Romidepsin in the treatment of cutaneous T-cell lymphoma

Figures & data

Table 1 Summary of the histone deacetylase (HDAC) inhibitors tested in cutaneous T-cell lymphoma

Properties	Vorinostat (Zolinza)	Depsipeptide (romidepsin)	Panobinostat (LBH589)	Belinostat (PXD101)
HDAC class specificity	I, II, IV	I, II, IV	I, II, IV	I, II, IV
In vitro potency^a	μM	nM	nM	μM
Half-life (h)	1.45	2.64	8	0.3–1.3
Route	Oral	Intravenous	Oral	Oral/intravenous
Dose and schedule	400 mg/day; 300 mg twice a day	14 mg/m^2 on days 1, 8, and 15	20 mg three times a week	1000 mg/m^2; 30 min intravenously for 5 days/3 weeks

Note:

a Reported range of drug concentration necessary for in vitro inhibition of HDAC in cell lines.

Table 2 Outcomes of histone deacetylase inhibitors in CTCL

Outcome	Vorinostat	Romidepsin	Panobinostat	Belinostat
Phase	II (Olsen et al)^Citation46	II (Whittaker et al)^Citation36	II (Duvic et al)^Citation47	II (Foss et al)^Citation48
ORR	29.7%	34%	20%	25%
N	74	96	95	16
CR	1	6	4 (skin and CT)	1
PR	21	27	11 (skin, CR 2)	3
DoR	6.1 months	15 months	NA	NA
TTP	9.8 months	8 months	NA	NA
Approval status	Approved as monotherapy for cutaneous manifestations of CTCL patients who have failed at least 2 prior systemic therapies	Approved as monotherapy for CTCL patients who have failed at least 1 prior systemic therapy	Not yet approved as monotherapy in CTCL Ongoing Phase II trials	Not yet approved as monotherapy in CTCL Ongoing Phase II trials

Abbreviations: CR, complete response; CTCL, cutaneous T-cell lymphoma; DoR, duration of response; NA, not available; N, number of patients enrolled in the trial; ORR, overall response rate; PR, partial response; TTP, time to progression.

Figure 1 Structure of romidepsin.

Table 3 Summary of major clinical trials performed to date with romidepsin as a single agent

Trial	Eligibility	Dose and schedule	Results	Toxicity	Conclusion
Phase I (Piekarz et al)^Citation30	CTCL PTCL	12.7 mg/m^2 or 17.8 mg/m^2 on days 1 and 5 every 3 weeks	3 patients with CTCL had PR and 1 patient with PTCL had CR	NA	Romidepsin is active in T-cell lymphoma
Phase I (Sandor et al)^Citation22	Variety of solid tumor malignancies	Dose escalation from 1 mg/m^2 to 24.9 mg/m^2 on days 1 and 5 every 3 weeks	1 patient with RCC had PR and 8 patients had SD out of 37 patients	Fatigue, nausea, vomiting, and transient thrombocytopenia	MTD of depsipeptide was 17.8 mg/m^2 on days 1 and 5 every 3 weeks
Phase I (Byrd et al)^Citation28	CLL AML	13 mg/m^2 on days 1, 8, and 15 every 4 weeks	Antitumor activity seen but no CR or PR in 20 patients	Fatigue, nausea, and constitutional symptoms	HDAC inhibition observed but too toxic at this schedule
Phase II (Parker et al)^Citation49	Metastatic hormone-refractory prostate cancer	13 mg/m^2 on days 1, 8, and 15 every 4 weeks	1 radiological PR in 31 patients	Nausea, fatigue, vomiting	Disease control rate of 14%. No grade 4 toxicity
Phase II (Stadler et al)^Citation50	Refractory metastatic RCC	13 mg/m^2 on days 1, 8, and 15 every 4 weeks	1 CR and 1 PR out of 29 patients	Fatigue, nausea, vomiting, anemia	No activity in this population at this dose and schedule
Phase II (Whitehead et al)^Citation51	Metastatic colorectal cancer	13 mg/m^2 on days 1, 8, and 15 every 4 weeks	No response	Fatigue, anorexia	No activity in this population at this dose and schedule
Phase II (Piekarz et al)^Citation31	CTCL	18 mg/m^2 on days 1 and 5 every 3 weeks	4 CR and 20 PR in 71 patients	Fatigue, nausea, transient cytopenias	One of the trials that led to the approval of romidepsin in CTCL
Phase II (Whittaker et al)^Citation36	CTCL	18 mg/m^2 on days 1 and 5 every 3 weeks	6 CR and 27 PR in 96 patients	GI intolerance and asthenia	The pivotal trial that supported the FDA approval of romidepsin for CTCL
Phase II (Niesvizky et al)^Citation52	Refractory multiple myeloma	13 mg/m^2 on days 1, 8, and 15 every 4 weeks	No objective responses in 13 patients except stabilization of M-protein in 4 secretory MM patients. Improved hypercalcemia and pain in 5 and 2 patients, respectively	Nausea, fatigue, thrombocytopenia	Romidepsin as single agent is associated with <30% response rate in MM

Abbreviations: AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; CR, complete response; CTCL, cutaneous T-cell lymphoma; FDA, Food and Drug Administration; GI, gastrointestinal; HDAC, histone deacetylation; MM, multiple myeloma; MTD, maximum tolerated dose; PR, partial response; PTCL, peripheral T-cell lymphoma; RCC, renal cell carcinoma; SD, stable disease.

OlsenEAKimYHKuzelTMPhase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphomaJ Clin Oncol2007253109311517577020

 PubMed Web of Science ®Google Scholar

WhittakerSDemierreMFKimEJFinal results from a multi-center, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphomaJ Clin Oncol201028294485449120697094

 PubMed Web of Science ®Google Scholar

DuvicMBeckerJCDalleSPhase II trial of oral panobinostat (LBH589) in patients with refractory cutaneous T-cell lymphoma (CTCL)Blood20081121005101118477770

 PubMed Web of Science ®Google Scholar

FossFAdvaniRHymesKActivity of belinostat in patients with recurrent or refractory peripheral or cutaneous T-cell lymphomaHaematol Meet Rep2009313940

 Google Scholar

PiekarzRLRobeyRSandorVInhibitor of histone deacetylation, depsipeptide (FR901228), in the treatment of peripheral and cutaneous T-cell lymphoma: a case reportBlood2001982865286811675364

 PubMed Web of Science ®Google Scholar

SandorVBakkeSRobeyRPhase I clinical trial of histone deacetylase inhibitor, depsipeptide (FR 901228, NSC 630176) in patients with refractory neoplasmsClin Cancer Res2002871811895901

 PubMed Web of Science ®Google Scholar

ByrdJCMarcuciGParthunMRA phase I and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemiaBlood200510595996715466934

 PubMed Web of Science ®Google Scholar

ParkerCMolifeRKaravasilisVRomidepsin (FK228), a histone deacetylase inhibitor: Final results of a phase II study in metastatic hormone refractory prostate cancer (HRPC)J Clin Oncol, ASCO Annual Meeting Proceedings2007518S15507

 Google Scholar

StadlerWMMargolinKFerberSA phase II study of depsipeptide in refractory metastatic renal cell cancerClin Genitourin Cancer200651576016859580

 PubMed Web of Science ®Google Scholar

WhiteheadRPRankinCHoffPMPhase II trial of romidepsin (NSC-630176) in previously treated colorectal cancer patients with advanced disease: a Southwest Oncology Group study (S0336)Invest New Drugs200927546947518941712

 PubMed Web of Science ®Google Scholar

PiekarzRFryeRTurnerMPhase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphomaJ Clin Oncol2009275410541719826128

 PubMed Web of Science ®Google Scholar

NiesvizkyRElySMarkTPhase 2 trial of the histone deacetylase inhibitor romidepsin for the treatment of refractory multiple myelomaCancer2011117233634220862746

 PubMed Web of Science ®Google Scholar