2 and DNMT1 levels and enhances decitabine mediated de-repression of JunB and loss of survival of human acute leukemia cells. Cancer Biol Ther 2009; 8: 939–950.
Catley L, Weisberg E, Kiziltepe T, Tai YT, Hideshima T, Neri P et al. Aggresome induction by proteasome inhibitor bortezomib and alpha-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells. Blood 2006; 108: 3441–3449.
Hideshima T, Richardson PG, Anderson KC . Mechanism of action of proteasome inhibitors and deacetylase inhibitors and the biological basis of synergy in multiple myeloma. Mol Cancer Ther 2011; 10: 2034–2042.
Badros A, Burger AM, Philip S, Niesvizky R, Kolla SS, Goloubeva O et al. Phase I study of vorinostat in combination with bortezomib for relapsed and refractory multiple myeloma. Clin Cancer Res 2009; 15: 5250–5257.
Harrison SJ, Quach H, Link E, Seymour JF, Ritchie DS, Ruell S et al. A high rate of durable responses with romidepsin, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma. Blood 2011; 118: 6274–6283.
Siegel DS, Dimopoulos MA, Yoon S, Laubach JP, Kaufman JL, Goldschmidt H et al. Vantage 095: vorinostat in combination with bortezomib in salvage multiple myeloma patients: final study results of a global phase 2b trial. Blood 2011; 118, (abstract 480).
San-Miguel JF, de Moraes Hungria VT, Yoon S, Wiktor-Jedrzejczak W, Elghandour A, Siritanaratkul N et al. Update on a phase III study of panobinostat with bortezomib and dexamethasone in patients with relapsed multiple myeloma: PANORAMA 1. Blood 2011; 118, (abstract 3976).
Dimopoulos MA, Jagannath S, Yoon S, Siegel DS, Lonial S, Hajek R et al. Vantage 088: vorinostat in combination with bortezomib in patients with relapsed/refractory multiple myeloma: results of a global, randomized phase 3 trial. Blood 2011; 118, (abstract 811).
Olsen EA, Kim YH, Kuzel TM, Pacheco TR, Foss FM, Parker S et al. Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol 2007; 25: 3109–3115.
Piekarz RL, Frye R, Prince HM, Kirschbaum MH, Zain J, Allen SL et al. Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma. Blood 2011; 117: 5827–5834.
Piekarz RL, Frye R, Turner M, Wright JJ, Allen SL, Kirschbaum MH et al. Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol 2009; 27: 5410–5417.
Kirschbaum M, Frankel P, Popplewell L, Zain J, Delioukina M, Pullarkat V et al. Phase II study of vorinostat for treatment of relapsed or refractory indolent non-Hodgkin's lymphoma and mantle cell lymphoma. J Clin Oncol 2011; 29: 1198–1203.
Oliver G Ottmann is an endowed professor of the German Jose Carreras Leukemia Foundation. Financial support for this study was provided by Novartis Pharmaceuticals. We thank William Fazzone, PhD, for medical editorial assistance with this manuscript and Tracy Liu, Hannah Mosca and Glen Laird for assistance with data collection and analysis.
PA, KB, DJD, TF, FJG, AL, OGO, HMP and JWS designed research; PA, KB, DJD, TF, FJG, TK, OGO, HMP, AS and MW performed research; PA contributed new analytical tools; KB, DJD, TF, FJG, TK, OGO, HMP and AS collected data; and KM performed statistical analyses. All authors analyzed and interpreted the data and approved the final manuscript.
TK: nothing to disclose; KB: Novartis research funding and honoraria; DJD: Novartis consultancy; TF: Novartis honoraria; FJG: Novartis consultancy and research funding; OGO: Novartis consultancy, research funding, honoraria and advisory committee; HMP: Novartis research funding, honoraria, speakers bureau and advisory committee; AS: Novartis research funding, honoraria and speakers bureau; PA, AL, KM, KP, JWS and MW: Novartis employment; and MW: Novartis equity ownership.
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DeAngelo, D., Spencer, A., Bhalla, K. et al. Phase Ia/II, two-arm, open-label, dose-escalation study of oral panobinostat administered via two dosing schedules in patients with advanced hematologic malignancies. Leukemia 27, 1628–1636 (2013) doi:10.1038/leu.2013.38
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