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The Isotype-Selective HDAC Inhibitor MGCD0103 Decreases Plasma TARC Concentrations and Produces Clinical Responses in Heavily Pretreated Patients
With Relapsed Classical Hodgkin’s Lymphoma
Anas Younes1, John Kuruvil a2, Barbara Pro1, Michel e Fanale1, Peter McLaughlin1, Sattva Neelapu1, Luis Fayad1, Amanda Wedgwood1, Daniela Buglio1, Marja Dubay3, Tracy-Ann Patterson3, André Karam3, Renée Ward4, Robert E. Martel 3, Gregory Bociek5
1MD Anderson Cancer Center, Houston, Texas; 2Princess Margaret Hospital, Toronto, Canada; 3MethylGene Inc., Montreal, Canada; 4Pharmion Corporation, Overland Park, Kansas City; 5University of Nebraska, Omaha, Nebraska
Figure 1. Study Design.
ABSTRACT
Figure 4. Inhibition of Whole-Cell HDAC Activity in Patient PBMCs
Figure 2. Change From Baseline in Tumor Measurements (Best Response) in the 110 mg (Purple) and 85 mg (Green) Cohorts (n=26).
(Cycle 1 Day 8 vs. Baseline).
Purpose: Hodgkin’s Lymphoma (HL) patients with recurrent or refractory disease have poor prognosis and are considered incurable with
currently available salvage therapy. Novel therapeutic agents are needed in this patient population. MGCD0103 is an oral isotype-selective

MGCD0103 (3x per week in 4-week cycles)*
110 mg (n=21)
85 mg (n=5)
inhibitor of histone deacetylases (HDACs) with significant biological activity in preclinical models of hematopoietic cancers.
Methods: A phase II trial of MGCD0103 is ongoing in patients with relapsed/refractory classical HL. Patients enrolled initially in the trial
received MGCD0103 at 110 mg 3x per week in 4-week cycles, with dose reductions to 85, 60, and 35–40 mg in case of toxicities (110 mg
Cycle 2 and Beyond
cohort). Following enrollment of 23 patients, a starting dose of 85 mg is being evaluated in an effort to ascertain alternate doses for poten-
Pretreatment
End of Study
tial future trials. Eligibility criteria included at least one target lesion (≥ 2 cm), ECOG performance status of 0–1, and platelet counts
≥ 25,000/µL. Previous treatment with autologous and/or allogeneic stem cell transplant, regardless of the number of prior treatment regi-

Activity
mens, was allowed. Tumor responses were determined every 8 weeks. Plasma TARC levels were determined by ELISA using blood samples
obtained before starting and 8 days after therapy.
To date, a total of 33 patients have been enrolled in the trial (median age, 31 yrs; range, 19–62 yrs). Among 23 patients enrolled at
the 110 mg starting dose, 21 were evaluable, of whom 2 (10%) had CRs and 6 (29%) had PRs for an OR rate of 38% (median time to response,
2 cycles). One additional patient (5%) had SD ≥ 6 cycles and 10 (48%) had SD > 2 cycles and < 6 cycles. The rate of disease control (CR + PR
+ SD [≥ 6 cycles]) was 43%. As assessed by CT scans, 18/21 patients (86%) enrolled at 110 mg exhibited tumor reductions: 12 (57%) had
Inhibition
reductions of > 30%, and 8 (38%) had reductions of ≥ 50%. Preliminary data from the 85 mg cohort revealed all 5 evaluable patients with
tumor reductions of ≥ 30% including 1 PR and 2 SDs (45% and 49% tumor reduction). Three of the evaluable patients are ongoing. The most
common non-hematological toxicities ≥ grade 3 were pneumonia (15%), fatigue (9%), abnormal liver function tests (6%), and sepsis (6%).
There were 2 deaths on study where association with study drug was possible, both in heavily pretreated patients: one of unknown cause
in a woman with a history of mantle x-ray therapy and BMT who suffered from significant GI AEs; and the other of neutropenic fever and sepsis
Baseline
PBMC, peripheral blood mononuclear cells; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; and NE, non-evaluable.
*Initial patients were enrolled at 110 mg with dose reductions to 85, 60, and 35-40 mg permitted in case of toxicities; later patients were enrolled at 85 mg with dose reductions to 60 in a man with severe marrow compromise at baseline. Significant HDAC inhibition (> 20% of total activity) was seen in PBMCs from 7 of 9
sampled patients. In 15 paired samples collected on Day 8 of therapy, plasma TARC levels were decreased from baseline by at least 40% in
and 35-40 mg permitted; †Tumor assessments were conducted at the ends of even-numbered cycles (i.e., Cycles 2, 4, 6, etc.).
5 patients who achieved major clinical responses (PR + CR).
-37 -40 -41
Figure 5. Plasma TARC Levels in Sera From HL Patients at Day 0 and Day 8.
Conclusions: Interim results from this ongoing trial suggest that single-agent MGCD0103 demonstrates significant anti-tumor activity in
-49 -50 -51 -51
relapsed/refractory classical HL and is well tolerated, with dose modifications used as necessary to manage toxicities. Patients treated at
Baseline
85 mg had significant evidence of tumor shrinkage; furthermore, modulation of TARC may be a biomarker of MGCD0103 clinical activity in
Table 1. Patient Characteristics.
HL patients.
BACKGROUND
Total patients enrolled
Relapsed/refractory Hodgkin’s Lymphoma (HL) is a life-threatening disease with no approved therapies. After bone marrow transplantation, patients Individual Patients
with relapsed or refractory disease are considered incurable and have relatively short survival.
MGCD0103 is a non-hydroxamate, orally-available, small molecule inhibitor of Class I and 4 HDACs (HDAC-1, -2, -3, and -11). Selectivity for HDAC-1, -2, -3 and -11 may increase the therapeutic index of MGCD0103 over other pan-HDAC inhibitors.
Evaluability
TARC,pg/m
■ Epigenetic modifications, including alterations to the acetylation patterns of histones (i.e., the “histone code”), have been described in cells from Figure 3. Duration on Study, Best Response, and Dosing (n=33). Colored bars indicate the
Table 3. Responder Characteristics in the 110 mg Cohort.
■ Inhibition of histone deacetylases with MGCD0103 has been shown to induce apoptosis in HL cell lines.
MGCD0103 dosage on the first day of the designated cycle.
Data from phase I studies on MGCD0103 showed that: – A dose of 45–60 mg/m2 (85–110 mg flat dose) appeared to be well tolerated and resulted in single agent activity.
Response
– Dose-limiting toxicities (DLTs) included fatigue and GI side effects.
Time to response (cycles*)
OBJECTIVES
Patients with
Patients with
Patients with
Not evaluated
Demographics
clinical response
stable disease
progressive disease
Duration of response (cycles*)
To assess the anticancer effects of MGCD0103 in patients with relapsed or refractory classical HL by estimating: – The disease control rate (complete response [CR] + partial response [PR] + stable disease [SD 6 cycles]); Gender, :
– The duration of objective response; and Treatment duration (cycles*)
Figure 6. Correlation of Plasma TARC Reduction and Tumor Shrinkage.
– The duration of progression-free survival.
Starting Dose (n=23)
Patients with response (50% tumor shrinkage) and at least 40% decrease in plasma TARC levels are highlighted.
To characterize the safety profile of MGCD0103; and Progression-free survival (months)†
■ To identify potential biomarkers and/or predictive markers for efficacy or toxicity of MGCD0103.
Final MGCD0103 dosage (mg)
Prior regimens
Study Design
■ This is an ongoing, multicenter, non-randomized, open-label, phase II trial in adults (18 years) with relapsed or refractory classical HL (Figure 1).
Transplant
The main eligibility criteria included: pathologic confirmation of classical HL; relapsed or refractory disease; at least 1 site of measurable disease Starting Dose (n=10)
Baseline
, ongoing; CR, complete response; PR, partial response; auto, autologous BMT; allo, allogeneic BMT.
(2.0 cm) as measured by conventional techniques (e.g., CT or MRI); ECOG performance status of 0 or 1; and adequate hematology (platelet counts *One cycle = 28 days; †The range of progression-free survival was from 56 to > 396 days.
25,000/µL), chemistry, and renal profiles.
r2=0.404
■ Previous treatment with autologous and/or allogeneic stem cell transplant, regardless of the number of prior treatment regimens, was allowed.
Relative
Patients enrolled initially in the trial received MGCD0103 at 110 mg 3x per week in 4-week cycles, with dose reductions to 85, 60, and 35–40 mg Prior treatment
■ Reasons for discontinuation included treatment completion, graft vs. host disease (possibly present at baseline), BMT as a result of response, non-compliance, and on-study death (3 patients). One of these deaths was considered not related and the other 2 were considered to have a possible Following enrollment of 23 patients, a starting dose of 85 mg is being evaluated in an effort to ascertain alternate doses for potential , Ongoing
NE*: Non-evaluable: off therapy at cycle 1 due to toxicity.
association with treatment (described under Table 4).
NE†: Non-evaluable: recently started therapy, too soon to assess response.
Efficacy Assessments
NE‡: Off study for toxicities and began chemotherapy.
■ Lesions 2 cm were measured bidimensionally by computed tomography (CT) or spiral CT (Figure 1).
■ Response to therapy was assessed according to the following criteria: ■ Thirteen patients in the trial discontinued with best responses of SD. Of these, 3 discontinued due to an AE (graft vs. host disease; thrombocytopenia Table 4. Toxicities Grade 3 Occurring in More than 1 Patient With MGCD0103
Complete response (CR): Complete disappearance of all clinical, physical, biochemical, and radiological abnormalities;
and hematuria; abdominal pain and worsening fatigue), 8 due to PD (new lesions), 1 due to PD (existing lesions; 25% increase), and 1 requested to Administration in the 110 mg and 85 mg Cohorts.* Total patients, n=33.
Partial response (PR): Reduction of 50% in the sum of the products of the perpendicular diameters of all measurable disease (no new lesions
Ratio of plasma TARC level (Day 8 / Baseline)
Stable disease (SD): The sum of the products of perpendicular diameters of the lesions does not meet criteria for CR, PR or PD (SD must be
Table 2. Clinical Response in the 110 mg Cohort.
maintained for at least 6 cycles to be considered for disease control endpoint); and – Progressive disease (PD): Appearance of new lesions or increase by 25% in the sum of the products of perpendicular diameters of the lesions.
CONCLUSIONS
Safety and Tolerability Assessments
Safety and tolerability was assessed by physical exam, vital signs, hematology, plasma chemistry, 12-lead ECG, and adverse events (AEs), utilizing ■ Oral monotherapy with MGCD0103 exhibited significant anti-tumor activity in patients with classical relapsed/refractory Hodgkin’s
Best response
standard methodologies (Figure 1).
Lymphoma, most with prior transplant, where there are currently no approved therapies (Tables 2 and 3 and Figure 2).
AEs were categorized according to their relationship to study treatment and assessed for severity (grades 1–5).
Pharmacodynamics and Biomarker Assessments
– Among 21 evaluable patients at the starting dose of 110 mg, 2 (10%) had CRs and 6 (29%) had PRs, for an OR rate of 38% and
■ Whole-cell HDAC activity levels were assessed in peripheral blood mononuclear cells (PBMCs) (Figure 1).
disease control rate (CR + PR + SD [≥ 6 cycles]) of 43% (Tables 2 and 3).
PBMC isolation: Whole blood was collected in heparin tubes and shipped at room temperature to be processed within 24 hours. PBMCs were
– Preliminary data from the 85 mg cohort revealed all 5 evaluable patients with tumor reductions ≥ 30%, including 1 PR and 2 near
enriched by centrifugation over Lymphoprep™ (Axis-Shield, Oslo, Norway), and any remaining erythrocytes in the sample were lysed by treatment PRs (49% and 45% reduction). Three of the evaluable patients are ongoing in this cohort.
with EL lysis buffer (Qiagen Inc., Valencia, CA, USA).
Whole-cell enzyme assay: Isolated PBMCs were incubated with Boc-Lys(ε-Ac)-AMC (Bachem, San Carlos, CA, USA), a membrane permeable
Pneumonia and fatigue were the most common non-hematological toxities ≥ grade 3 (Table 4).
HDAC substrate. After one hour at 37°C, the reaction was quenched with 1 µM TSA (BioMol International, LP, Exeter, England), cells were lysed with Objective response
HDAC inhibition was observed in surrogate tissue (PBMCs) in 8 of 10 patients (Figure 4).
1% NP-40, and the deacetylated product was cleaved with the Fluor-de-Lys developer (BioMol International, LP, Exeter, England). Fluorescence was Other (donor lymphocyte infusion, BCL-2 antagonist) read at Ex 360, Em 470, Cutoff 435 on a SpectraMax GeminiXS fluorometer (Molecular Devices, Sunnyvale, CA, USA).
Plasma TARC levels were reduced in most patients and this reduction may correlate with response (Figures 5 and 6).
Plasma TARC Expression Level: Plasma from patients was separated and frozen until use. To determine the plasma levels of TARC, frozen plasma
These data are supportive for potential future trials.
was thawed, centrifuged at 2,500 RPM for 10 minutes, and analyzed using the Quantikine Human CCL17/TARC ELISA (R&D Systems, Inc., Minneapolis, MN, USA) according to the manufacturer’s instructions. TARC concentration (pg/ml) in the samples was calculated from a curve *Two on-study deaths with possible association to drug: 1) heavily pretreated, 23-year-old male who had anemia and thrombocytopenia prior to study treatment and developed ECOG, Eastern Cooperative Oncology Group; BMT, bone marrow transplantation.
■ Among 5 evaluable patients in the 85 mg cohort, 1 patient had a PR and 2 had near PR (49% and 45% reduction). Three of the evaluable patients are neutropenic fever, and sepsis while on study, and subsequently died; 2) heavily pretreated (including mantle x-ray therapy and bone marrow transplant), 40-year-old female with Poster presented at the American Society of Hematology 49th Annual Meeting and Exposition, December 8-11, 2007, Atlanta, GA, USA.
generated by the TARC standard provided in the kit. Plasma samples that tested above the detection level of the assay (2,000 pg/mL) were diluted *Completed 1 cycle of treatment and had their disease reassessed or had early progressive disease; †includes patients with a history of autologous BMT (28), allogeneic BMT (7), multiple concomitant medications and a history of hypertension, hypothyroidism, and bipolar disorder who developed protracted diarrhea and intermittent nausea/vomiting; the and both autologous and allogeneic BMT (6).
MethylGene Inc. and Pharmion provided financial support for this study.
patient died of unknown cause 3 days after the last dose of study medication.

Source: http://methylgene.solocom.biz/files/2011/10/poster083.pdf

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