Clinical trial NCT00426764: A Trial of Romidepsin for Progressive or Relapsed Peripheral T-cell Lymphoma
Official title: A Phase II, Multicenter, Open-Label Trial Evaluating The Activity And Tolerability Of Romidepsin (Depsipeptide, FK228) In Progressive Or Relapsed Peripheral T-Cell Lymphoma Following Prior Systemic Therapy (GPI-06-0002)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Peripheral T-cell Lymphoma
Keywords: peripheral T-cell lymphoma
T-cell lymphoma
romidepsin
Lead sponsor: Celgene
Sponsor class: INDUSTRY
First posted: 2007-01-25
Enrollment: 131
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the activity of romidepsin in patients with progressive or relapsed peripheral T-cell lymphoma (PTCL) who have already been treated with systemic therapy.

Detailed description: This is a Phase II, non-randomized, open-label, single-arm trial. This study is designed on the basis of complete response (CR) or unconfirmed CR \[CR(u)\] as the measure of efficacy, based on the best overall response of each patient. The sample size of 65 patients evaluable for efficacy would yield lower 95% confidence limits on the rate of CR + CR(u) that would range from 2.2% to 7.7%, if the observed rate of CR + CR(u) ranges from 8% to 15%. The study was amended to include an Extension Phase, during which patients at non-US sites who are benefitting from treatment can continue to receive romidepsin. The Extension Study Phase is active in EU countries where currently no Marketing Authorisation exists for romidepsin. Patients may remain on study until progressive disease occurs or they withdraw their consent and only serious adverse events and study drug administration data will continue to be collected and reported for these patients.

Eligibility criteria: Inclusion Criteria:

Patients must fulfill all of the following criteria to be eligible for study participation and have:

* Histologically confirmed PTCL not otherwise specified, angioimmunoblastic T-cell lymphoma, extranodal natural killer (NK)/T-cell lymphoma nasal type, enteropathy- type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, cutaneous γδ T-cell lymphoma (excludes mycosis fungoides or Sezary syndrome), transformed mycosis fungoides, hepatosplenic T-cell lymphoma, anaplastic large cell lymphoma (ALCL; anaplastic lymphoma kinase \[ALK\]-1 negative), or patients with ALK 1 expressing ALCL (ALK-1 positive) who have relapsed disease after autologous stem cell transplant (ASCT);
* Age ≥18 years;
* Written informed consent;
* Progressive disease following at least one systemic therapy or refractory to at least one prior systemic therapy;
* Measurable disease according to the International Workshop Response (IWC) criteria and/or measurable cutaneous disease;
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-2;
* Serum potassium ≥3.8 mmol/L and magnesium ≥0.85 mmol/L (electrolyte abnormalities can be corrected with supplementation to meet inclusion criteria);
* Negative urine or serum pregnancy test on females of childbearing potential; and
* All women of childbearing potential must use an effective barrier method of contraception (either an intrauterine contraceptive device \[IUCD\] or double barrier method using condoms or a diaphragm plus spermicide) during the treatment period and for at least 1 month thereafter. Male patients should use a barrier method of contraception during the treatment period and for at least 1 month thereafter. Hormonal methods of contraception such as the contraceptive pill or patch (particularly those containing ethinyl-estradiol) should be avoided due to a potential drug interaction.

Exclusion Criteria:

Patients are ineligible for entry if any of the following criteria are met:

* Known central nervous system (CNS) lymphoma \[computed tomography (CT) or magnetic resonance imaging (MRI) scans are required only if brain metastasis is suspected clinically\];
* Chemotherapy or immunotherapy within 4 weeks of study entry (6 weeks if nitrosoureas given);
* Initiation of corticosteroids during study (defined as 7 days prior to Cycle 1 Day 1\[C1D1\] until study drug discontinuation)

  * Patients treated with a pulse of steroids were to discontinue steroid use 7 days prior to C1D1 and have a repeat CT scan and disease assessment after discontinuation of corticosteroids and before starting romidepsin;
* Concomitant use of any other anti-cancer therapy;
* Concomitant use of any investigational agent;
* Use of any investigational agent within 4 weeks of study entry;
* Any known cardiac abnormalities such as:

  * Congenital long QT syndrome;
  * QTc interval \>480 milliseconds (msec);
  * A myocardial infarction within 6 months of C1D1. Patients with a history of myocardial infraction between 6 and 12 months prior to C1D1 who are asymptomatic and have had a negative cardiac risk assessment (treadmill stress test, nuclear medicine stress test, or stress echocardiogram) since the event may participate;
  * Other significant electrocardiogram (ECG) abnormalities including 2nd degree atrio-ventricular (AV) block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50 beats/min).
  * Symptomatic coronary artery disease (CAD), e.g., angina Canadian Class II-IV. In any patient in whom there is doubt, the patient should be referred to a cardiologist for evaluation;
  * An ECG recorded at screening showing significant ST depression (ST depression of ≥2 mm, measured from isoelectric line to the ST segment at a point 60 msec at the end of the QRS complex). If in any doubt, the patient should have a stress imaging study and, if abnormal, angiography to define whether or not CAD is present;
  * Congestive heart failure (CHF) that meets New York Heart Association (NYHA) Class II to IV definitions and/or ejection fraction \<40% by MUGA scan or \<50% by echocardiogram and/or MRI;
  * A known history of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), Torsade de Pointes, or cardiac arrest unless currently addressed with an automatic implantable cardioverter defibrillator (AICD);
  * Hypertrophic cardiomyopathy or restrictive cardiomyopathy from prior treatment or other causes (if in doubt, see ejection fraction criteria above);
  * Uncontrolled hypertension, i.e., blood pressure (BP) of ≥160/95; patients who have a history of hypertension controlled by medication must be on a stable dose (for at least one month) and meet all other inclusion criteria;
  * Any cardiac arrhythmia requiring anti-arrhythmic medication;
* Serum potassium \<3.8 mmol/L or serum magnesium \<0.85 mmol/L (electrolyte abnormalities can be corrected with supplementation to meet inclusion criteria);
* Concomitant use of drugs that may cause a significant prolongation of the QTc;
* Concomitant use of CYP3A4 significant or moderate inhibitors;
* Concomitant use of therapeutic warfarin or another anticoagulant due to a potential drug interaction. Use of a small dose of a anticoagulant to maintain patency of venous access port and cannulas is permitted;
* Clinically significant active infection;
* Known infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C;
* Previous extensive radiotherapy involving ≥30% of bone marrow (e.g., whole pelvis, half spine), excluding patients who have had total body irradiation as part of a conditioning regimen for ASCT;
* Major surgery within 2 weeks of study entry;
* Previous allogeneic stem cell transplant;
* Inadequate bone marrow or other organ function as evidenced by:

  * Hemoglobin \<9 g/dL (transfusions and/or erythropoietin are permitted);
  * Absolute neutrophil count (ANC) ≤1.0 × 10\^9 cells/L \[patients with neutropenia (ANC 1-1.5 10\^9 cells/L) as a function of their disease may be supported with granulocyte-colony stimulating factor (G-CSF)\];
  * Platelet count \<100 × 10\^9 cells/L or platelet count \<75 × 10\^9 cells/L if bone marrow disease involvement is documented;
  * Total bilirubin \>2.0 × upper limit of normal (ULN) or \>3.0 × ULN in the presence of demonstrable liver metastases;
  * Aspartate transaminase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine transaminase/serum glutamic pyruvic transaminase (ALT/SGPT) \>2.0 × ULN or \>3.0 × ULN in the presence of demonstrable liver metastases; or
  * Serum creatinine \>2.0 × ULN;
* Patients who are pregnant or breast-feeding;
* Coexistent second malignancy or history of prior solid organ malignancy within previous 3 years (excluding basal or squamous cell carcinoma of the skin, and in situ carcinoma of the cervix (CIN 1) that has been treated curatively);
* Any prior history of a hematologic malignancy (other than T-cell lymphoma);
* Any significant medical or psychiatric condition that might prevent the patient from complying with all study procedures; or
* Prior exposure to romidepsin (other histone deacetylase inhibitors are allowed).

Primary outcomes:
measure: Percentage of Participants With a Complete Response According to the International Workshop Response Criteria (IWC) for Non-Hodgkin's Lymphomas (NHL) Assessed by an Independent Review Committee
timeFrame: Response was assessed after every 2 cycles of treatment and at completion of therapy, up until 30 September 2012 (data cutoff for analysis). Maximum duration on study was 1931 days.
Secondary outcomes:
measure: Percentage of Participants With Objective Disease Response
timeFrame: Response was assessed after every 2 cycles of treatment and at completion of therapy, up until 30 September 2012 (data cutoff for analysis). Maximum duration on study was 1931 days.
measure: Duration of Objective Disease Response
timeFrame: Response was assessed after every 2 cycles of treatment and at completion of therapy, up until 30 September 2012 (data cutoff for analysis). Maximum duration on study was 1931 days.
measure: Duration of Complete Disease Response
timeFrame: Response was assessed after every 2 cycles of treatment and at completion of therapy, up until 30 September 2012 (data cutoff for analysis). Maximum duration on study was 1931 days.
measure: Time to Disease Progression
timeFrame: Response was assessed after every 2 cycles of treatment and at completion of therapy, up until 30 September 2012 (data cutoff for analysis). Maximum duration on study was 1931 days.
measure: Change in Eastern Cooperative Oncology Group (ECOG) Performance Status
timeFrame: From Baseline up until 30 September 2012 (data cutoff for analysis). Maximum duration on study was 1931 days.
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
timeFrame: From first dose of study treatment until the final study visit, which occurred 30 days after receiving the last dose. Mean duration of treatment up until 30 September 2012 (data cutoff for analysis) was 169 days.
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: Moore UCSD Cancer Center
state: California
city: Los Angeles
country: United States
facility: UCLA Division of Hematology Oncology
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Aurora
country: United States
facility: Rocky Mountain Cancer Centers-Aurora
state: Colorado
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Washington
country: United States
facility: Georgetown University IRB
state: District of Columbia
city: Washington
country: United States
facility: Washington Hospital Center
state: District of Columbia
city: Orlando
country: United States
facility: Cancer Centers of Florida, PA
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center and Research Institute
state: Florida
city: Atlanta
country: United States
facility: Winship Cancer Institute of Emory University
state: Georgia
city: Augusta
country: United States
facility: Augusta Oncology Associates, P.C.
state: Georgia
city: Macon
country: United States
facility: Central Georgia Cancer Care
state: Georgia
city: Arlington Heights
country: United States
facility: Cancer Care and Hematology Specialists of Chicagoland
state: Illinois
city: Chicago
country: United States
facility: Hematology Oncology Assoc. of IL Orchard Research LLC
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Louisville
country: United States
facility: Consultants in Blood Disorders and Cancer
state: Kentucky
city: Baltimore
country: United States
facility: St. Agnes - Medical Center
state: Maryland
city: Bethesda
country: United States
facility: Center for Cancer And Blood Disorders
state: Maryland
city: Bethesda
country: United States
facility: Center for Cancer Research CAMC
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Burnsville
country: United States
facility: Minnesota Oncology Hematology, PA
state: Minnesota
city: Saint Joseph
country: United States
facility: St. Joseph Oncology, Inc
state: Missouri
city: Saint Louis
country: United States
facility: Arch Medical Services
state: Missouri
city: Omaha
country: United States
facility: Nebraska Cancer Specialists
state: Nebraska
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Cleveland
country: United States
facility: Taussig Cancer Center Cleveland Clinic Foundation
state: Ohio
city: Portland
country: United States
facility: Northwest Cancer Specialists, P.C.
state: Oregon
city: Memphis
country: United States
facility: Accelerated Community Oncology Research Network Inc ACORN
state: Tennessee
city: Beaumont
country: United States
facility: Mamie McFadden Ward Center
state: Texas
city: Dallas
country: United States
facility: Methodist Charlton Cancer Center
state: Texas
city: Dallas
country: United States
facility: UT Southwestern Medical Center Simmons Comprehensive Cancer Center
state: Texas
city: El Paso
country: United States
facility: El Paso Cancer Treatment Center
state: Texas
city: Fort Worth
country: United States
facility: Texas Oncology, P.A.-Fort Worth
state: Texas
city: Houston
country: United States
facility: UT MD Anderson Cancer Center
state: Texas
city: Midland
country: United States
facility: Allison Cancer Center
state: Texas
city: Plano
country: United States
facility: US Oncology
state: Texas
city: San Antonio
country: United States
facility: HOAST
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: Tyler
country: United States
facility: Tyler Cancer Center
state: Texas
city: Waco
country: United States
facility: Texas Oncology, PA
state: Texas
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: South Brisbane
country: Australia
facility: Mater Private Medical Centre - Haematology and Oncology Clinics of Australasia Research Centre
state: Queensland
city: East Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
city: Fitzroy
country: Australia
facility: St. Vincent Hospital
city: St Leonards
country: Australia
facility: Royal North Shore Hospital
city: Brno
country: Czechia
facility: University Hospital Brno
city: Hradec Kralove
country: Czechia
facility: University Hospital Hradec Kralove
city: Prague 10
country: Czechia
facility: University Hospital of Kralovske Vinohrady
city: Prague 2
country: Czechia
facility: Charles University General Hospital
city: Bordeaux
country: France
facility: Polyclinique Bordeaux Nord Aquitaine
city: Créteil
country: France
facility: Hopital Henri Mondor
city: Lille
country: France
facility: Hopital Claude Huriez
city: Nantes
country: France
facility: CHU Nantes Hotel Dieu
city: Paris
country: France
facility: Hopital Saint-Louis
city: Pessac
country: France
facility: Service des Maladies du Sang
city: Pierre Bénite
country: France
facility: Centre Hospitalier Lyon Sud
city: Rennes
country: France
facility: Centre Eugene Marquis
city: Rouen Cedex
country: France
facility: Centre Henri Becquerel
city: Berlin
country: Germany
facility: Charite Universitatsmedizin Berlin campus Virchow Klinikum Centrum fur Tumormedizin
city: Frankfurt a.M.
country: Germany
facility: Krankenhaus Nordwest
city: Göttingen
country: Germany
facility: Georg-August-Universität Göttingen
city: Köln
country: Germany
facility: Uniklinik Koln
city: Muenchen
country: Germany
facility: Klinikum der Universitat Munchen-Grosshadern
city: Nürnberg
country: Germany
facility: Klinikum Nurnberg Nord
city: Tuebingen
country: Germany
facility: UKT Universitaetsklinikum Tuebingen
city: Gdansk
country: Poland
facility: Klinika Hematologii Akademickie Centrum Kliniczne Akademii Medycznej w Gdansku
city: Kraków
country: Poland
facility: Oddzial Kliniczny Kliniki Hematologii
city: Lodz
country: Poland
facility: Wojewodzki Szpital Specjalistczny im. Mikolaja Kopernika
city: Warszawa
country: Poland
facility: Klinika Nowotworow Ukladu Chlonnego
city: Barcelona
country: Spain
facility: Hospital Universitario Vall D Hebron
city: Madrid
country: Spain
facility: Hospital de La Princesa
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Pamplona
country: Spain
facility: Clinica Universitaria de Navarra
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Santandar
country: Spain
facility: Hospital Marques de Valdecilla
city: Lund
country: Sweden
facility: Lund University Hosptial
city: Uppsala
country: Sweden
facility: Akademiska Sjukhuset
city: Dnipropetrovsk
country: Ukraine
facility: Dnipropetrovsk State Medical Academy
city: Kyiv
country: Ukraine
facility: National Cancer Institute Department Of Conservative Methods Of Treatment
city: Kyiv
country: Ukraine
facility: R.E.Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology
city: Lviv
country: Ukraine
facility: Institute of Blood Pathology and Transfusion Medicine of the AMS of Ukraine
city: London Hampstead
country: United Kingdom
facility: Royal Free Hospital
city: London
country: United Kingdom
facility: Barts Cancer Institute, Queen Mary University of London, Charterhouse Square
city: London
country: United Kingdom
facility: Guy's and St. Thomas' Hospital
city: London
country: United Kingdom
facility: Catherine Lewis Centre - Hematology Department
city: Southampton
country: United Kingdom
facility: Somers Cancer Research Building
Study officials:
affiliation: Celgene
name: Myron Czuczman, MD
role: STUDY_DIRECTOR
References:
citation: Foss F, Pro B, Miles Prince H, Sokol L, Caballero D, Horwitz S, Coiffier B. Responses to romidepsin by line of therapy in patients with relapsed or refractory peripheral T-cell lymphoma. Cancer Med. 2017 Jan;6(1):36-44. doi: 10.1002/cam4.939. Epub 2016 Dec 16.
citation: Shustov A, Coiffier B, Horwitz S, Sokol L, Pro B, Wolfson J, Balser B, Eisch R, Popplewell L, Prince HM, Allen SL, Piekarz R, Bates S. Romidepsin is effective and well tolerated in older patients with peripheral T-cell lymphoma: analysis of two phase II trials. Leuk Lymphoma. 2017 Oct;58(10):2335-2341. doi: 10.1080/10428194.2017.1295143. Epub 2017 Mar 7.
citation: Coiffier B, Pro B, Prince HM, Foss F, Sokol L, Greenwood M, Caballero D, Borchmann P, Morschhauser F, Wilhelm M, Pinter-Brown L, Padmanabhan S, Shustov A, Nichols J, Carroll S, Balser J, Balser B, Horwitz S. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol. 2012 Feb 20;30(6):631-6. doi: 10.1200/JCO.2011.37.4223. Epub 2012 Jan 23.
citation: Horwitz S, Coiffier B, Foss F, Prince HM, Sokol L, Greenwood M, Caballero D, Morschhauser F, Pinter-Brown L, Iyer SP, Shustov A, Nichols J, Balser J, Balser B, Pro B. Utility of (1)(8)fluoro-deoxyglucose positron emission tomography for prognosis and response assessments in a phase 2 study of romidepsin in patients with relapsed or refractory peripheral T-cell lymphoma. Ann Oncol. 2015 Apr;26(4):774-779. doi: 10.1093/annonc/mdv010. Epub 2015 Jan 20.
citation: Foss F, Horwitz S, Pro B, Prince HM, Sokol L, Balser B, Wolfson J, Coiffier B. Romidepsin for the treatment of relapsed/refractory peripheral T cell lymphoma: prolonged stable disease provides clinical benefits for patients in the pivotal trial. J Hematol Oncol. 2016 Mar 10;9:22. doi: 10.1186/s13045-016-0243-8.
citation: Foss F, Coiffier B, Horwitz S, Pro B, Prince HM, Sokol L, Greenwood M, Lerner A, Caballero D, Baran E, Kim E, Nichols J, Balser B, Wolfson J, Whittaker S. Tolerability to romidepsin in patients with relapsed/refractory T-cell lymphoma. Biomark Res. 2014 Sep 8;2:16. doi: 10.1186/2050-7771-2-16. eCollection 2014.
citation: Coiffier B, Pro B, Prince HM, Foss F, Sokol L, Greenwood M, Caballero D, Morschhauser F, Wilhelm M, Pinter-Brown L, Padmanabhan Iyer S, Shustov A, Nielsen T, Nichols J, Wolfson J, Balser B, Horwitz S. Romidepsin for the treatment of relapsed/refractory peripheral T-cell lymphoma: pivotal study update demonstrates durable responses. J Hematol Oncol. 2014 Jan 23;7:11. doi: 10.1186/1756-8722-7-11.