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The Oncologist, Vol. 12, No. 10, 1247-1252, October 2007; doi:10.1634/theoncologist.12-10-1247
© 2007 AlphaMed Press

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Regulatory Issues: FDA

FDA Approval Summary: Vorinostat for Treatment of Advanced Primary Cutaneous T-Cell Lymphoma

Bhupinder S. Mann, John R. Johnson, Martin H. Cohen, Robert Justice, Richard Pazdur

Division of Oncology Drug Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland, USA

Key Words. Vorinostat • Histone deacetylase inhibitor • HDAC • Cutaneous T-cell lymphoma • CTCL

Correspondence: Bhupinder S. Mann, M.D., U.S. Food and Drug Administration, White Oak Campus, 10903 New Hampshire Avenue, Building 22, Room 2103, Silver Spring, Maryland 20993-0002, USA. Telephone: 301-796-1411; Fax: 301-796-9845; e-mail: bhupinder.mann{at}fda.hhs.gov

Received December 6, 2006; accepted for publication July 24, 2007.

Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.


   Learning Objectives
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 Learning Objectives
Abstract
 Introduction
 Patients and Methods
 Results
 Safety
 Discussion
 Acknowledgments
 References
 
After completing this course, the reader will be able to:

  1. Add vorinostat to the armamentarium of drugs for CTCL.
  2. Identify the mechanism of action of vorinostat.
  3. Identify goals of therapy of CTCL.
  4. Identify active CTCL therapies.
  5. Identify CTCL response criteria.

Access and take the CME test online and receive 1 AMA PRA Category 1 CreditTM at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Patients and Methods
 Results
 Safety
 Discussion
 Acknowledgments
 References
 
On October 6, 2006, the U.S. Food and Drug Administration granted regular approval to vorinostat (Zolinza®; Merck & Co., Inc., Whitehouse Station, NJ), a histone deacetylase inhibitor, for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients with progressive, persistent, or recurrent disease on or following two systemic therapies. The pivotal study supporting approval was a single-arm open-label phase II trial that enrolled 74 patients with stage IB and higher CTCL who had failed two systemic therapies (one of which must have contained bexarotene). Patients received vorinostat at a dose of 400 mg orally once daily, which could be reduced for toxicity to 300 mg daily or 300 mg 5 days a week. The median age of patients was 61 years. Sixty-one patients (82%) had stage IIB or higher CTCL and 30 patients (41%) had Sézary syndrome. The median duration of protocol treatment was 118 days. The primary efficacy endpoint was objective response assessed by the Severity-Weighted Assessment Tool. The objective response rate was 30% (95% confidence interval [CI], 19.7%–41.5%), the estimated median response duration was 168 days, and the median time to tumor progression was 202 days. An additional single-center study enrolled 33 patients with similar baseline and demographic features as the pivotal trial. Thirteen of the 33 received vorinostat (400 mg/day). The response rate in these 13 patients was 31% (95% CI, 9.1%–61.4%). The most common clinical adverse events (AEs) of any grade were diarrhea (52%), fatigue (52%), nausea (41%), and anorexia (24%). Grade 3 or 4 clinical AEs included fatigue (4%) and pulmonary embolism (5%). Hematologic laboratory abnormalities included thrombocytopenia (26%) and anemia (14%). Chemistry laboratory abnormalities included increased creatinine (16%), increased serum glucose (69%), and proteinuria (51%). Most abnormalities were National Cancer Institute Common Terminology Criteria for Adverse Events grade 1 or 2. Grade 3 or greater chemistry abnormalities included hyperglycemia, hypertriglyceridemia, and hyperuricemia, hypoglycemia, hypokalemia, hyponatremia, hyperkalemia, hypercholesterolemia, hypophosphatemia, and increased creatinine.


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Patients and Methods
 Results
 Safety
 Discussion
 Acknowledgments
 References
 
Epigenetic changes in gene expression may play an important role in cancer growth. The opposing activities of histone acyltransferases (HATs) and histone deacetylases (HDACs) regulate gene expression by altering chromatin structure. HATs, by acylating histones, produce an open chromatin structure, resulting in greater accessibility of regulatory proteins to DNA. HDACs, by contrast, catalyze acyl group removal, leading to a closed chromosomal configuration and transcriptional repression [1, 2]. HDAC inhibition may permit re-expression of proteins that promote apoptosis and cell differentiation while inhibiting cell cycling and cell division [3].

Vorinostat (suberoylanilide hydroxamic acid, Zolinza®; Merck & Co., Inc., Whitehouse Station, NJ) is an orally active, potent inhibitor of HDAC activity whose structure is shown in Figure 1. Vorinostat inhibits HDAC by binding to a zinc ion in the catalytic domain of the enzyme [4]. Vorinostat demonstrated activity in murine xenograft models and it was additive or synergistic when combined with chemotherapy drugs in induction of differentiation and apoptosis of various cancer cell lines [5].


Figure 1
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  		Figure 1. Structure of vorinostat (suberoylanilide hydroxamic acid, SAHA).

 
Phase I vorinostat clinical trials were initiated with both an i.v. and an oral drug formulation [2, 6, 7]. The oral formulation was developed for ease in daily administration and is the approved formulation of the drug. At steady state in the fed-state, oral administration of multiple 400-mg doses of vorinostat resulted in a mean area under the concentration–time curve and maximum concentration and a median maximum time of 6.0 ± 2.0 µM·hour, 1.2 ± 0.53 µM, and 4 (0.5–14) hours, respectively.

Both the i.v. and oral vorinostat formulations were reasonably well tolerated. Dose-limiting toxicity included myelosuppression, gastrointestinal toxicity, and fatigue. Responses were noted in both solid tumors and hematologic malignancies, including one patient with heavily pretreated cutaneous T-cell lymphoma (CTCL), who had stable disease.

Vorinostat and other HDAC inhibitors have demonstrated activity in CTCL. Zhang and colleagues [8] investigated the effect of vorinostat in CTCL cell lines and freshly isolated peripheral blood lymphocytes (PBLs) from 11 patients with circulating malignant T cells. Vorinostat treatment (1.0–5.0 µM for 48 hours) induced dose-dependent apoptosis in all three CTCL cell lines and also induced apoptosis up to 59% in 10 of 11 CTCL PBLs.

While vorinostat evaluation was being conducted in a variety of tumors, a cyclic tetrapeptide HDAC inhibitor, depsipeptide, was being evaluated primarily in hematologic malignancies. Using a human T-cell lymphoma cell line, Piekarz et al. [9] demonstrated substantial apoptosis without significant cell cycle arrest.

A phase I depsipeptide study reported partial responses (PRs) in three of three study patients with CTCL and a complete response (CR) in one patient with peripheral T-cell lymphoma, unspecified [10]. A phase II depsipeptide study reported objective responses in five of 19 assessable CTCL patients, including two patients who achieved CRs [11].

A similar phase II trial of vorinostat (400 mg/day) enrolled 13 advanced, refractory CTCL patients who had received a mean of five prior therapies (range, 1–19). Five patients (38%) experienced a PR, with a mean duration of response of 15 weeks. More than 50% of the study patients reported clinically significant decreases in pruritus [12].

These CTCL results led the sponsor (Merck & Co. Inc., Whitehouse Station, NJ) to conduct and submit a single-arm trial evaluating vorinostat efficacy, safety, and tolerability in the treatment of CTCL patients who had failed two prior systemic therapies for consideration of regulatory approval [13].


   PATIENTS AND METHODS
Top
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
Results
 Safety
 Discussion
 Acknowledgments
 References
 
Two phase II single-arm trials were submitted in support of the efficacy of vorinostat and an additional 10 other phase I and II clinical studies were reviewed to evaluate the safety of vorinostat. The pivotal trial was an open-label, single-arm, multicenter study. The supportive trial was an open-label, three-arm, nonrandomized, single-center study conducted prior to the pivotal trial. Details of these trials have recently been published [12, 13].

Eligible CTCL patients were ≥18 years old, with an Eastern Cooperative Oncology Group performance status score of 0–2, life expectancy >3 months, and stage IB or higher disease [7]. Patients had to have progressive, persistent, or recurrent disease following two systemic therapies, one of which must have contained bexarotene (unless the patient was intolerant to or not a candidate for bexarotene as described in the bexarotene package insert). Persistent disease was defined by a lack of at least a 50% improvement on therapy for at least 3 months unless the patient was intolerant to therapy because of the toxicities. Use of topical or systemic corticosteroids was not allowed on study except in Sézary syndrome patients who were on systemic steroids for at least 3 months, in patients on a stable daily dose equivalent to ≤10 mg of prednisone for at least 4 weeks immediately prior to receiving study therapy, or in patients who had been on topical steroids for at least 3 months on a dose that did not exceed 0.1% triamcinolone acetonide cream or equivalent for at least 4 weeks immediately prior to receiving study therapy.

The starting dose of vorinostat was 400 mg once daily, preferably taken with food. Two dose reductions were allowed for toxicity: 300 mg once daily or 300 mg once daily for 5 consecutive days per week, if necessary. Treatment was continued until progressive disease, unacceptable toxicity, lack of efficacy, or a patient's withdrawal of consent.

The primary study objective was the objective response rate. Secondary objectives were time to objective response, response duration, time to progression, pruritis relief, and safety and tolerability of vorinostat. Skin disease was assessed and scored at baseline and at scheduled follow-up visits using the Severity-Weighted Assessment Tool (SWAT). Abnormal skin not elevated from the normal skin was defined as patch, abnormal skin elevated from the normal skin by <5 mm was defined as plaque, and a plaque elevated ≥5 mm was considered as tumor. Percentages of the total body surface area involved with patch, plaque, and tumor were severity-weighted by multiplying by factors of 1, 2, and 4, respectively, and summed to give an overall SWAT score.

A clinical complete response (CCR) required a 100% improvement with no evidence of the disease and a PR required at least a 50% decrease in SWAT score compared with baseline, with confirmation by a second assessment after at least 4 weeks. Patients who achieved a CCR or PR by SWAT had a full computed tomography assessment of their nodal disease after the response was confirmed by a second assessment. Progressive disease (PD) required at least a 25% increase in SWAT score compared with baseline in responding patients, a 50% increase in SWAT score compared with the nadir, or at least a 50% increase in the sum of the products of the greatest diameters of pathologically positive lymph nodes (documented by biopsy) compared with baseline. PD required confirmation by a second assessment 1–4 weeks later whenever possible. Stable disease (SD) did not meet the criteria for either response or progression. Follow-up study evaluations were performed at weeks 2, 4, 6, and 8, and every 4 weeks thereafter until the patient was discontinued from the study. For each study patient, global half-body photographs and close-up photographs of distinct individual lesions were taken serially to document changes in the skin disease. These photographs were supportive only and were not used to derive SWAT scores.

The intensity of pruritus was evaluated using a patient-completed questionnaire at baseline and at each follow-up visit. A 10-point scale was used and skin itch over the past week was assessed: 0 = no itching and 10 = itching as bad as it can be. A baseline pruritus score of ≥3 was required for assessment. A three-point decrease in pruritis intensity, without an increase in the use of antipruritic medications and confirmed by a second assessment at least 4 weeks later, was considered clinically significant.

The safety and tolerability of vorinostat were assessed in the two submitted phase II CTCL trials and in 10 other trials that included vorinostat treatment in patients with other solid tumors and hematologic malignancies. Adverse events were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0.


   RESULTS
Top
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
 Results
Safety
 Discussion
 Acknowledgments
 References
 
The larger phase II trial, conducted by 18 centers in the U.S. and Canada, enrolled 74 patients who had stage IB or higher advanced CTCL. Patient and disease characteristics are shown in Table 1. Previous CTCL therapies included: bexarotene, 71 (96%); interferon, 47 (64%); photopheresis, 27 (37%); methotrexate, 26 (35%); denileukin diftitox, 23 (31%); glucocorticoids, 18 (24%); doxorubicin, 13 (18%); gemcitabine, 12 (16%); cyclophosphamide, 9 (12%); and chlorambucil, 7 (10%).


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  		Table 1. Patient and disease characteristics at baseline (n = 74)

 
Objective response rates (all treated patients) are shown in Table 2. The median times to response were 55 and 56 days, respectively, in the overall and stage IIB or higher disease patients. All responses except one were partial. In all analyzed subsets, the response rate was about 30%. The observed response rate in patients with IIB or higher stage disease was 30% (95% confidence interval [CI], 18.5%–42.6%). Patients who had failed bexarotene had a response rate of 31% (5 of 16), similar to the rate (29%, 2 of 7) observed in patients who had earlier responded to bexarotene. The median response duration (based on a 50% increase in SWAT score from the nadir) was estimated to be 168 days. The median time to tumor progression was estimated as 202 days.


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  		Table 2. Objective response rates to vorinostat

 
The smaller phase II study included 33 CTCL patients who were refractory or intolerant to at least one treatment. Patients were assigned to one of three cohorts: cohort 1, 400 mg once daily (13 patients); cohort 2, 300 mg twice daily 3 days/week (11 patients); or cohort 3, 300 mg twice daily for 14 days followed by a 7-day rest (induction) followed by 200 mg twice daily (nine patients). The primary efficacy endpoint, objective response, was measured by the seven-point Physician's Global Assessment scale. The median age was 67.0 years (range, 26.0–82.0). Fifty-five percent of patients were male. Eighty-five percent of patients had stage IIB, III, IVA, or IVB disease. The median number of prior systemic therapies was four (range, 0–11). Response rates (all partial) were 30.8%, 9.1%, and 33.3% in cohorts 1, 2 and 3, respectively. The overall objective response rates were 24.2% (8 of 33) and 25% (7 of 28) in patients with stage IIB or higher disease and 36.4% (4 of 11) in patients with Sézary syndrome. The 300-mg twice-daily regimen had higher toxicity with no additional clinical benefit over the 400-mg once-daily regimen. The median time to response was 83.5 days (range, 25–153 days). The median response duration was 106 days (range, 66–136 days). The median time to progression was 211.5 days (range, 94–255 days).

Although pruritis relief was a secondary endpoint of the large phase II trial, the absence of both a control arm and of blinding led the U.S. Food and Drug Administration (FDA) reviewers to consider the results as unreliable. Pruritis data were not included in the label.


   SAFETY
Top
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
 Results
 Safety
Discussion
 Acknowledgments
 References
 
Safety data from 86 CTCL patients who received vorinostat (400 mg daily) in the two submitted phase II trials are summarized in Table 3. Other submitted trials included vorinostat doses and schedules different from the recommended dose and schedule for CTCL or included patients with diseases other than CTCL.


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  		Table 3. Clinical adverse events reported by ≥10% of patients

 
The median number of days on protocol treatment was 97.5 (range, 2–480+ days). Seventeen (19.8%) patients received treatment for >24 weeks and eight (9.3%) patients were treated beyond 1 year. Adverse events resulted in discontinuation of therapy in eight patients (9.3%). An additional nine patients (10.5%) required a dose reduction.

Table 3 summarizes clinical or laboratory adverse events, regardless of causality, occurring in ≥10% of patients. Thrombocytopenia and anemia were the most common hematologic toxicities. Other laboratory abnormalities reported included increased serum glucose in 69% of CTCL patients (59 of 86), transient increases in serum creatinine in 46.5% of patients (40 of 86), and proteinuria in 51.4% of patients (38 of 74).

Serious adverse events occurring in this patient population included pulmonary embolism, reported in four patients (4.7%); squamous cell carcinoma, three patients (3.5%); and anemia, two patients (2.3%). There were single events of cholecystitis, death (of unknown cause), deep vein thrombosis, enterococcal infection, exfoliative dermatitis, gastrointestinal hemorrhage, infection, lobar pneumonia, myocardial infarction, ischemic stroke, pelviureteric obstruction, sepsis, spinal cord injury, streptococcal bacteremia, syncope, T-cell lymphoma, thrombocytopenia, and ureteric obstruction. Whereas cardiac toxicity was expected, based on preclinical data, myocardial damage was not detected.


   DISCUSSION
Top
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
 Results
 Safety
 Discussion
Acknowledgments
 References
 
CTCL is an uncommon, chronic, debilitating, heterogeneous disease. Early-stage patients (i.e., those with limited patches and plaques) achieve reasonable results with skin-directed therapies such as topical agents, total skin electron beam radiation, and psoralen photochemotherapy. For the more advanced stages of disease, where tumors and/or erythroderma are present, systemic therapies are usually required [14]. Goals of therapy are improved cosmesis, reduction in tumor burden, decreased tumor ulceration and secondary infection, and relief of symptoms of pain and pruritis [15]. Prolongation of survival is obviously an important goal, but one difficult to access because of the rarity and chronic nature of disease and because most patients receive many treatment regimens during the course of their illness.

The observed response rates and response durations observed with vorinostat appear comparable with those obtained with the other FDA-approved CTCL therapies, bexarotene (Targretin®; Ligand Pharmaceuticals, San Diego, CA) and denileukin diftitox, although response assessment in the vorinostat and denileukin diftitox trials was based on the SWAT whereas assessment in the bexarotene trials was by the Composite Assessment of Index Lesion Disease Severity tool. Bexarotene, at a dose of 300 mg/m2 per day orally, produced an overall response rate of 32.3% (one complete tumor response and 19 partial tumor responses) [16, 17] and denileukin diftitox, at a dose of 9 or 18 µg/kg per day, had an overall tumor response rate of 30% (seven complete tumor responses and 14 partial tumor responses) in 71 treated patients [18].

The observed 30% objective response rate of skin disease (evaluated using SWAT, supported by patient photographs) with a median response duration of 168 days in a heavily pretreated advanced CTCL patient population was felt by the FDA reviewers to represent clinical benefit. Vorinostat was thus granted regular approval on October 6, 2006. The approved indication is that vorinostat is indicated for treatment of cutaneous manifestations of CTCL in patients with progressive, persistent, or recurrent disease on or following two systemic therapies. The recommended vorinostat dose is 400 mg orally once daily with food.


   ACKNOWLEDGMENTS
Top
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
 Results
 Safety
 Discussion
 Acknowledgments
References
 
The views expressed are the result of independent work and do not necessarily represent the views and findings of the U.S. Food and Drug Administration.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
 Results
 Safety
 Discussion
 Acknowledgments
 References
 

  1. Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 2006;5:769–784.[CrossRef][Medline]
  2. O'Connor OA, Heaney ML, Schwartz L et al. Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies. J Clin Oncol 2006;24:166–173.[Abstract/Free Full Text]
  3. Minucci S, Pelicci PG. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 2006;6:38–51.[CrossRef][Medline]
  4. Yoo CB, Jones PA. Epigenetic therapy of cancer: Past, present and future. Nat Rev Drug Discov 2006;5:37–50.[CrossRef][Medline]
  5. Marks PA. Discovery and development of SAHA as an anticancer agent. Oncogene 2007;26:1351–1356.[CrossRef][Medline]
  6. Ramalingam SS, Parise RA, Ramananthan RK et al. Phase I and pharmacokinetic study of vorinostat, a histone deacetylase inhibitor, in combination with carboplatin and paclitaxel for advanced solid malignancies. Clin Cancer Res 2007;13:3605–3610.[Abstract/Free Full Text]
  7. Kelly WK, O'Connor OA, Krug LM et al. Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol 2005;23:3923–3931.[Abstract/Free Full Text]
  8. Zhang C, Richon V, Ni X et al. Selective induction of apoptosis by histone deacetylase inhibitor SAHA in cutaneous T-cell lymphoma cells: Relevance to mechanism of therapeutic action. J Invest Dermatol 2005;125:1045–1052.[Medline]
  9. Piekarz RL, Robey RW, Zhan Z et al. T-cell lymphoma as a model for the use of histone deacetylase inhibitors in cancer therapy: Impact of depsipeptide on molecular markers, therapeutic targets, and mechanisms of resistance. Blood 2004;103:4636–4643.[Abstract/Free Full Text]
  10. Piekarz RL, Robey R, Sandor V et al. Inhibitor of histone deacetylation, depsipeptide (FR901228), in the treatment of peripheral and cutaneous T-cell lymphoma: A case report. Blood 2001;98:2865–2868.[Abstract/Free Full Text]
  11. Piekarz RL, Frye M, Turner J et al. Responses and molecular markers in patients with peripheral T-cell lymphoma treated on a phase II trial of depsipeptide, FK228. Proc Am Soc Clin Oncol 2005;23:207s.
  12. Duvic M, Talpur R, Ni X et al. Phase II trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood 2007;109:31–39.[Abstract/Free Full Text]
  13. Olsen EA, Kim YH, Kuzel TM et al. Phase IIB multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol 2007;25:3109–3115.[Abstract/Free Full Text]
  14. American Joint Committee on Cancer. AJCC Cancer Staging Manual. Lymphoid neoplasms. Sixth Edition. New York: Springer, 2002:393-406.
  15. Knobler E. Current management strategies for cutaneous T-cell lymphoma. Clin Dermatol 2004;22:197–208.[Medline]
  16. 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 2001;19:2456–2471.[Abstract/Free Full Text]
  17. Duvic M, Martin AG, Kim Y et al. Phase 2 and 3 clinical trial of oral bexarotene (Targretin capsules) for the treatment of refractory or persistent early-stage cutaneous T-cell lymphoma. Arch Dermatol 2001;137:581–593.[Abstract/Free Full Text]
  18. Olsen E, Duvic M, Frankel A et al. Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma. J Clin Oncol 2001;19:376–388.[Abstract/Free Full Text]



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