Originally published as JCO Early Release 10.1200/JCO.2006.10.2434 on June 18 2007

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Phase IIB Multicenter Trial of Vorinostat in Patients With Persistent, Progressive, or Treatment Refractory Cutaneous T-Cell Lymphoma

Elise 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, 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; Tufts-New England Medical Center, Boston, MA; Emory University, Atlanta, GA; Merck Research Laboratories, Upper Gwynedd, PA; and the M.D. Anderson Cancer Center, Houston, TX

Address reprint requests to Elise A. Olsen, MD, Divisions of Dermatology and Oncology, Duke University Medical Center, Durham, NC 27710; e-mail: olsen001{at}mc.duke.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Purpose To evaluate the activity and safety of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid) in persistent, progressive, or recurrent mycosis fungoides or Sézary syndrome (MF/SS) cutaneous t-cell lymphoma (CTCL) subtypes.

Patients and Methods Patients with stage IB-IVA MF/SS were treated with 400 mg of oral vorinostat daily until disease progression or intolerable toxicity in this open-label phase IIb trial (NCT00091559). Patients must have received at least two prior systemic therapies at least one of which included bexarotene unless intolerable. The primary end point was the objective response rate (ORR) measured by the modified severity weighted assessment tool and secondary end points were time to response (TTR), time to progression (TTP), duration of response (DOR), and pruritus relief ( 3-point improvement on a 10-point visual analog scale). Safety and tolerability were also evaluated.

Results Seventy-four patients were enrolled, including 61 with at least stage IIB disease. The ORR was 29.7% overall; 29.5% in stage IIB or higher patients. Median TTR in stage IIB or higher patients was 56 days. Median DOR was not reached but estimated to be 185 days (34+ to 441+). Median TTP was 4.9 months overall, and 9.8 months for stage IIB or higher responders. Overall, 32% of patients had pruritus relief. The most common drug-related adverse experiences (AE) were diarrhea (49%), fatigue (46%), nausea (43%), and anorexia (26%); most were grade 2 or lower but those grade 3 or higher included fatigue (5%), pulmonary embolism (5%), thrombocytopenia (5%), and nausea (4%). Eleven patients required dose modification and nine discontinued due to AE.

Conclusion Oral vorinostat was effective in treatment refractory MF/SS with an acceptable safety profile.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Cutaneous T-cell lymphomas (CTCLs) are a group of non-Hodgkin's lymphomas that initially present in the skin and may ultimately involve lymph nodes, blood, and visceral organs.^1,2 The majority of instances of CTCL are classified as mycosis fungoides (MF) or Sézary syndrome (SS), both characterized by proliferation of mature CD4+/CD45RO+ T cells and sharing the same classification and staging system.^3,4 MF may present clinically as plaques, patches, tumors, or erythroderma. SS is defined as erythroderma with leukemic involvement with or without adenopathy or visceral involvement.^2,5 Patient prognosis is based on disease stage.⁶ Curative modalities for MF/SS remain elusive and patients with advanced (stage IIB or higher) disease usually develop progressive disease (PD)⁶ after becoming intolerant of, or refractory to, multiple treatments. Novel effective treatments are needed, especially for advanced MF/SS patients, with the goals of durable remission, prevention of progression, and improvement in quality of life.

Vorinostat (Zolinza; Merck & Co, Whitehouse Station, NJ; suberoylanilide hydroxamic acid) is a histone deacetylase (HDAC) inhibitor.⁷ HDAC inhibition results in histone acetylation and activation of gene expression.⁸ Defective histone-acetylation regulatory enzymes have been identified in malignant cells,^9,10 and HDAC inhibition may have anticancer properties through restoration of normal acetylation. Vorinostat has induced histone acetylation, cell cycle arrest, apoptosis, and antitumor activity in preclinical cancer models.^11-14 In phase I studies, vorinostat has been generally well-tolerated with dose-limiting toxicities of anorexia, dehydration, diarrhea, fatigue, nausea, vomiting, and thrombocytopenia.^7,15-18 In these trials, activity was observed in patients with solid and hematologic malignancies, including CTCL. A phase II trial confirmed the activity and safety of oral vorinostat in patients with treatment-refractory CTCL and provided the basis for the selection of a 400-mg once daily dose for further study.¹⁹

The primary objective of this phase IIb trial (NCT00091559) was to determine the response rate of oral vorinostat for patients with stage IIB or higher SS/MF who had progressive, persistent, or recurrent disease. Assessment of the safety and tolerability of vorinostat in this population as well as time to response (TTR), duration of response (DOR), time to progression (TTP), and pruritus relief were secondary objectives.

	PATIENTS AND METHODS

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This multicenter, open-label, single-arm, nonrandomized phase IIb trial was approved by the institutional review boards of each of the participating medical centers. All patients provided written informed consent before enrollment.

Patient Eligibility
All patients must have had histologically confirmed MF/SS documented as stage IB or higher at study entry and with progressive, persistent, or recurrent 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 steroids ( 10 mg prednisone/d) for 3 months before study entry were allowed to continue on these medications during the study. Supportive treatment with antihistamines was permitted. Patients who were pregnant or lactating, had acute infection requiring intravenous antibiotics, known HIV infection, active hepatitis B or C infection, or other uncontrolled intercurrent illness were also excluded.

Study Design
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 nondrug-related toxicities until resolution to 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 weighted assessment tool [mSWAT], photographs, and pruritus intensity) 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 baseline to help establish peripheral lymph node size and assign TNM classification and repeated for tracking purposes in patients with a documented cutaneous response.

Patients with PD, unacceptable toxicity, or uncontrolled intercurrent illness were discontinued from the trial. Other criteria for discontinuation included: patient withdrawal of consent, noncompliance with study medication or visits, lack of efficacy, or any change that would render the patient ineligible for further treatment. Patients who completed 6 study months were offered vorinostat treatment in a continuation trial.

Efficacy and Safety Measurements
The mSWAT is an instrument utilized to track the skin tumor burden in MF/SS. The investigator measured the percentage total body-surface area (TBSA, %) involvement separately for patches, plaques, and tumors within 12 body regions using the patient's palm and fingers representing 1% of TBSA. Patients with erythroderma were assessed for percentage of TBSA involved with patches and/or plaques. The percentage of TBSA for each lesion type was multiplied by a number (patch = 1, plaque = 2; tumor = 4) and summed to derive the mSWAT score. The mSWAT was determined by the same individual at all study visits.

A complete response (CR) required 100% clearing of skin disease and a partial response (PR) required 50% reduction in the mSWAT score compared with baseline. CR/PR required confirmation by repeat assessment after 4 weeks. Stable disease was defined as less than 50% reduction to less than 25% increase in the mSWAT score compared with baseline. PD was defined as 25% increase in the mSWAT score from baseline or 50% increase in the sum of the products of the greatest diameters of pathologically positive lymph nodes compared with baseline. TTR was the time from the first vorinostat dose until the patient first met the criteria for a 50% decrease in the mSWAT score. The DOR was the time from first CR/PR until the mSWAT score was increased from nadir to more than 50% of the difference between the baseline and nadir scores. TTP was the time from start of treatment until PD. If patients went off vorinostat for any purpose, this date was utilized for determination of TTP and/or DOR. Although no global score was derived from skin, nodes, and blood, a reduction of 50% in index lymph node size or 25% blood tumor burden were reported individually and in comparison with the mSWAT score. Patients rated their pruritus intensity on a 10-point visual analog scale (0 = no pruritus; 10 = worst imaginable). Pruritus relief was defined as a 3-point reduction in those who had a baseline pruritus score of 3 points or complete resolution of pruritus for 4 continuous weeks without an increase in the use of antipruritus medications.

The severity (National Cancer Institute Common Terminology Criteria, version 3.0), duration, and relationship to vorinostat were determined for each adverse experience. Safety data were collected from the first treatment day until 30 days after the last vorinostat dose.

Statistical Analysis
All data from March 2004 to May 2006 were analyzed with the median time on drug of 115.5 days (range, 2 to 480+ days). All patients who received one or more vorinostat doses were assessable for efficacy and safety analyses. PR/CR rates were determined with corresponding 95% CI by the exact method. Enrollment of 50 assessable patients with stage IIB or higher MF/SS was planned. In patients with stage IIB or higher MF/SS who had received two or more prior systemic therapies, a conservative estimate of the maximum spontaneous response rate was 5%.²⁰ Vorinostat would be considered active for MF/SS treatment if the observed response rate was 20% with the lower bound of the 95% CI more than 5%. With a sample size of 50, the study would have 90% power to meet the joint criteria if the true response rate was 27% and 90% power to exclude 5% alone if the true response rate was 20%. There were three prespecified subgroup analyses: all patients, those with SS, and those with tumor disease.

	RESULTS

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Patient Population
Seventy-four patients with MF/SS, including 61 (82%) with stage IIB or higher disease, were enrolled in this trial. Table 1 summarizes the baseline patient and disease characteristics. Forty-point five percent were designated by the investigator as SS (29.7% had confirmed SS by the International Society for Cutaneous Lymphomas criteria).⁵ The average treatment duration was 5.3 months and treatment compliance while patients were on active treatment was more than 94%. Sixty-one patients discontinued: 27 specifically due to progressive disease, nine due to a clinical adverse experience, and 25 for other reasons, such as patient withdrawal of consent or lack of efficacy. One patient completed 12 study months and 12 patients remained on vorinostat at the time of data cutoff.

View larger version (117K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   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.

View larger version (90K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. Photographs at baseline and during vorinostat treatment. This 64-year-old man with Sézary syndrome had previously received methotrexate, bexarotene, and interferon alpha before achieving a partial response on vorinostat. Time to response, duration of response, and time to progression were 61, 190+, and 251+ days, respectively.

Twenty-nine additional patients (48%) with stage IIB or higher disease attained clinical benefit as signified by mSWAT score improvement (Fig 2) but did not meet the objective response criteria: 10 of these patients experienced stable disease for 24 weeks. One of the most important quality of life issues in MF/SS patients is pruritus. Among study patients with baseline pruritus scores 3 points, 32.3% had pruritus relief with improvement in pruritus noted in both responders and nonresponders (Table 3). In those patients with the most severe pruritus (baseline scores of 7 to 10 points), 43.3% had pruritus relief, including five of 16 SS patients and 30% who achieved a score less than 3 at two or more consecutive visits. The median time to and duration of pruritus relief among patients with stage IIB or higher disease were 16 and 113 days, respectively.

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Best individual modified severity weighted assessment tool (mSWAT) score improvement at any one study visit among stage IIB or higher patients. Negative change signifies the percentage of improvement in the mSWAT score. Forty-seven (77%) of 61 patients had a reduced mSWAT score during vorinostat treatment. Two patients did not have valid follow-up skin assessments and were not included in the analysis.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
The primary objective of this multicenter, phase IIb trial was to determine the response rate of oral vorinostat in the treatment of patients with stage IIB or higher MF/SS who had progressive, persistent, or recurrent disease. Approximately 30% of patients overall, and of those with stage IIB or higher disease, achieved an objective response. These results are encouraging and comparable with the findings of the phase IIa trial of oral vorinostat (31% at 400 mg/d).¹⁹ In the current trial, 33% of SS patients and 23% of those with tumor disease had objective responses, signifying activity in more aggressive CTCL forms. There was no obvious impact observed of the response to last treatment, either bexarotene or other therapies, on subsequent vorinostat activity. These results suggest that vorinostat is noncrossresistant to currently available treatments and may be of benefit to patients regardless of prior treatment failure.

The secondary study objectives were to assess TTR, DOR, TTP, and pruritus relief, as well as the safety and tolerability, of oral vorinostat in this patient population. The median TTR was relatively quick (< 2 months). The median DOR was not reached, but was estimated to be 6.1 months in patients with stage IIB or higher CTCL. The median TTP was 4.9 months overall, and was not reached, but estimated to be 9.8 months in responding patients with stage IIB or higher CTCL. The durability of response and prolonged TTP provide meaningful clinical benefit. It is difficult to directly compare these results with other clinical trials of approved agents in the treatment of CTCL as other trials used different definitions of response, DOR, and TTP.^20-22

Posthoc analyses were performed using more conservative definitions of DOR and TTP that were not prespecified in the protocol. DOR was redefined as the time from first CR/PR until the mSWAT score was increased more than 50% from nadir (v > 50% of the difference between baseline and nadir scores) and PD was redefined as 25% increase in the mSWAT score or 50% increase in the sum of the products of the greatest diameters of pathologically positive lymph nodes compared with nadir (v baseline) measurements. In responders with stage IIB or higher CTCL, the median DOR and TTP were 5.6 and 7.0 months, respectively, compared with an estimated 6.1 and 9.8 months using the protocol-defined methods.

As in the phase IIa vorinostat CTCL trial,¹⁹ a number of patients who did not achieve an objective response still obtained clinical benefit from vorinostat therapy, including 11 of 74 with prolonged stable disease and six with 50% reduction in abnormal index lymph node size. The symptom of pruritus negatively influences quality of life for CTCL patients^23,24; however, 32% of assessable patients, including 25% of those who did not meet the objective response criteria, also achieved pruritus relief with vorinostat. This latter clinical benefit was 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 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 previous trials with oral vorinostat,^7,15,17-19 the most common toxicities were related to gastrointestinal or constitutional symptoms, hematologic 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 of QTc changes than reported with two other HDAC inhibitors, depsipeptide and LBH589.^25,26 The only serious adverse experience observed in more than one patient was thromboembolic events (5%). The explanation for this is unclear and further investigations are ongoing. Importantly, infections were notably lacking in this study, an impressive finding given the normally high rate of 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 responses in 30% and pruritus relief in 32% of patients with treatment-refractory MF including those with tumor disease and SS. Clinically valuable long lasting responses were observed. Distinct from other agents used to treat CTCL, median TTR was relatively short. The median DOR was 6.1 months and the median TTP was 9.8 months among stage IIB or higher patients. As responses to vorinostat therapy were observed in patients who were refractory to prior bexarotene and other therapies, vorinostat appears to work in a manner that is noncrossresistant to other CTCL treatments. Vorinostat was generally well-tolerated, is an effective single agent, and should be considered an appropriate therapeutic option for patients with advanced MF/SS CTCL subtypes. Vorinostat may also find utility in a combination regimen with either skin-directed or other systemic agents.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: Stanley R. Frankel, Merck Research Laboratories; Cong Chen, Merck Research Laboratories; Justin L. Ricker, Merck Research Laboratories; Jean Marie Arduino, Merck Research Laboratories Leadership: N/A Consultant: Elise A. Olsen, Merck & Co; Youn H. Kim, Merck & Co; Theresa R. Pacheco, Merck & Co; Madeleine Duvic, Merck & Co Stock: Stanley R. Frankel, Merck & Co; Cong Chen, Merck & Co; Justin L. Ricker, Merck & Co; Jean Marie Arduino, Merck & Co Honoraria: Madeleine Duvic, Merck & Co Research Funds: Elise A. Olsen, Merck & Co; Youn H. Kim, Merck & Co; Sareeta Parker, Merck & Co; Madeleine Duvic, Merck & Co Testimony: Timothy M. Kuzel, Merck & Co Other: Timothy M. Kuzel, Merck & Co

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Elise A. Olsen, Timothy M. Kuzel, Stanley R. Frankel, Cong Chen, Jean Marie Arduino, Madeleine Duvic

Financial support: Stanley R. Frankel

Administrative support: Stanley R. Frankel

Provision of study materials or patients: Elise A. Olsen, Youn H. Kim, Timothy M. Kuzel, Theresa R. Pacheco, Sareeta Parker, Stanley R. Frankel, Madeleine Duvic

Collection and assembly of data: Elise A. Olsen, Youn H. Kim, Theresa R. Pacheco, Francine M. Foss, Sareeta Parker, Stanley R. Frankel, Madeleine Duvic

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

Final approval of manuscript: Elise 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, Madeleine Duvic

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 

	ACKNOWLEDGMENTS

 
We thank all of the patients and investigators for their participation.

	NOTES

 
published online ahead of print at www.jco.org on July 18, 2007.

Supported by research funding from Merck Research Laboratories.

Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology in Atlanta, GA, June 3-6, 2006; and at the 48th Annual Meeting of the American Society of Hematology in Orlando, FL, December 9-12, 2006.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
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20. Duvic M, Hymes K, Heald P, et al: Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: Multinational phase II-III trial results. J Clin Oncol 19:2456-2471, 2001[Abstract/Free Full Text]

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Submitted December 4, 2006; accepted April 20, 2007.

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