JOURNAL OF CLINICAL ONCOLOGY Phase IIB Multicenter Trial of Vorinostat in Patients WithPersistent, Progressive, or Treatment Refractory CutaneousT-Cell LymphomaElise A. Olsen, Youn H. Kim, Timothy M. Kuzel, Theresa R. Pacheco, Francine M. Foss, Sareeta Parker,Stanley R. Frankel, Cong Chen, Justin L. Ricker, Jean Marie Arduino, and Madeleine Duvic From Duke University, Durham, NC; Stanford University, Stanford, CA; Northwestern University, Chicago, IL; University of Colorado Health Sciences Center at Fitzsimons, Aurora, CO; To evaluate the activity and safety of the histone deacetylase inhibitor vorinostat (suberoylanilide Tufts-New England Medical Center, hydroxamic acid) in persistent, progressive, or recurrent mycosis fungoides or Sézary syndrome Boston, MA; Emory University, Atlanta, (MF/SS) cutaneous t-cell lymphoma (CTCL) subtypes.
GA; Merck Research Laboratories, Upper Gwynedd, PA; and the M.D.
Patients and Methods
Anderson Cancer Center, Houston, TX.
Patients with stage IB-IVA MF/SS were treated with 400 mg of oral vorinostat daily until diseaseprogression or intolerable toxicity in this open-label phase IIb trial (NCT00091559). Patients must Submitted December 4, 2006; accepted have received at least two prior systemic therapies at least one of which included bexarotene April 20, 2007; published online ahead of print at on June 18, 2007.
unless intolerable. The primary end point was the objective response rate (ORR) measured by themodified severity weighted assessment tool and secondary end points were time to response Supported by research funding from Merck Research Laboratories.
(TTR), time to progression (TTP), duration of response (DOR), and pruritus relief (ⱖ 3-pointimprovement on a 10-point visual analog scale). Safety and tolerability were also evaluated.
Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology in Atlanta, GA, June Seventy-four patients were enrolled, including 61 with at least stage IIB disease. The ORR was 3-6, 2006; and at the 48th Annual 29.7% overall; 29.5% in stage IIB or higher patients. Median TTR in stage IIB or higher patients Meeting of the American Society of was 56 days. Median DOR was not reached but estimated to be ⱖ 185 days (34⫹ to 441⫹).
Hematology in Orlando, FL, December Median TTP was 4.9 months overall, and ⱖ 9.8 months for stage IIB or higher responders. Overall, 32% of patients had pruritus relief. The most common drug-related adverse experiences (AE) Authors' disclosures of potential con- were diarrhea (49%), fatigue (46%), nausea (43%), and anorexia (26%); most were grade 2 or flicts of interest and author contribu- tions are found at the end of this lower but those grade 3 or higher included fatigue (5%), pulmonary embolism (5%), thrombocy- topenia (5%), and nausea (4%). Eleven patients required dose modification and nine discontinueddue to AE.
Address reprint requests to Elise A.
Olsen, MD, Divisions of Dermatology and Oncology, Duke University Medical Oral vorinostat was effective in treatment refractory MF/SS with an acceptable safety profile.
Center, Durham, NC 27710; e-mail: J Clin Oncol 25:3109-3115. 2007 by American Society of Clinical Oncology 2007 by American Society of Clinical with advanced (stage IIB or higher) disease usually develop progressive disease (PD)6 after becoming Cutaneous T-cell lymphomas (CTCLs) are a group intolerant of, or refractory to, multiple treatments.
of non-Hodgkin's lymphomas that initially present Novel effective treatments are needed, especially for in the skin and may ultimately involve lymph nodes, advanced MF/SS patients, with the goals of durable blood, and visceral organs.1,2 The majority of in- remission, prevention of progression, and improve- stances of CTCL are classified as mycosis fungoides ment in quality of life.
(MF) or Sézary syndrome (SS), both characterized Vorinostat (Zolinza; Merck & Co, White- by proliferation of mature CD4⫹/CD45RO⫹ T house Station, NJ; suberoylanilide hydroxamic cells and sharing the same classification and staging acid) is a histone deacetylase (HDAC) inhibitor.7 system.3,4 MF may present clinically as plaques, HDAC inhibition results in histone acetylation patches, tumors, or erythroderma. SS is defined as and activation of gene expression.8 Defective erythroderma with leukemic involvement with or histone-acetylation regulatory enzymes have been without adenopathy or visceral involvement.2,5 Pa- identified in malignant cells,9,10 and HDAC inhi- tient prognosis is based on disease stage.6 Curative bition may have anticancer properties through modalities for MF/SS remain elusive and patients restoration of normal acetylation. Vorinostat has Information downloaded from and provided by SEMMELWEIS UNIV OF MEDICINE on October 4, 2009 from Copyright 2007 by the American Society of Clinical Oncology. All rights reserved. Olsen et al
induced histone acetylation, cell cycle arrest, apoptosis, and anti- Patients with PD, unacceptable toxicity, or uncontrolled intercurrent tumor activity in preclinical cancer models.11-14 In phase I studies, illness were discontinued from the trial. Other criteria for discontinuation vorinostat has been generally well-tolerated with dose-limiting included: patient withdrawal of consent, noncompliance with study medica-tion or visits, lack of efficacy, or any change that would render the patient toxicities of anorexia, dehydration, diarrhea, fatigue, nausea, vom- ineligible for further treatment. Patients who completed ⱖ 6 study months iting, and thrombocytopenia.7,15-18 In these trials, activity was were offered vorinostat treatment in a continuation trial.
observed in patients with solid and hematologic malignancies,including CTCL. A phase II trial confirmed the activity and safety Efficacy and Safety Measurements
The mSWAT is an instrument utilized to track the skin tumor burden in of oral vorinostat in patients with treatment-refractory CTCL and MF/SS. The investigator measured the percentage total body-surface area provided the basis for the selection of a 400-mg once daily dose for (TBSA, %) involvement separately for patches, plaques, and tumors within 12 body regions using the patient's palm and fingers representing 1% of The primary objective of this phase IIb trial (NCT00091559) was TBSA. Patients with erythroderma were assessed for percentage of TBSA to determine the response rate of oral vorinostat for patients with stage involved with patches and/or plaques. The percentage of TBSA for each lesion IIB or higher SS/MF who had progressive, persistent, or recurrent type was multiplied by a number (patch ⫽ 1, plaque ⫽ 2; tumor ⫽ 4) andsummed to derive the mSWAT score. The mSWAT was determined by the disease. Assessment of the safety and tolerability of vorinostat in this same individual at all study visits.
population as well as time to response (TTR), duration of response A complete response (CR) required 100% clearing of skin disease and a (DOR), time to progression (TTP), and pruritus relief were second- partial response (PR) required ⱖ 50% reduction in the mSWAT score com- ary objectives.
pared with baseline. CR/PR required confirmation by repeat assessment after ⱖ 4 weeks. Stable disease was defined as less than 50% reduction to less than25% increase in the mSWAT score compared with baseline. PD was defined as PATIENTS AND METHODS
ⱖ 25% increase in the mSWAT score from baseline or ⱖ 50% increase in the This multicenter, open-label, single-arm, nonrandomized phase IIb trial wasapproved by the institutional review boards of each of the participating med- Table 1. Baseline Characteristics
ical centers. All patients provided written informed consent before enrollment.
All patients must have had histologically confirmed MF/SS documented as stage IB or higher at study entry and with progressive, persistent, or recur- rent disease. Patients must have received at least two prior systemic therapies, at least one of which must have included bexarotene unless the patient was unable to tolerate this therapy. Other inclusion criteria were: age 18 years or older, Eastern Cooperative Oncology Group performance status of 0 to 2, life expectancy longer than 3 months, and adequate hematologic, hepatic, and renal function. Patients must have agreed to practice effective contraception unless infertility was documented. Exclusion criteria included prior HDAC inhibitor therapy or any other anticancer therapy given concurrently or within 3 weeks of baseline. Only patients on stable doses of topical steroids (potency 0.1% triamcinolone acetonide) or SS patients on stable doses of systemic Time from first CTCL treatment or diagnosis, yearsⴱ steroids (ⱕ 10 mg prednisone/d) for ⱖ 3 months before study entry were allowed to continue on these medications during the study. Supportive treat- ment with antihistamines was permitted. Patients who were pregnant or No. of prior systemic treatments lactating, had acute infection requiring intravenous antibiotics, known HIV infection, active hepatitis B or C infection, or other uncontrolled intercurrent illness were also excluded.
Patients received 400 mg of oral vorinostat once daily for 7 days per week.
Vorinostat was withheld for grade 4 anemia or thrombocytopenia, other grade 3 to 4 drug-related toxicities, or, at the investigator's discretion, grade 3 to 4 Denileukin diftitox nondrug-related toxicities until resolution to ⱕ grade 1. After recovery from a drug-related toxicity, the dose was modified to 300 mg once daily for 7 days per week. If a second dose modification was required, the dose was reduced to 300 mg once daily for 5 consecutive days per week.
Study visits were conducted biweekly for the first 2 months, and every 4 weeks thereafter for the remainder of the study. Patient medical histories, physical examinations, laboratory tests, and assessments of compliance with study medication, adverse experiences, and efficacy (modified severity Se´zary syndrome weighted assessment tool [mSWAT], photographs, and pruritus intensity) Clinically abnormal lymph nodes were conducted during study visits. ECGs were conducted at baseline and every 4 weeks after starting therapy. Computed tomography with or without positron emission tomography scans were performed within 6 weeks of base- line to help establish peripheral lymph node size and assign TNM classifica- Abbreviation: CTCL, cutaneous T-cell lymphoma.
tion and repeated for tracking purposes in patients with a documented ⴱWhichever event occurred first.
cutaneous response.
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sum of the products of the greatest diameters of pathologically positive lymph and treatment compliance while patients were on active treatment nodes compared with baseline. TTR was the time from the first vorinostat dose was more than 94%. Sixty-one patients discontinued: 27 specifi- until the patient first met the criteria for a 50% decrease in the mSWAT score.
cally due to progressive disease, nine due to a clinical adverse The DOR was the time from first CR/PR until the mSWAT score was increased experience, and 25 for other reasons, such as patient withdrawal of from nadir to more than 50% of the difference between the baseline and nadirscores. TTP was the time from start of treatment until PD. If patients went off consent or lack of efficacy. One patient completed 12 study months vorinostat for any purpose, this date was utilized for determination of TTP and 12 patients remained on vorinostat at the time of data cutoff.
and/or DOR. Although no global score was derived from skin, nodes, andblood, a reduction of ⱖ 50% in index lymph node size or ⱖ 25% blood tumor burden were reported individually and in comparison with the mSWAT score.
The objective response rate was 29.7% overall, and 29.5% in Patients rated their pruritus intensity on a 10-point visual analog scale (0 ⫽ no MF/SS patients with stage IIB or higher disease (Table 2). All initial pruritus; 10 ⫽ worst imaginable). Pruritus relief was defined as a ⱖ 3-point responses were confirmed PRs; one patient achieved a CR after 281 reduction in those who had a baseline pruritus score of ⱖ 3 points or complete days on vorinostat treatment. One third of patients (10 of 30) with SS resolution of pruritus for ⱖ 4 continuous weeks without an increase in the use responded (36.4% of those with confirmed SS by the International of antipruritus medications.
The severity (National Cancer Institute Common Terminology Criteria, Society for Cutaneous Lymphomas criteria); four of these 10 respond- version 3.0), duration, and relationship to vorinostat were determined for each ers had a concomitant blood tumor burden reduction ⱖ 25%. Over- adverse experience. Safety data were collected from the first treatment day until all, 14 of 27 assessable SS patients had a blood tumor burden reduction 30 days after the last vorinostat dose.
ⱖ 25%. Representative photographs of MF lesions are shown (Fig 1 and Appendix Fig A1, online only). Of the 24 assessable patients All data from March 2004 to May 2006 were analyzed with the median with clinically abnormal lymph nodes, 10 (41.7%) had a ⱖ 50% time on drug of 115.5 days (range, 2 to 480⫹ days). All patients who received reduction in lymph node size, including four of 10 with an objec- one or more vorinostat doses were assessable for efficacy and safety analyses.
tive cutaneous response.
PR/CR rates were determined with corresponding 95% CI by the exact Among patients with stage IIB or higher MF/SS, the median TTR method. Enrollment of ⱖ 50 assessable patients with stage IIB or higher MF/SS was 56 days (range, 28 to 171 days) and the median DOR was not was planned. In patients with stage IIB or higher MF/SS who had received twoor more prior systemic therapies, a conservative estimate of the maximum reached but was ⱖ 185 days (range, 34⫹ to 441⫹ days). The median spontaneous response rate was 5%.20 Vorinostat would be considered active TTP was 148 days for all patients, and was not reached but was ⱖ 299 for MF/SS treatment if the observed response rate was ⱖ 20% with the lower days (range, 85 to 470⫹ days) for responding patients with stage IIB or bound of the 95% CI more than 5%. With a sample size of 50, the study would higher CTCL. Response to vorinostat was not impacted by response to have 90% power to meet the joint criteria if the true response rate was 27% and the last systemic treatment (Appendix Table A1).
90% power to exclude 5% alone if the true response rate was 20%. There were Twenty-nine additional patients (48%) with stage IIB or higher three prespecified subgroup analyses: all patients, those with SS, and those with disease attained clinical benefit as signified by mSWAT score improve- tumor disease.
ment (Fig 2) but did not meet the objective response criteria: 10 ofthese patients experienced stable disease for ⱖ 24 weeks. One of the most important quality of life issues in MF/SS patients is pruritus.
Among study patients with baseline pruritus scores ⱖ 3 points, 32.3% had pruritus relief with improvement in pruritus noted in both re- Seventy-four patients with MF/SS, including 61 (82%) with sponders and nonresponders (Table 3). In those patients with the stage IIB or higher disease, were enrolled in this trial. Table 1 most severe pruritus (baseline scores of 7 to 10 points), 43.3% had summarizes the baseline patient and disease characteristics. Forty- pruritus relief, including five of 16 SS patients and 30% who achieved point five percent were designated by the investigator as SS (29.7% a score less than 3 at two or more consecutive visits. The median time had confirmed SS by the International Society for Cutaneous Lym- to and duration of pruritus relief among patients with stage IIB or phomas criteria).5 The average treatment duration was 5.3 months higher disease were 16 and 113 days, respectively.
Table 2. Response
Patients With an Objective Responseⴱ Duration of Response Time to Progressive Stage IIB and higher§ With Se´zary syndrome With tumor disease Abbreviation: NR, not reached.
ⴱObjective response was confirmed complete response or partial response.
†The Kaplan-Meier estimates were NR, but were estimated to be at least 165, 185, and 165 days, respectively.
‡The Kaplan-Meier estimates were NR, but were estimated to be at least 256, 299, 209, and 448 days, respectively.
§Stages IIB, III, IVA, and IVB.
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Fig 1. Photographs: baseline and during vorinostat treatment. (A) This patient (IIB) had previously received radiation, interferon alpha, and bexarotene. Time to
response (TTR), duration of response (DOR), and time to progression (TTP) were 87, 55, and 448 days. (B) This patient (IIB) received four prior therapies. TTR, DOR,and TTP were 29, 441⫹, and 470⫹ days. The patient achieved a complete response after 281 days.
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Patients with more than 100% increase in SWAT Fig 2. Best individual modified severity
weighted assessment tool (mSWAT) scoreimprovement at any one study visit amongstage IIB or higher patients. Negative change signifies the percentage of improvement inthe mSWAT score. Forty-seven (77%) of 61patients had a reduced mSWAT score duringvorinostat treatment. Two patients did nothave valid follow-up skin assessments and were not included in the analysis.
Percentage of Change in mSW Individual Patients Safety and Toxicity
median time to onset of drug-related grade 3 or higher events was 43 The most common drug-related adverse experiences were gas- days (1 to 263 days), and the median duration of these events was 12 trointestinal, constitutional, and hematologic abnormalities, or taste days (range, 1 to 257⫹ days). Eight (11%) of 74 patients had drug- disorders presented in Table 4. Most adverse effects were mild to related serious adverse experiences, which included: thromboembolic moderate in severity and did not require dose reduction or interrup- events (pulmonary embolism [three], pulmonary embolism/deep tion of therapy. One of three patients on warfarin at baseline required vein thrombosis [one]), anemia, blood creatinine increase, death, dose reduction in warfarin while on vorinostat to maintain target dehydration, gastrointestinal hemorrhage, ischemic stroke, strepto- international normalized ratio. ECG changes were noted in 15 pa- coccal bacteremia, syncope, and thrombocytopenia (Table 4). The tients, 10 who had a history of cardiovascular disease or a baseline median time to onset of these events was 42 days (range, 2 to 227 abnormal ECG (Appendix Table A2, online only). There were no days). Of these patients, four recovered from the serious adverse drug-related grade 3 or higher ECG adverse experiences. One patient experiences and four discontinued the study because of these events.
had grade 2 QTc prolongation (⬎ 470 to 500 milliseconds or increase There were three deaths on study: one secondary to disease progres- of ⬎ 60 milliseconds above baseline) and two had grade 1 QTc pro- sion (day 52), one secondary to ischemic stroke (day 227), and one of longation (⬎ 450 to 470 milliseconds) without other cardiac symp- unexplained cause (day 2). This latter patient had hypertension and toms. None of the ECG adverse experiences resulted in vorinostat dose valvular heart disease and died within 24 hours of changing blood modification or discontinuation. Overall, nine patients had one dose pressure medication and without confirmation of having taken the modification and two patients required two dose modifications due to first dose of vorinostat.
adverse experiences; nine patients discontinued due to adverse expe-riences, including seven that were drug-related.
Twenty-one (28%) of 74 patients had drug-related grade 3/4 adverse experiences. The most common were fatigue (5%), pulmo-nary embolism (5%), thrombocytopenia (5%), and nausea (4%). The The primary objective of this multicenter, phase IIb trial was to deter-mine the response rate of oral vorinostat in the treatment of patientswith stage IIB or higher MF/SS who had progressive, persistent, or Table 3. Pruritus Relief
recurrent disease. Approximately 30% of patients overall, and of those Patients With Pruritus with stage IIB or higher disease, achieved an objective response. These results are encouraging and comparable with the findings of the phase No. of Patients No.
IIa trial of oral vorinostat (31% at 400 mg/d).19 In the current trial, With baseline pruritus score 33% of SS patients and 23% of those with tumor disease had objective responses, signifying activity in more aggressive CTCL forms. There 7-10 points (severe pruritus) was no obvious impact observed of the response to last treatment, With an objective response either bexarotene or other therapies, on subsequent vorinostat activ- Without an objective response ity. These results suggest that vorinostat is noncrossresistant to cur- ⴱTwo patients had missing baseline pruritus scores and were excluded from rently available treatments and may be of benefit to patients regardless the analyses.
of prior treatment failure.
†Pruritus relief is pruritus reduction of ⱖ 3 points or complete resolution for ⱖ 4 continuous weeks.
The secondary study objectives were to assess TTR, DOR, TTP, and pruritus relief, as well as the safety and tolerability, of oral Information downloaded from and provided by SEMMELWEIS UNIV OF MEDICINE on October 4, 2009 from Copyright 2007 by the American Society of Clinical Oncology. All rights reserved. Olsen et al
from vorinostat therapy, including 11 of 74 with prolonged stable Table 4. Drug-Related Adverse Experiences (N ⫽ 74)
disease and six with ⱖ 50% reduction in abnormal index lymph node size. The symptom of pruritus negatively influences quality of life for CTCL patients23,24; however, 32% of assessable patients, including 25% of those who did not meet the objective response criteria, alsoachieved pruritus relief with vorinostat. This latter clinical benefit was Most common (⬎ 10%)ⴱ achieved early and typically sustained for the duration of the study.
The 400-mg dose of vorinostat was generally well-tolerated.
As of March 1, 2007, 15 patients have received treatment for ⱖ 1 year (range, 12.0 to 27.6⫹ months) and six patients are continuing to receive vorinostat after data cutoff. Less than 15% of MF/SS patients overall required a dose reduction in vorinostat, 9% were discontinued due to drug-related adverse experiences, and 11% had any drug-related serious adverse experiences. Similar to previ- Blood creatinine increase ous trials with oral vorinostat,7,15,17-19 the most common toxicities were related to gastrointestinal or constitutional symptoms, hema- tologic abnormalities, or taste disorders, and were mostly mild to moderate in severity. QTc prolongation was observed in three patients (only one of which was grade 2), and no associated clinical sequelae were reported. This is a much lower incidence and severity Thromboembolic events† of QTc changes than reported with two other HDAC inhibitors, depsipeptide and LBH589.25,26 The only serious adverse experi- Blood creatinine increase ence observed in more than one patient was thromboembolic events (5%). The explanation for this is unclear and further inves- tigations are ongoing. Importantly, infections were notably lacking in this study, an impressive finding given the normally high rate of Streptococcal bacteremia infections in CTCL, particularly those with SS. The lack of need for venous access probably contributed to this salutary effect.
Vorinostat is a novel anticancer agent that provided objective NOTE. Based on National Cancer Institute Common Terminology Criteria, responses in 30% and pruritus relief in 32% of patients with version 3.0.
treatment-refractory MF including those with tumor disease and ⴱNone of these experiences required discontinuation of vorinostat.
†Including three patients with pulmonary embolism and one with pulmonary SS. Clinically valuable long lasting responses were observed. Dis- embolism and deep vein thrombosis.
tinct from other agents used to treat CTCL, median TTR wasrelatively short. The median DOR was ⱖ 6.1 months and themedian TTP was ⱖ 9.8 months among stage IIB or higher patients.
vorinostat in this patient population. The median TTR was rela- As responses to vorinostat therapy were observed in patients who tively quick (⬍ 2 months). The median DOR was not reached, but were refractory to prior bexarotene and other therapies, vorinostat was estimated to be ⱖ 6.1 months in patients with stage IIB or appears to work in a manner that is noncrossresistant to other higher CTCL. The median TTP was 4.9 months overall, and was CTCL treatments. Vorinostat was generally well-tolerated, is an not reached, but estimated to be ⱖ 9.8 months in responding effective single agent, and should be considered an appropriate patients with stage IIB or higher CTCL. The durability of response therapeutic option for patients with advanced MF/SS CTCL sub- and prolonged TTP provide meaningful clinical benefit. It is diffi- types. Vorinostat may also find utility in a combination regimen cult to directly compare these results with other clinical trials of with either skin-directed or other systemic agents.
approved agents in the treatment of CTCL as other trials useddifferent definitions of response, DOR, and TTP.20-22 Posthoc analyses were performed using more conservative defi- AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS
nitions of DOR and TTP that were not prespecified in the protocol.
DOR was redefined as the time from first CR/PR until the mSWAT Although all authors completed the disclosure declaration, the following score was increased more than 50% from nadir (v ⬎ 50% of the authors or their immediate family members indicated a financial interest. difference between baseline and nadir scores) and PD was redefined as No conflict exists for drugs or devices used in a study if they are not being ⱖ 25% increase in the mSWAT score or ⱖ 50% increase in the sum of evaluated as part of the investigation. For a detailed description of the the products of the greatest diameters of pathologically positive lymph disclosure categories, or for more information about ASCO's conflict of nodes compared with nadir (v baseline) measurements. In responders interest policy, please refer to the Author Disclosure Declaration and the with stage IIB or higher CTCL, the median DOR and TTP were 5.6 and Disclosures of Potential Conflicts of Interest section in Informationfor Contributors. 7.0 months, respectively, compared with an estimated 6.1 and 9.8 Employment: Stanley R. Frankel, Merck Research Laboratories; Cong
months using the protocol-defined methods.
Chen, Merck Research Laboratories; Justin L. Ricker, Merck Research As in the phase IIa vorinostat CTCL trial,19 a number of patients Laboratories; Jean Marie Arduino, Merck Research Laboratories who did not achieve an objective response still obtained clinical benefit Leadership: N/A Consultant: Elise A. Olsen, Merck & Co; Youn H. Kim,
JOURNAL OF CLINICAL ONCOLOGY Information downloaded from and provided by SEMMELWEIS UNIV OF MEDICINE on October 4, 2009 from Copyright 2007 by the American Society of Clinical Oncology. All rights reserved. Phase IIb Trial of Vorinostat in CTCL
Merck & Co; Theresa R. Pacheco, Merck & Co; Madeleine Duvic, Merck Provision of study materials or patients: Elise A. Olsen, Youn H. Kim,
& Co Stock: Stanley R. Frankel, Merck & Co; Cong Chen, Merck & Co;
Timothy M. Kuzel, Theresa R. Pacheco, Sareeta Parker, Stanley R.
Justin L. Ricker, Merck & Co; Jean Marie Arduino, Merck & Co Frankel, Madeleine Duvic Honoraria: Madeleine Duvic, Merck & Co Research Funds: Elise A.
Collection and assembly of data: Elise A. Olsen, Youn H. Kim, Theresa
Olsen, Merck & Co; Youn H. Kim, Merck & Co; Sareeta Parker, Merck & R. Pacheco, Francine M. Foss, Sareeta Parker, Stanley R. Frankel, Co; Madeleine Duvic, Merck & Co Testimony: Timothy M. Kuzel,
Merck & Co Other: Timothy M. Kuzel, Merck & Co
Data analysis and interpretation: Elise A. Olsen, Timothy M. Kuzel,
Sareeta Parker, Stanley R. Frankel, Cong Chen, Justin L. Ricker, Jean
Marie Arduino, Madeleine Duvic
Manuscript writing: Elise A. Olsen, Timothy M. Kuzel, Stanley R.
Frankel, Justin L. Ricker
Conception and design: Elise A. Olsen, Timothy M. Kuzel, Stanley R.
Final approval of manuscript: Elise A. Olsen, Youn H. Kim, Timothy M.
Frankel, Cong Chen, Jean Marie Arduino, Madeleine Duvic Kuzel, Theresa R. Pacheco, Francine M. Foss, Sareeta Parker, Stanley R.
Financial support: Stanley R. Frankel
Frankel, Cong Chen, Justin L. Ricker, Jean Marie Arduino, Madeleine Administrative support: Stanley R. Frankel
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Information downloaded from and provided by SEMMELWEIS UNIV OF MEDICINE on October 4, 2009 from Copyright 2007 by the American Society of Clinical Oncology. All rights reserved.


Marine ecology progress series 530:119

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