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

2007 ◽  
Vol 25 (21) ◽  
pp. 3109-3115 ◽  
Author(s):  
Elise A. Olsen ◽  
Youn H. Kim ◽  
Timothy M. Kuzel ◽  
Theresa R. Pacheco ◽  
Francine M. Foss ◽  
...  
Keyword(s):  
T Cell ◽  
Assessment Tool ◽  
Cell Lymphoma ◽  
Objective Response ◽  
Multicenter Trial ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Open Label ◽  
Open Label Phase ◽  
Treatment Refractory

PurposeTo 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 MethodsPatients 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.ResultsSeventy-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.ConclusionOral vorinostat was effective in treatment refractory MF/SS with an acceptable safety profile.

Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) Provides Prolonged Clinical Benefit to Advanced Cutaneous T-Cell Lymphoma Patients: Updated Results of the Phase IIb Multicenter Clinical Trial.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 399-399 ◽  
Author(s):  
Madeleine Duvic ◽  
Youn H. Kim ◽  
Timothy M. Kuzel ◽  
Theresa R. Pacheco ◽  
Francine M. Foss ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Assessment Tool ◽  
Cell Lymphoma ◽  
Objective Response ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Open Label ◽  
Systemic Therapies

Abstract Purpose: To evaluate the activity and safety of the histone deacetylase inhibitor vorinostat in advanced cutaneous T-cell lymphoma (CTCL) patients (pts). Patients and Methods: Advanced CTCL pts received oral vorinostat 400 mg daily until disease progression (PD) or intolerable toxicity in this open label Phase IIb trial. Eligible pts must have received ≥ 2 prior systemic therapies which included bexarotene unless intolerable. The planned sample size was ≥ 50 evaluable pts with stage ≥ IIB. The primary endpoint was the objective response rate (ORR) as measured by a modified skin severity weighted assessment tool (SWAT). The study would be positive if the ORR in ≥ stage IIB pts was ≥ 20%. Time to response, time to progression (TTP), response duration (DOR, from time of first response), pruritus relief, safety and gene expression changes were also evaluated. Results: Seventy-four pts (median age, 60 y [range, 39–83]; median 3 prior systemic therapies) were enrolled (61 pts ≥ stage IIB) at 18 centers. Data cut-off was 5/06 with a median follow-up of 10 m. Efficacy data are shown (Table 1). The ORR was 29.5% in ≥ stage IIB pts. The median DOR and TTP were not reached but estimated to be at least 6.1 m and 9.8 m, respectively, for ≥ stage IIB responders. Median TTP was 4.9 m for all pts. Overall, 32% of pts had pruritus relief. The most common drug-related adverse experiences (AE) were diarrhea (49%), fatigue (46%), nausea (43%) and anorexia (26%), and were mostly ≤ grade 2. Seven pts discontinued and 10 had dose modification due to drug-related AE. Drug-related AE ≥ grade 3 included fatigue (5%), pulmonary embolism (5%), thrombocytopenia (5%) and nausea (4%). Fifteen pts, including 9 responders, were receiving treatment as of 11/05. Three of these pts discontinued due to PD (n = 2) or unacceptable toxicity (n = 1), and 12 have received vorinostat for > 1 y. A pharmacodynamic signature of vorinostat exposure based on gene expression changes was detected. Conclusion: These updated results with additional follow-up continue to demonstrate that oral vorinostat remains effective in advanced CTCL with an acceptable safety profile. Table 1. Efficacy of Vorinostat in Advanced CTCL Population n Objective Response* Median (range) n Pruritus Relief† *Objective response = confirmed complete or partial response. †Sustained pruritus reduction of ≥ 3 points or complete resolution for ≥ 4 wks; 2 pts with missing baseline scores were excluded. ‡Kaplan-Meier estimates were not reached but DOR was ≥ 165, 185 and 165 d, respectively, with a median follow-up of 10 m. §Stages IIB, III, IVA or IVB. CI = confidence interval n (%) (95% CI) TTR, d DOR, d n (%; 95% CI) All pts 74 22 (29.7) (19.7, 41.5) 55 (28–171) NR‡ (34+, 441+) 72 23 (31.9; 21.4, 44.0) Stage IB or IIA 13 4 (30.8) (9.1, 61.4) 42.5 (30–57) 80.5 (48+, 418+) 13 5 (38.5; 13.9, 68.4) ≥Stage IIB§ 61 18 (29.5) (18.5, 42.6) 56 (28–171) NR‡ (34+, 441+) 59 18 (30.5; 19.2, 43.9) Sezary syndrome 30 10 (33.3) (17.3, 52.8) 56 (28–171) NR‡ (34+, 244+) 30 9 (30.0; 14.7, 49.4)

Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) Provides Prolonged Safety and Clinical Benefit to Patients with Advanced Cutaneous T-Cell Lymphoma (CTCL).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2582-2582 ◽  
Author(s):  
Madeleine Duvic ◽  
Elise A. Olsen ◽  
Debra Breneman ◽  
Theresa R. Pacheco ◽  
Sareeta Parker ◽  
...  
Keyword(s):  
T Cell ◽  
Clinical Benefit ◽  
Assessment Tool ◽  
Cell Lymphoma ◽  
Objective Response ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Open Label ◽  
Cutaneous Manifestations ◽  
Adverse Experiences

Abstract Background: Vorinostat is a histone deacetylase inhibitor that has been approved by the US FDA for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent or recurrent disease on or following 2 prior therapies. Patients and Methods: A Phase IIb, open-label trial of oral vorinostat 400 mg daily until progressive disease (PD) or intolerable toxicity was conducted in patients with advanced CTCL. Patients must have received at least 2 prior therapies and recovered from all prior treatment-related toxicities. The primary end point was the objective response rate in patients with stage IIB or higher CTCL as measured by the severity weighted assessment tool. Time to response (TTR), duration of response (DOR), pruritus relief, safety, and tolerability were also evaluated. Patients who had received vorinostat therapy for at least 2 years as of August 1, 2007 were further evaluated in this post-hoc subset analysis. Results: Six of 74 patients originally treated in the study have received vorinostat therapy for at least 2 years as of 8/1/07, including 5 responders (1 complete responder, 4 partial responders) and 1 with prolonged stable disease (Figure 1). The median age was 65 years (range, 57–74), the median number of prior systemic therapies was 2.5 (range, 1–5), and the median time from CTCL diagnosis to enrollment was 1.8 years (range, 0–5.9). The most common drug-related adverse experiences were diarrhea (100%), fatigue (67%), nausea (50%), and alopecia (50%). Grade ≥ 3 drug-related adverse experiences were anorexia (n = 1), pulmonary embolism (PE, n = 1), and thrombocytopenia (n = 1). The PE (Day 144) was a serious adverse experience (SAE) that resolved within 7 days, and this patient is continuing on therapy as of Day 848. The only other SAE was a rash (Day 925). Two patients discontinued due to PD and 4 are continuing on therapy as of August 1, 2007. Conclusions: Vorinostat has demonstrated prolonged safety and clinical benefit in patients with advanced CTCL. Figure 1. Time on study of patients on vorinostat therapy for ≥ 2 years (available data as of August 1, 2007). Figure 1. Time on study of patients on vorinostat therapy for ≥ 2 years (available data as of August 1, 2007).

A multicenter, open label, phase II study to assess the efficacy and safety of APO866 in the treatment of patients with refractory or relapsed cutaneous T-cell lymphoma.

2015 ◽  
Vol 33 (15_suppl) ◽  
pp. e20044-e20044
Author(s):  
Simone M. Goldinger ◽  
Sharon Gobbi ◽  
Michelle Ding ◽  
Anna Lisa Frauchiger ◽  
Regina Fink-Puches ◽  
...  
Keyword(s):  
T Cell ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Efficacy And Safety ◽  
Open Label ◽  
Open Label Phase

Response to Oral Forodesine in Refractory Cutaneous T-Cell Lymphoma: Interim Results of a Phase I/II Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 122-122 ◽  
Author(s):  
Madeleine Duvic ◽  
Andres Forero-Torres ◽  
Francine Foss ◽  
Elise Olsen ◽  
Youn Kim
Keyword(s):  
T Cell ◽  
Phase I ◽  
Median Time ◽  
Assessment Tool ◽  
Cell Lymphoma ◽  
Objective Response ◽  
T Cell Lymphoma ◽  
Clinical Activity ◽  
Cutaneous T Cell Lymphoma ◽  
Grade 3

Abstract Background: Forodesine is a rationally designed, potent inhibitor of purine nucleoside phosphorylase (PNP) that leads to intracellular accumulation of dGTP and then apoptosis. Intravenous forodesine has demonstrated activity in treatment of cutaneous T-cell lymphoma (CTCL) and served as the basis for the design of an oral forodesine Phase I/II trial Methods: An open label dose escalation study of oral forodesine (40 mg/m2 to 320 mg/m2 QD) for 4 weeks was performed to determine the maximum tolerated dose (MTD) and/or the optimal biologic dose (OBD) based on PK, and PNP inhibition as evidenced by elevation of plasma deoxyguanosine (dGuo) levels. Additional subjects were accrued at the optimal dose (80 mg/m2) to further assess clinical safety and efficacy. Patients with previously treated, refractory CTCL with stage IB disease or higher were eligible. The primary efficacy endpoint (objective response rate [ORR]) for this analysis was defined as at least a 50% decrease in modified severity-weighted assessment tool (mSWAT) from baseline maintained for at least 28 days. Only subjects who had at least 6 months follow-up as of March 1, 2007 were included in this analysis. Results: Although an MTD was not reached, based on plateau of the AUC versus dose plot at and above 80 mg/m2, and the same observation for plasma dGuo versus dose, 80 mg/m2 was judged as an OBD. The 36 subjects treated at 80 mg/m2 are the main subject of this report. Median age was 61.6 years (range 28.4–81.1) and 67% were males and were exposed to a median of 3 prior systemic therapies (range 0, 8). The ORR using mSWAT was 39% (14/36) with a median duration of response of 127 days (25%–75%, 71 - NA). Response by stage was: IB 3/9, IIA 1/1, IIB 3/5, III 4/12, IVA 2/5, IVB 1/4. Median time to response was 42 days (25%–75%, 29–58). The median time on treatment was 131 days (range 1, 479) with 6 subjects remaining on treatment. For subjects with Sezary Syndrome (n=20, defined by ISCL B2 classification), the ORR by mSWAT was 40%, and 65% by erythroderma score. More than a 50% reduction in Sezary cells (detected by flow cytometry) was observed in 9/20 (45%) subjects with SS. For all 56 forodesine-treated subjects, the only grade 3 or higher non-laboratory adverse events (without regard to attribution and observed in at least 2 subjects) were diarrhea, acute renal failure (not related), cellulitis, and rash (2 subjects each). The only grade 3 or higher related non-laboratory AEs were vertigo, diarrhea, generalized edema, and pneumonia (1 each). For laboratory events, a single grade 3 elevation for each of the following liver-related parameters was noted: AST, ALT, bilirubin, and alkaline phosphatase. There were no grade 3 or higher elevations of creatinine. Grade 3 or higher lymphopenia and low CD4 counts were observed in 71% and 31% of subjects and these rates were similar across dose groups. Median baseline, nadir, and last visit lymphocytes counts (1000/mm3) were 0.8 (95%CI: 0.0, 6.0), 0.2 (95% CI: 0.0, 0.8), and 0.6 (95% CI: 0.0, 2.9) respectively. Hematopoietic toxicity was limited to 1 episode of grade 3 neutropenia, and 1 episode of grade 3 anemia. Conclusion: Oral forodesine demonstrates clinical activity in subjects with refractory CTCL, including those with SS, with minimal toxicity to date.

Final Results From a Multicenter, International, Pivotal Study of Romidepsin in Refractory Cutaneous T-Cell Lymphoma

2010 ◽  
Vol 28 (29) ◽  
pp. 4485-4491 ◽  
Author(s):  
Sean J. Whittaker ◽  
Marie-France Demierre ◽  
Ellen J. Kim ◽  
Alain H. Rook ◽  
Adam Lerner ◽  
...  
Keyword(s):  
T Cell ◽  
Median Duration ◽  
Cell Lymphoma ◽  
Therapeutic Option ◽  
Single Agent ◽  
Objective Response ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Meaningful Improvement ◽  
Treatment Refractory

PurposeThe primary objective of this study was to confirm the efficacy of romidepsin in patients with treatment refractory cutaneous T-cell lymphoma (CTCL).Patients and MethodsThis international, pivotal, single-arm, open-label, phase II study was conducted in patients with stage IB to IVA CTCL who had received one or more prior systemic therapies. Patients received romidepsin as an intravenous infusion at a dose of 14 mg/m2on days 1, 8, and 15 every 28 days. Response was determined by a composite assessment of total tumor burden including cutaneous disease, lymph node involvement, and blood (Sézary cells).ResultsNinety-six patients were enrolled and received one or more doses of romidepsin. Most patients (71%) had advanced stage disease (≥ IIB). The response rate was 34% (primary end point), including six patients with complete response (CR). Twenty-six of 68 patients (38%) with advanced disease achieved a response, including five CRs. The median time to response was 2 months, and the median duration of response was 15 months. A clinically meaningful improvement in pruritus was observed in 28 (43%) of 65 patients, including patients who did not achieve an objective response. Median duration of reduction in pruritus was 6 months. Drug-related adverse events were generally mild and consisted mainly of GI disturbances and asthenic conditions. Nonspecific, reversible ECG changes were noted in some patients.ConclusionRomidepsin has significant and sustainable single-agent activity (including improvement in pruritus) and an acceptable safety profile, making it an important therapeutic option for treatment refractory CTCL.

Belinostat (PXD101) in Patients with Recurrent or Refractory Peripheral or Cutaneous T-Cell Lymphoma: Results of a Phase II Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3453-3453 ◽  
Author(s):  
Ranjana Advani ◽  
K. Hymes ◽  
B. Pohlman ◽  
E. Jacobsen ◽  
J. McDonnell ◽  
...  
Keyword(s):  
T Cell ◽  
Phase Ii ◽  
Assessment Tool ◽  
Cell Lymphoma ◽  
Objective Response ◽  
T Cell Lymphoma ◽  
Clinical Activity ◽  
Cutaneous T Cell Lymphoma

Abstract Background: Belinostat (PXD101) is a hydroxamate pan-histone deacetylase inhibitor which demonstrates broad anti-neoplastic activity in vitro and in vivo. Phase I studies have shown that belinostat is well-tolerated. Methods: This Phase II trial evaluated the activity of belinostat in patients (pts) with peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL) who failed ≥ 1 prior systemic therapy. Belinostat (1000 mg/m2) was administered as a 30-min IV infusion on Days 1–5 of a 3-wk cycle. The primary endpoint was objective response (OR) rate analyzed separately for PTCL and CTCL using the Cheson criteria and Severity Weighted Assessment Tool (SWAT), respectively. For each arm, a Simon 2-stage design was used based on target OR rate of 25%, with expansion to 34 pts if ≥ 2/13 OR were observed. Results: In the PTCL arm, 12 pts (9 with stage III/IV disease) were enrolled; (7 PTCL-unspecified (PTCL-U), 2 anaplastic large cell lymphoma (ALCL), 2 angioimmunoblastic T-cell lymphoma and 1 NK-T-cell lymphoma), treated for a median of 2 cycles (range 1–8). Of 11 evaluable pts, 2 achieved a CR and 5 pts had SD. The two CR (11+ and 15+ wks) were both in pts with PTCL-U. A third pt with PTCL-U had SD lasting 14 wks and discontinued treatment due to an adverse event (AE). Both pts with ALCL had durable SD (20+ and 14 wks). In the CTCL arm, 16 pts were enrolled (9 Mycosis Fungoides (MF), 5 Sezary Syndrome (SS), 2 primary cutaneous ALCL) and treated for a median of 2 cycles (range 1–6). Four ORs were observed (25%): 1 CR (ALCL) and 3 PR (MF/SS). The median duration of the OR was 10 wks (range 7 to 39+ wks). Four additional pts had a 25 – 50% decrease in SWAT. Improvement in pruritus score by ≥ 3 on a visual analog scale was reported in 5/6 patients with significant pruritus at baseline. Overall in both study arms the drug was well-tolerated and most AE were grade 1/2 (nausea, fatigue, constipation, diarrhea, and vomiting). Grade 3 AE attributed to the study drug was reported in 7 pts and included peripheral edema, apraxia, adynamic ileus, pruritus, rash, and infections. Only 1 treatment related Grade 4 AE was noted (thrombocytopenia). One patient with progressive PTCL died 6 days after last belinostat dose with ventricular fibrillation and drug causality could not be excluded. Conclusions: Belinostat (PXD101) is generally well tolerated and demonstrates encouraging clinical activity in recurrent or refractory PTCL and CTCL. The objective response rate in both arms has met the pre-defined criteria for study expansion to stage II of enrollment.

Vorinostat in combination with bexarotene in advanced cutaneous T-cell lymphoma: A phase I study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8572-8572 ◽  
Author(s):  
R. Dummer ◽  
K. Hymes ◽  
W. Sterry ◽  
M. Steinhoff ◽  
C. Assaf ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Dose Escalation ◽  
Anticancer Agents ◽  
Cell Lymphoma ◽  
Objective Response ◽  
T Cell Lymphoma ◽  
Clinical Activity ◽  
Cutaneous T Cell Lymphoma ◽  
Open Label

8572 Background: Vorinostat, a histone deacetylase inhibitor, is registered for the treatment of advanced cutaneous T-cell lymphoma (CTCL) in the US. Preclinical studies suggest that vorinostat may enhance the activity of chemotherapeutic or biological anticancer agents in a variety of cancers. This Phase I, multicenter, open-label study systematically evaluated vorinostat combined with the retinoid bexarotene in patients (pts) with advanced CTCL. Methods: Eligible pts were aged ≥18 years with stage ≥IB progressive, persistent, or recurrent CTCL refractory to ≥1 systemic therapy. Primary objective was to determine the maximum tolerated dose (MTD). Phase Ia Part I: dose escalation of vorinostat (200–400 mg/day) and bexarotene (150–300 mg/m2/day); Part II: fixed vorinostat dose (400 mg/day) with bexarotene dose escalation (150–450 mg/day). Cycles were repeated every 28 days for ≤6 cycles. Clinical activity and safety of the combination was also assessed. Results: 23 pts received ≥1 dose of study medication. Three pts in dose level (DL) 2 experienced dose-limiting toxicities (DLTs) ( Table ). No DLTs were observed in the first cycle of DL 2a and 2b. The MTD (Part I) was vorinostat 200 mg/day plus bexarotene 300 mg/m2/day. The Part II MTD was not reached as the study was discontinued early due to low enrollment; no DLTs were observed at DL 6 or 7. The most common drug-related adverse events (DRAEs) were hypothyroidism (35%), fatigue (30%), and hypertriglyceridemia (30%). No Grade 4 or 5 DRAEs were reported and 4 pts had serious DRAEs (Grade ≤3). Eighteen pts have discontinued: 5 due to AEs, 5 due to progressive disease, and 8 withdrew consent. Of 22 pts evaluable for efficacy, 4 (18%) had an objective response, and 7 (32%) derived clinical benefit (pruritis relief). Conclusions: These preliminary data suggest that the vorinostat/bexarotene combination is feasible in pts with advanced CTCL; however, the dosage of either drug must be reduced to avoid unacceptable side effects. [Table: see text] [Table: see text]

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