Isotype-selective Histone Deacetylase Research Articles

Development and validation of a sensitive HPLC–MS/MS method for determination of chidamide (epidaza), a new benzamide class of selective histone deacetylase inhibitor, in human plasma and its clinical application

Chidamide (epidaza), a new oral isotype-selective histone deacetylase inhibitor (HDACi), which is just approved in China for the treatment of recurrent or refractory peripheral T-cell lymphoma (PTCL) in December 2014, is the first listed benzamide class of HDACi in the world, and is currently undergoing global clinical trials for solid tumor treatments. Here, we report a sensitive, rapid and robust HPLC-MS/MS method for determination of chidamide in human plasma. Plasma sample was subjected to a simple acetonitrile protein precipitation containing MS-275 used as an internal standard (IS). Chromatography was performed on a Hypersil GOLD C18 analytical column, using a gradient methanol/water mobile phase containing 0.1% formic acid. A tandem mass spectrometer equipped with electrospray ionization source was used as detector and operated in the positive-ion mode. Selected reaction monitoring (SRM) using the precursor/ product transitions (m/z) of 391.1/265.1 for chidamide and 377.1/359.2 for IS were used for quantification, respectively. Good linearity was obtained in the range of 1-1000ng/mL. The method gave R.S.D.% values for precision always lower than 13.8% and R.E.% values for accuracy between -3.7 and 9.1%. In addition, the specificity, recovery, stability and matrix effect were satisfactory too. The method is now being successfully applied to plasma samples as part of an ongoing chidamide phase Ib clinical trial in patients with solid tumors, and had demonstrated consistent AUClast and t1/2 results with the published phase I pharmacokinetic data, which was also analyzed by this method, thus further confirming the reproducibility and accuracy during its clinical application. Considering the excellent performance of this method, it will continue being utilized for future clinical developments of chidamide and for routine monitoring of plasma exposure of chidamide during its clinical therapy.

The Effect of MGCD0103 on CYP450 Isoforms Activity of Rats by Cocktail Method.

MGCD0103, an isotype-selective histone deacetylase inhibitor (HDACi), has been clinically evaluated for the treatment of hematologic malignancies and advanced solid tumors, alone and in combination with standard-of-care agents. In order to investigate the effects of MGCD0103 on the metabolic capacity of cytochrome P450 (CYP) enzymes, a cocktail method was employed to evaluate the activities of human CYP2B1, CYP1A2, CYP2C11, CYP2D6, CYP3A4, and CYP2C9. The rats were randomly divided into MGCD0103 group (Low, Medium, and High) and control group. The MGCD0103 group rats were given 20, 40, and 80 mg/kg (Low, Medium, and High) MGCD0103 by continuous intragastric administration for 7 days. Six probe drugs, bupropion, phenacetin, tolbutamide, metoprolol, testosterone, and omeprazole, were given to rats through intragastric administration, and the plasma concentrations were determined by UPLC-MS/MS. Statistical pharmacokinetics difference for tolbutamide in rats were observed by comparing MGCD0103 group with control group. Continuous 7-day intragastric administration of MGCD0103 slightly induces the activities of CYP2C11 of rats.

A phase II study of mocetinostat, an oral isotype-selective histone deacetylase (HDAC) inhibitor, in combination with 5-azacitidine in patients with myelodysplastic syndrome (MDS).

7116 Background: Mocetinostat (MGCD0103) is an orally available, isotype-selective, non-hydroxamate HDAC inhibitor targeting HDACs 1,2, 3 and 11 with single agent activity in AML and both Hodgkin’s and non-Hodgkin’s lymphomas. Preclinical evaluation demonstrating in vitro and in vivo synergy and antileukemic activity with demethylating agents, including 5-azacitidine (AZA), prompted clinical evaluation of mocetinostat + AZA in MDS and AML. Methods: This open-label, Phase II trial enrolled patients with MDS or AML. Patients received AZA (75 mg/m2SC; days 1-7 every 28 days) and mocetinostat (90-110 mg 3x/wk starting on AZA day 5). Anticancer activity, safety and pharmacokinetics and pharmacodynamics were evaluated. We report here on the MDS cohort. Results: Twenty patients with MDS were enrolled. Eight patients had received prior therapy for MDS including decitabine (n=1), lenalidomide (n=3), tipifarnib (n=2) and cytarabine (n=2). Median age was 70.5 yrs (range 41-81). Disease control rate (defined as CR + marrow-CR + PR + SD) was 80% (16/20). Ten patients (50%) had baseline marrow blast counts ≥10% (protocol-defined high risk). Responses in high-risk patients included 5 (50%) with CR + marrow-CR and 2 (20%) with SD. Six patients (30%) had an on-treatment marrow blast count of 0. These included 3 patients in the high-risk category, with baseline blast counts of 11%-15%. CR was observed in one patient, a 74-yr-old male with previously untreated RAEB. In this patient, marrow blasts fell from a baseline of 11% to 0% following 1 cycle of treatment; CR with normalization of all cell lines was achieved by late Cycle 3. He remained on study for 1 yr. Most drug-related AEs in the study were grade 1 or 2. The most common drug-related grade 3/4 events were nausea (15%), vomiting, fatigue, anemia, thrombocytopenia and febrile neutropenia (10% each). There was one death (5%), due to pneumonia that was not felt by the investigator to be drug related. Conclusions: The combination of mocetinostat and 5-azacitidine in patients with MDS demonstrated an acceptable safety profile and encouraging evidence of clinical benefit. Further clinical studies are warranted. Clinical trial information: NCT00324220.

A phase II study of single agent mocetinostat, an oral isotype-selective histone deacetylase (HDAC) inhibitor, in patients with diffuse large cell B-cell (DLBCL) and follicular (FL) lymphomas.

8535 Background: Mocetinostat (MGCD0103) is an orally available, isotype-selective, non-hydroxamate HDAC inhibitor targeting HDACs 1,2, 3 and 11 with single-agent activity in Hodgkin’s lymphoma and in AML and MDS (in combination with 5-azacitidine). More than 430 patients have been treated to date. Methods: This open-label, phase II trial enrolled patients with DLBCL and FL. Patients received mocetinostat at doses ranging from 70-110 mg 3x/wk every 28 days. Anticancer activity, safety, pharmacokinetics and pharmacodynamics were evaluated. Results: Sixty-nine patients with DLBCL (n=41) and FL (n=28) were enrolled for treatment at starting doses of 85-110 mg. Median age was 62 years (range: 32 to 81). Median duration of treatment was ~3 months (range: <1 to 24). Objective response rate in DLBCL and FL, respectively, was 7/41 (17%; including 2 unconfirmed PRs) and 3/28 (11%; including 1 CR). Median time to response was 2.0 mos (range 1.7-21.0) and 5.3 mos (range 4.3-6.0) respectively. Stable disease was achieved by 13/41 (32%) and 14/28 (50%), respectively, for a disease control rate of 49% and 61%, respectively. Mean duration of SD in patients with DBLCL was ~4.5 mos (range 2-12 mos), with 10 patients remaining stable for ≥3 mos. Among FL patients, mean duration of SD was approximately 4.1 mos (range 1.7-13 mos), with 9 patients remaining stable for ≥3 mos. The FL CR occurred in a 62-year-old female with paratracheal, subcarinal and portal target lesions who achieved a PR after 4 cycles and CR after 12 cycles that persisted through the remaining 4 mos on study. Study drug was discontinued for adverse events in 19/69 (28%). Fatigue, weight loss or anorexia were most common (n=4 each). A total of 26 drug-related SAEs were reported among 12 patients (17%; 1-6 events per pt). There were no drug related deaths. Enrollment is complete and final data will be presented. Conclusions: Single-agent mocetinostat has activity in DLBCL and FL. Fatigue, gastrointestinal, and cardiac symptoms are the most common adverse events resulting in discontinuation of dosing. Based on the acceptable tolerability and clinical activity further development is warranted. Clinical trial information: NCT00359086.

Mocetinostat for relapsed classical Hodgkin's lymphoma: an open-label, single-arm, phase 2 trial

The prognosis of patients with relapsed Hodgkin's lymphoma, especially those who relapse after stem-cell transplantation, is poor, and the development of new agents for this patient population is an unmet medical need. We tested the safety and efficacy of mocetinostat, an oral isotype-selective histone deacetylase inhibitor, in patients with relapsed classical Hodgkin's lymphoma. Patients with relapsed or refractory classical Hodgkin's lymphoma aged 18 years or older were treated with mocetinostat administered orally three times per week, in 28-day cycles. Two doses were assessed (85 mg and 110 mg). Patients were treated until disease progression or prohibitive toxicity. The primary outcome was disease control rate, defined as complete response, partial response, or stable disease (for at least six cycles), analysed by intention to treat. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00358982. 51 patients were enrolled. Initially, 23 patients were enrolled in the 110 mg cohort. Subsequently, because toxicity-related dose reductions were necessary in the 110 mg cohort, we treated 28 additional patients with a dose of 85 mg. On the basis of intent-to-treat analysis, the disease control rate was 35% (eight of 23 patients) in the 110 mg group and 25% (seven of 28) in the 85 mg group. 12 patients (24%) discontinued treatment because of adverse events, nine (32%) in the 85 mg cohort and three (13%) in the 110 mg cohort. The most frequent treatment-related grade 3 and 4 adverse events were neutropenia (four patients [17%] in the 110 mg group, three [11%] in the 85 mg group); fatigue (five patients [22%] in the 110 mg group, three [11%] in the 85 mg group); and pneumonia (four patients [17%] in the 110 mg group, two [7%] in the 85 mg group). Four patients, all in the 110 mg cohort, died during the study, of which two might have been related to treatment. Mocetinostat, 85 mg three times per week, has promising single-agent clinical activity with manageable toxicity in patients with relapsed classical Hodgkin's lymphoma. MethylGene Inc, Montreal, Canada; Celgene Corporation, Summit, NJ, USA; Tufts Medical Center, Boston, MA, USA.

The Histone Deacetylase Inhibitor MGCD0103 Induces Apoptosis in B-Cell Chronic Lymphocytic Leukemia Cells through a Mitochondria-Mediated Caspase Activation Cascade

Clinical trials have shown activity of the isotype-selective histone deacetylase (HDAC) inhibitor MGCD0103 in different hematologic malignancies. There are data to support the use of HDAC inhibitors in association with other cancer therapies. To propose a rational combination therapy, it is necessary to depict the molecular basis behind the cytotoxic effect of MGCD0103. In this study, we found that MGCD0103 was substantially more toxic in neoplastic B cells relative to normal cells, and we described the death pathways activated by MGCD0103 in B-cell chronic lymphocytic leukemia (CLL) cells from 32 patients. MGCD0103 decreased the expression of Mcl-1 and induced translocation of Bax to the mitochondria, mitochondrial depolarization, and release of cytochrome c in the cytosol. Caspase processing in the presence of the caspase inhibitor Q-VD-OPh and time course experiments showed that caspase-9 was the apical caspase. Thus, MGCD0103 induced the intrinsic pathway of apoptosis in CLL cells. Moreover, MGCD0103 treatment resulted in the activation of a caspase cascade downstream of caspase-9, caspase-dependent amplification of mitochondrial depolarization, activation of calpain, and Bax cleavage. We propose a model whereby the intrinsic pathway of apoptosis triggered by MGCD0103 in CLL is associated with a mitochondrial death amplification loop.

Promising antitumor activity with MGCD0103, a novel isotype-selective histone deacetylase inhibitor

Background: Histone deacetylases (HDACs), which target histones as well as non-histone proteins as substrates, have the potential to regulate aberrant gene expression and restore normal growth control in malignancies. Objective: This review provides an updated summary of preclinical and clinical experience with the oral isotype-selective HDAC inhibitor MGCD0103 in cancer. Methods: Data presented in abstract form from international conferences or journal articles found within a PubMed search of article up to May 2008 are described in this review. Results/conclusions: MGCD0103 appears tolerable and exhibits favorable pharmacokinetic and pharmacodynamic profiles with evidence of target inhibition in surrogate tissues. Clinical and pharmacodynamic data support a three-times-weekly administration at a 90-mg fixed dose. MGCD0103 displays promising antitumor activity in hematological and lymphoproliferative diseases.

Isotype-selective histone deacetylase (HDAC) inhibitor MGCD0103 demonstrates clinical activity and safety in patients with relapsed/refractory classical Hodgkin Lymphoma (HL)

8507 Background: With no approved post-transplant therapies, HL patients (pts) with relapsed or refractory disease have poor prognosis. MGCD0103 is an oral isotype-selective inhibitor of histone deacetylases (HDACs) with significant preclinical and clinical activity in hematopoietic cancers. Methods: Open-label, Phase II trial in adults with relapsed/refractory HL (Trial 010); most with prior transplant. Pts received MGCD0103 at 110 or 85 mg 3x per week in 4-week cycles. Plasma Thymus and Activation Regulated Chemokine (TARC) levels were determined by ELISA. Responses were assessed by CT and PET. Results: 33 pts have been enrolled to date (median age, 31 yrs; range, 19–62 yrs) of which 29 (88%) had prior transplant. Among 23 pts in the 110 mg cohort, 21 were evaluable, of whom 2 (10%) had a complete response (CR) and 6 (29%) had a partial response (PR) for an overall response (OR) rate of 38% (median time to response, 2 cycles). The 2 pts with CR had progression free survival lasting >270 and >420 days with both responses ongoing. One additional pt (5%) had SD >6 cycles. Among 10 pts in the 85 mg cohort, 5 were evaluable for efficacy, all of whom had tumor reductions of ≥30%, including 1 PR and 2 SDs (45% and 49% tumor reduction). Comparison between 85 and 110 mg revealed 20% and 39% of pts respectively with ≥ grade 3 toxicity. Decrease in Day 8 plasma TARC levels correlated with clinical response (PR+CR). Conclusions: MGCD0103 demonstrated significant anti-tumor activity in relapsed/refractory post-transplant HL. The 85 mg dose exhibited meaningful activity and may be better tolerated. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration MethylGene Inc., Pharmion Corporation MethylGene Inc. MethylGene Inc.

Treatment of relapsed or refractory non-hodgkin lymphoma with the oral isotype-selective histone deacetylase inhibitor MGCD0103: Interim results from a phase II study

8528 Background: MGCD0103 is an orally available selective inhibitor of histone deacetylases (HDACs) with significant biological activity in preclinical models of both solid tumors and hematopoietic cancers. Methods: Open-label, Phase II trial in adults (Trial 008) with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL). Eligibility included: ≥1 site of measurable disease (≥2.0 cm), ECOG 0 or 1. MGCD0103 was given 3x/week starting at 110 mg; after 32 patients (pts) the starting dose was reduced to 85 mg. Tumor responses were determined every 2 cycles. PK was evaluated on Day 1, Cycle 1. Results: 50 pts received treatment; 33 DLBCL and 17 FL (median age [range], 61.5 years [32−80]; male, n=27; prior rituximab therapy: 96%; prior stem cell transplant: 33%). The response rate in pts with DLBCL met the protocol defined criteria for expansion beyond 21 pts, and enrollment of this cohort is now complete. Of 17 DLBCL pts with tumor reassessed by CT, most had tumor reduction, including 1 CR & 3 PRs (response rate 23.5%), with progression free survival (PFS) for responders ranging from 168 to >336 days. Five DLBCL pts with stable disease had PFS ranging from 112 to >336 days. One of 10 FL pts with tumor reassessment had a PR. All 50 pts were evaluable for safety: the most common toxicities grade ≥3 were fatigue (14%), neutropenia (12%), thrombocytopenia (10%), and anemia (6%). Comparison of data available to date of the 85 mg and 110 mg cohorts revealed 16% and 53% of patients, respectively, with ≥ grade 3 toxicity. MGCD0103 was rapidly absorbed (median Tmax = 1 hr), and disappeared biphasically (plasma t½, approximately 8 hrs). Similar exposures (Cmax & AUC) were observed at 85 (n=8) and 110 (n=17) mg, suggesting a trend towards saturable absorption. Inhibition of HDAC activity in PBMCs was seen in 13/18 pts (9/13 at 85 mg and 4/5 at 110 mg) and is similar between the group treated with 85 mg or with 110 mg. Conclusions: MGCD0103 demonstrated significant anti-cancer activity in relapsed or refractory NHL (DLCBL and FL subtypes) and had a manageable side effect profile. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration MethylGene, Pharmion MethylGene MethylGene

MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo

Nonselective inhibitors of human histone deacetylases (HDAC) are known to have antitumor activity in mice in vivo, and several of them are under clinical investigation. The first of these, Vorinostat (SAHA), has been approved for treatment of cutaneous T-cell lymphoma. Questions remain concerning which HDAC isotype(s) are the best to target for anticancer activity and whether increased efficacy and safety will result with an isotype-selective HDAC inhibitor. We have developed an isotype-selective HDAC inhibitor, MGCD0103, which potently targets human HDAC1 but also has inhibitory activity against HDAC2, HDAC3, and HDAC11 in vitro. In intact cells, MGCD0103 inhibited only a fraction of the total HDAC activity and showed long-lasting inhibitory activity even upon drug removal. MGCD0103 induced hyperacetylation of histones, selectively induced apoptosis, and caused cell cycle blockade in various human cancer cell lines in a dose-dependent manner. MGCD0103 exhibited potent and selective antiproliferative activities against a broad spectrum of human cancer cell lines in vitro, and HDAC inhibitory activity was required for these effects. In vivo, MGCD0103 significantly inhibited growth of human tumor xenografts in nude mice in a dose-dependent manner and the antitumor activity correlated with induction of histone acetylation in tumors. Our findings suggest that the isotype-selective HDAC inhibition by MGCD0103 is sufficient for antitumor activity in vivo and that further clinical investigation is warranted.

Treatment of Relapsed or Refractory Lymphoma with the Oral Isotype-Selective Histone Deacetylase Inhibitor MGCD0103: Interim Results from a Phase II Study.

Purpose: MGCD0103 is an oral inhibitor of histone deacetylases (HDACs) with isotype-selective activity against HDAC-1, -2, -3, and -11. MGCD0103 exhibits significant biological activity in preclinical models of hematopoietic cancers. Although several HDAC inhibitors have shown promising clinical activity in patients (pts) with T-cell lymphoid malignancies, the clinical activity of HDAC inhibitors have not been previously examined in B-cell lymphoma. The purpose of this study was to examine the efficacy and tolerability of MGCD0103 as monotherapy for the treatment of relapsed or refractory follicular and diffuse large B-cell lymphoma.Methods : This was an open-label, multi-center, phase II trial in adults (≥18 years) with relapsed or refractory lymphoma. The trial contained 2 cohorts of pts with diagnoses of either diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL). Eligibility required the presence of ≥1 site of measurable disease (≥2.0 cm) and an ECOG performance status of 0 or 1. Oral MGCD0103 was initially dosed at 110 mg 3× per week in 4-week cycles, with escalation to 135 mg or reductions to 85 and 60 mg permitted based on patient tolerance. Pts enrolled later in the trial had starting doses of 85 mg, with escalation to 110 mg and reductions to 60 and 40 mg permitted. On day 1 of cycle 1, blood samples were collected for PK analysis before dosing and at 0.5, 1, 2, 4, 6, and 24 hours.Results: To date, 38 pts (mean age, 60.3 ± 13.0 yrs; male, n=18) have been dosed: 19 with DLCBL and 19 with FL, all of whom have received prior Rituxan. Nineteen of 24 pts (79%) who had tumor size reassessed by CT scan after treatment initiation exhibited some tumor reduction; 12 (50%) exhibited >30% reduction and 7 (29%) exhibited >40% reduction. Twenty-five pts (1 pt has not yet had disease reassessed) were formally evaluable for clinical response; 16 (64%) have completed ≥3 cycles (12 weeks) of treatment. A CR was observed in 1 pt with FL after 2 cycles. PRs were observed in 2 pts with DLBCL after 2 and 4 cycles respectively and 1 pt with FL after 6 cycles. Twenty pts required dose reductions for management of toxicities. In 35 pts evaluable for safety, the most common non-hematologic toxicities were fatigue (24 pts), nausea (22), diarrhea (17), anorexia and decreased appetite (12), vomiting (10), and weight loss (9). Grade 3 toxicities occurred in 10 pts; fatigue and weight decrease being the most common. There were no grade 4 non-hematological toxicities. Hematological toxicities were minimal, with 1 pt requiring dose modification for thrombocytopenia and 2 for neutropenia. Significant inhibition of HDAC activity in PBMCs was seen in the majority of pts evaluated. Population PK (N=16) revealed: Cmax 119 ± 73 ng/ml, AUC (0–24) 715 ± 495 ng*hr/ml.Conclusions: Interim results from this ongoing trial suggest that single-agent MGCD0103 demonstrates significant anti-cancer activity in relapsed or refractory non-Hodgkin's lymphoma (DLCBL and FL subtypes) and has a manageable side effect profile.

Phase I/II Study of MGCD0103, an Oral Isotype-Selective Histone Deacetylase (HDAC) Inhibitor, in Combination with 5-Azacitidine in Higher-Risk Myelodysplastic Syndrome (MDS) and Acute Myelogenous Leukemia (AML).

Epigenetic alterations are common in leukemia. MGCD0103 in an oral isotype-selective HDAC inhibitor that synergizes in vitro with the DNA methyltransferase inhibitor 5-azacitidine (Vidaza, Pharmion). Both agents have single-agent clinical activity in MDS and AML (Garcia-Manero, ASCO, 2006 & Silverman, JCO, 2002). We have developed a Phase I/II study of 5-azacitidine in combination with MGCD0103 in patients with AML and MDS. Patients with MDS (≥10% marrow blasts), relapsed/refractory AML, or untreated elderly patients with AML were eligible. Adequate performance status, renal and hepatic functions were required. 5-azacitidine was administered at its approved dose/schedule: 75 mg/m2 SC daily for the first 7 days of a 28 day cycle. MGCD0103 was administered as a flat dose orally three-times a week starting on the 5th day of 5-azacitidine administration. The phase I portion of the study design followed a classic “3+3” model and only MGCD0103 was dose escalated. The phase II portion targeted a 30% response rate. Final data from the Phase I and II portions of the study will be presented at the Meeting. Five dose levels of MGCD0103 have been evaluated: 35, 60, 90, 110 and 135 mg. At current data cut-off, 37 patients registered in the study were fully evaluable: median age was 67 (range 27–85); 31 patients had AML and 6 MDS. A total of 97 cycles were administered to date, mean = 2.6 (range 1–12). Dose limiting toxicities included nausea, vomiting, anorexia, diarrhea and dehydration which appear similar to dose limiting toxicities for MGCD0103 alone. The MTD of MGCD0103 was initially determined to be 110 mg, however, upon cohort expansion, this dose level was associated with excess toxicity and the starting dose was decreased to 90 mg. Eleven (30%) patients have achieved response: 4 CR, 5 CR-i, and 2 PR. Of these 11 patients, 6 continue on study with mean duration on study of 7 cycles. Of the 5 patients discontinued, 3 discontinued due to SAEs, 1 due to progressive disease and 1 to undergo transplantation. Of the 27 patients at the phase II dose levels of 90 and 110mg, 10 achieved a response (37%; same rate at both doses). Preliminary response data are available at the time of abstract preparation for 13 additional patients, revealing 4 with CR (one of which had 1% residual peripheral blast) and 3 with CR-I for a response rate of 53% in this subset. MGCD0103 pharmacokinetics were not affected by 5-azacitidine. Likewise, co-administration of MGCD0103 had no impact on the pharmacokinetics of 5-azacitidine. A majority of patients exhibited a substantial reduction in PBMC HDAC activity during treatment with the combination. Analysis of DNA methylation is ongoing. In conclusion, the combination of 5-azacitidine with MGCD0103 is safe in patients with advanced AML/MDS and has clinical activity potentially superior to that expected with 5-azacitidine alone in this patient population. These results form the bases of a planned randomized study of 5-azacitidine with or without MGCD0103 in AML and MDS.

Phase I/II study of a novel oral isotype-selective histone deacetylase (HDAC) inhibitor MGCD0103 in combination with azacitidine in patients (pts) with high-risk myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML)

7062 Background: Aberrant DNA methylation and histone acetylation are common in leukemia. The HDAC inhibitor MGCD0103 (0103) and the DNA methyltransferase inhibitor azacitidine (aza); which is approved for all FAB subtypes of MDS, synergize preclinically and both have single-agent activity in MDS and AML. Based on these data, we developed a Phase I/II study of combination aza + 0103 in pts with AML and MDS. Phase I data is presented. Methods: Pts with advanced MDS (=10% marrow blasts), relapsed/refractory or untreated elderly patients with AML were treated with aza 75 mg/m2 SC daily for 7d of each 28-day cycle and 0103 110mg 3x/week starting on day 5. The primary endpoint was determination of the maximum tolerated dose (MTD) of the combination. The phase I portion followed “3+3” model; only 0103 was escalated. Results: Dose levels of 0103 explored were 35, 60, 90, 110 and 135 mg. 24 pts (those having received =1 dose of MGCD0103) have been evaluated; AML=22, MDS=2. Median age 67 (40–85), total cycles=56 (mean=2.3, range=1–11). Dose limiting toxicities observed: vomiting (1/8 pts at 90 mg), nausea & anorexia (2/3 pts at 135 mg), and anorexia (1/6 pts at 110 mg). The MTD of 0103 in the combination was determined to be110 mg. PK characteristics of neither drug was altered by co-administration. 7/9 pts had significant reduction of whole cell HDAC activity during treatment with the combination. Antileukemia activity was documented in 7 pts; 6 of which were among 14 at the 2 most relevant dose levels (90 & 110 mg): 3 CR, 1 PR, and 3 CR without platelet or neutrophil recovery (required for per- protocol response). Of these 7, 4 are ongoing and 3 have been discontinued: 1 to transplant and 2 for SAEs. Conclusions: The Phase I portion of the trial demonstrates that the 0103+aza combination is safe in pts with advanced AML/MDS, and has encouraging biologic & clinical activity. Phase II portion of the study is ongoing at MTD. Molecular studies are ongoing. No significant financial relationships to disclose.

A phase II study of a novel oral isotype-selective histone deacetylase (HDAC) inhibitor in patients with relapsed or refractory Hodgkin lymphoma

8000 Background: MGCD0103 is a non-hydroxamate, isotype-selective, inhibitor of human HDACs. Abnormal regulation of HDAC activity is associated with malignant disease in humans, and small molecule HDAC inhibitors are a novel drug class with anticancer potential. Their proposed anti-Hodgkin activity is through regulation of aberrant gene expression at the transcriptional level by inhibiting proliferation, inducing apoptosis, and/or initiating differentiation in cancer cells. Methods: A phase II trial of MGCD0103 (110 mg 3x/week in 4- week cycles) is ongoing in patients (pts) with relapsed/refractory Hodgkin Lymphoma (RRHL). The primary endpoint is a composite of objective response and stable disease. Results: As of Dec 15th, 2006, 18 pts out of a planned 12–35 have been enrolled; median age 28 (range: 21–62). All pts were previously treated with autologous and/or allogeneic stem cell transplant. The median number of cycles received to date is 2 (range: 1–4). Seven pts have completed =8 weeks (2 cycles) of therapy and are evaluable for response analysis; 5 of these had tumor reduction ranging between 21% and 70% by CT, which is associated with a significant reduction in FDG-PET activity in 4 pts. Of the 18 pts, 5 have had dose reductions/discontinuations due to: mucositis (n=1); fatigue/nausea/diarrhea (n=1); nausea/vomiting (n=1); fatigue (n=1) and pancreatitis/hypotension (n=1). Significant HDAC inhibition (>20% of total activity), was seen in PBMCs from 7/9 pts with samples. Treatment is ongoing in 14 pts; including those with tumor reduction. Criteria have been met to expand to the second stage of the study (>1 response demonstrated in the first 12 patients). Conclusions: Preliminary results suggest that single-agent MGCD0103 demonstrates significant anti-tumor activity in RRHL and is well tolerated at a Phase II dose of 110mg in this ongoing trial. No significant financial relationships to disclose.

Phase I/II Study of the Oral Isotype-Selective Histone Deacetylase (HDAC) Inhibitor MGCD0103 in Combination with Azacitidine in Patients (pts) with High-Risk Myelodysplastic Syndrome (MDS) or Acute Myelogenous Leukemia (AML).

Aberrant DNA methylation and histone code alterations are common in leukemia. The oral isotype-selective HDAC inhibitor MGCD0103 and the DNA methyltransferase inhibitor azacitidine have been shown to have synergistic antileukemia activity in preclinical models. Both agents have single-agent clinical activity in MDS and AML (Garcia-Manero, ASCO, 2006 & Silverman, JCO, 2002). Based on this, we have developed a Phase I/II study of the combination in leukemia. Patients with relapsed/refractory MDS (10% or more marrow blasts) or AML, or untreated older patients with AML are eligible. Adequate performance status, renal and hepatic functions are required. Azacitidine is administered at its approved dose/schedule: 75 mg/m2 SC daily x 7 every 28 days. MGCD0103 was started on day 5 of azacitidine and was given as an oral dose 3 times a week without adjusting for body weight, without interruption. The phase I portion of the study design followed a classic “3+3” model and only MGCD0103 was dose escalated. Three dose levels of MGCD0103 have been studied so far: 35, 60 and 90 mg. Twelve patients have been registered in this study. The median age is 61 (range 45–85). All, but 1 patient with MDS, had AML. All patients had relapsed or refractory disease. A total of 24 cycles have been administered, mean = 2.0 (range 1–4). Only 1 patient has experienced dose limiting toxicity: grade 3 vomiting at a dose of 90 mg of MGCD0103. Otherwise, the combination has been very well tolerated and the MTD has not yet been defined, with dosing currently ongoing at the approximate MTD of single agent MGCD0103: 110 mg orally three times a week without interruption. Preliminary PK data indicate that the t1/2 for azacitidine is less than 2 h, and does not appear to be affected by MGCD0103. Likewise, MGCD0103 pharmacokinetic characteristics do not appear to be affected by azacitidine. The majority of patients exhibited substantial reduction in HDAC activity during treatment with the combination. Analysis of DNA methylation is ongoing. Two patients have achieved response: 1 complete remission after 4 courses of therapy (in an older patient in first relapsed AML with an initial CR duration of 11 months and multiple cytogenetic abnormalities). A second older patient with refractory AML achieved a complete marrow CR (marrow blasts less than 5%) but died from pneumonia (not drug-related) after the second course of therapy on day 28 before peripheral count recovery. In conclusion, the combination of azacitidine with MGCD0103 is safe in patients with advanced AML/MDS. The combination has encouraging safety, PK, and clinical activity profiles. The study continues at the MTD of single agent MGCD013 in combination with azacitidine. Once the MTD of the combination is documented, the study will continue as a phase II study in this patient population.

300 POSTER Phase I study of an oral isotype-selective histone deacetylase (HDAC) inhibitor in patients (pts) with advanced solid tumors

300 POSTER Phase I study of an oral isotype-selective histone deacetylase (HDAC) inhibitor in patients (pts) with advanced solid tumors

Phase I study of isotype-selective histone deacetylase (HDAC) inhibitor MGCD0103 given as three-times weekly oral dose in patients (pts) with advanced solid tumors

3007 Background: MGCD0103 is a novel isotype-selective inhibitor of human HDACs. Deacetylation of histones by HDACs is postulated to inactivate tumor suppressor genes leading to neoplastic transformation. Inhibition of these enzymes might restore normal growth control. Methods: A phase I trial of MGCD0103, given as a three-times weekly oral dose 2 out of every 3 weeks, has been performed in pts with advanced solid tumors. Main endpoints are safety, tolerability, pharmacokinetics (PK), pharmacodynamic (PD) assessments of HDAC activity and histone acetylation status in buffy coat white cells. Results: Five dose levels have been evaluated (mg/m2): 12.5, 20, 27, 36, and 45. As of January, 2006, 28 pts have been enrolled with the following demographics: M:F = 18:10; median age (range) = 60 (29–75); ECOG 0:1:2 = 9:13:1 (n = 23); primary tumor sites: colorectal (8), renal (5), lung (4), others (11); prior chemotherapy, radiotherapy, immunotherapy were given to 22, 12 and 2 pts, respectively (n=23). A total of 62 cycles have been administered, with median = 2 and range=1–7 cycles. MGCD0103 has been well tolerated; most common AEs (23 pts): grade 1–3 fatigue (91% of pts), grade 1–2 nausea and vomiting (70 and 48%), anorexia (26%), constipation (39%). Disease stabilization > 2 cycles has been observed in 3 renal cell cancer pts (4, 6, and 7 cycles) and 1 colorectal cancer pt (4 cycles). Preliminary PK analyses demonstrated intra-pt PK variability, however co-administration of acidic carbonated beverage (protocol amendment) appears to reduce variability without altering average Cmax or AUC (0–24) comparing Day 1 with Day 14. There was little accumulation or decrease in concentrations with extended dosing, and t1/2 was dose-independent at 7.7–11.3 hr. (±0.6–1.6). PD data reveal dose-dependent maximal inhibition of HDAC activity in patients co-administered an acidic beverage. Conclusions: At doses evaluated MGCD0103 appears tolerated and exhibits favourable PK and PD. [Table: see text]

Pharmacodynamic effect of MGCD0103, an oral isotype-selective histone deacetylase (HDAC) inhibitor, on HDAC enzyme inhibition and histone acetylation induction in phase I clinical trials in patients (pts) with advanced solid tumors or non-Hodgkin’s lymphoma (NHL)

9631 Background: Histone deacetylase inhibitors represent a new class of targeted anticancer agents. Deacetylation of histones by HDACs is postulated to inactivate tumor suppressor genes leading to neoplastic transformation. Thus, inhibition of these enzymes might restore normal growth control. Several HDAC inhibitors, including MGCD0103, are in clinical trials. Methods: To analyze the pharmacodynamic properties of MGCD0103 in Phase I clinical studies, we have used a variety of biological assays to monitor HDAC inhibitory activity. An HDAC enzyme assay using intact white cells from patients was used to monitor the enzyme inhibitory activity of MGCD0103, while histone acetylation in these cells was analyzed by Western blotting, fluorescence-activated cell sorting (FACS) and enzyme-linked immunosorbent assay (ELISA). Results: We demonstrate that, in 3 of the first 7 patients for whom comparative data are available, HDAC enzyme inhibition correlates positively with histone acetylation induction in their peri...

83 Antitumor activities of MGCD0103, a novel isotype-selective histone deacetylase inhibitor

83 Antitumor activities of MGCD0103, a novel isotype-selective histone deacetylase inhibitor