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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,
Efficacy and Safety Measurements
including CTCL. A phase II trial confirmed the activity and safety
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
further study.19 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) and
summed 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 than
25% 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
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 nadir
scores. 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, and
blood, a reduction of ⱖ 50% in index lymph node size or ⱖ 25% blood tumor Efficacy
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
of antipruritus medications.
responded (36.4% of those with confirmed SS by the International
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
Statistical Analysis 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 planned. In patients with stage IIB or higher MF/SS who had received two
was 56 days (range, 28 to 171 days) and the median DOR was not
or 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
tumor disease. disease attained clinical benefit as signified by mSWAT score improve-
ment (Fig 2) but did not meet the objective response criteria: 10 of
these patients experienced stable disease for ⱖ 24 weeks. One of the
RESULTS most important quality of life issues in MF/SS patients is pruritus.
Among study patients with baseline pruritus scores ⱖ 3 points, 32.3%
Patient Population 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
Time to Response Duration of Response Time to Progressive
(days) (days) Disease (days)
No. of
Patient Group Patients No. % 95% CI Median Range Median Range Median Range
All patients 74 22 29.7 19.7 to 41.5 55 28-171 NR† 34⫹-441⫹ NR‡ 78⫹-470⫹
Stage IB or IIA 13 4 30.8 9.1 to 61.4 42.5 30-57 80.5 48⫹-418⫹ 136.5 78⫹-448⫹
Stage IIB and higher§ 61 18 29.5 18.5 to 42.6 56 28-171 NR† 34⫹-441⫹ NR‡ 85-470⫹
With Sézary syndrome 30 10 33.3 17.3 to 52.8 56 28-171 NR† 34⫹-244⫹ NR‡ 85-365⫹
With tumor disease 22 5 22.7 7.8 to 45.4 31 29-87 187 55-441⫹ NR‡ 148-470⫹
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Olsen et al
Elbow
Baseline Week 13 Week 45
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.
100
Patients with more than 100% increase in SWAT
Percentage of Change in mSWAT
50
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
0 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
-50 were not included in the analysis.
-100
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 DISCUSSION
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 patients
with 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
Relief† results are encouraging and comparable with the findings of the phase
Patient Groupⴱ No. of Patients No. % 95% CI 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
ⱖ 3 points 65 21 32.3 21.2 to 45.1 responses, signifying activity in more aggressive CTCL forms. There
7-10 points (severe pruritus) 30 13 43.3 25.5 to 62.6 was no obvious impact observed of the response to last treatment,
With an objective response 21 10 47.6 25.7 to 70.2 either bexarotene or other therapies, on subsequent vorinostat activ-
Without an objective response 51 13 25.5 14.3 to 39.6
ity. These results suggest that vorinostat is noncrossresistant to cur-
ⴱ
Two patients had missing baseline pruritus scores and were excluded from rently available treatments and may be of benefit to patients regardless
the analyses.
†Pruritus relief is pruritus reduction of ⱖ 3 points or complete resolution for
of prior treatment failure.
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
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Olsen et al
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, Madeleine Duvic
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
AUTHOR CONTRIBUTIONS 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 Duvic
9. Marks P, Rifkind RA, Richon VM, et al: His- advanced hematologic malignancies. J Clin Oncol
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■ ■ ■
Acknowledgment
We thank all of the patients and investigators for their participation.
Appendix
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(via Adobe® Reader®).
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