A Trial of Romidepsin for Progressive or Relapsed Peripheral T-cell Lymphoma

Peripheral T-cell Lymphoma Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00426764
• Other study ID #: GPI-06-0002
• Secondary ID: 2006-006228-21
• Status: Completed
• Phase: Phase 2
• Start date: June 19, 2007
• Est. completion date: May 17, 2018

Study information

• Verified date: January 2020
• Source: Celgene
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Other known NCT identifiers

• NCT00924378

Recruitment information / eligibility

• Status: Completed
• Enrollment: 131
• Est. completion date: May 17, 2018
• Est. primary completion date: November 11, 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 ?d 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).

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, T-Cell
• Lymphoma, T-Cell, Peripheral
• Peripheral T-cell Lymphoma

Intervention

Drug:
• Romidepsin
Romidepsin intravenously (through a vein) over 4 hours on Days 1, 8 and 15 of each 28-day cycle.

Locations

Country	Name	City	State
Australia	Peter MacCallum Cancer Centre	East Melbourne
Australia	St. Vincent Hospital	Fitzroy
Australia	Mater Private Medical Centre - Haematology and Oncology Clinics of Australasia Research Centre	South Brisbane	Queensland
Australia	Royal North Shore Hospital	St Leonards
Czechia	University Hospital Brno	Brno
Czechia	University Hospital Hradec Kralove	Hradec Kralove
Czechia	University Hospital of Kralovske Vinohrady	Prague 10
Czechia	Charles University General Hospital	Prague 2
France	Polyclinique Bordeaux Nord Aquitaine	Bordeaux
France	Hopital Henri Mondor	Créteil
France	Hopital Claude Huriez	Lille
France	CHU Nantes Hotel Dieu	Nantes
France	Hopital Saint-Louis	Paris
France	Service des Maladies du Sang	Pessac
France	Centre Hospitalier Lyon Sud	Pierre Bénite
France	Centre Eugene Marquis	Rennes
France	Centre Henri Becquerel	Rouen Cedex
Germany	Charite Universitatsmedizin Berlin campus Virchow Klinikum Centrum fur Tumormedizin	Berlin
Germany	Krankenhaus Nordwest	Frankfurt a.M.
Germany	Georg-August-Universität Göttingen	Göttingen
Germany	Uniklinik Koln	Köln
Germany	Klinikum der Universitat Munchen-Grosshadern	Muenchen
Germany	Klinikum Nurnberg Nord	Nürnberg
Germany	UKT Universitaetsklinikum Tuebingen	Tuebingen
Poland	Klinika Hematologii Akademickie Centrum Kliniczne Akademii Medycznej w Gdansku	Gdansk
Poland	Oddzial Kliniczny Kliniki Hematologii	Kraków
Poland	Wojewodzki Szpital Specjalistczny im. Mikolaja Kopernika	Lodz
Poland	Klinika Nowotworow Ukladu Chlonnego	Warszawa
Spain	Hospital Universitario Vall D Hebron	Barcelona
Spain	Hospital de La Princesa	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Clinica Universitaria de Navarra	Pamplona
Spain	Hospital Universitario de Salamanca	Salamanca
Spain	Hospital Marques de Valdecilla	Santandar
Sweden	Lund University Hosptial	Lund
Sweden	Akademiska Sjukhuset	Uppsala
Ukraine	Dnipropetrovsk State Medical Academy	Dnipropetrovsk
Ukraine	National Cancer Institute Department Of Conservative Methods Of Treatment	Kyiv
Ukraine	R.E.Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology	Kyiv
Ukraine	Institute of Blood Pathology and Transfusion Medicine of the AMS of Ukraine	Lviv
United Kingdom	Barts Cancer Institute, Queen Mary University of London, Charterhouse Square	London
United Kingdom	Catherine Lewis Centre - Hematology Department	London
United Kingdom	Guy's and St. Thomas' Hospital	London
United Kingdom	Royal Free Hospital	London Hampstead
United Kingdom	Somers Cancer Research Building	Southampton
United States	Cancer Care and Hematology Specialists of Chicagoland	Arlington Heights	Illinois
United States	Winship Cancer Institute of Emory University	Atlanta	Georgia
United States	Augusta Oncology Associates, P.C.	Augusta	Georgia
United States	Rocky Mountain Cancer Centers-Aurora	Aurora	Colorado
United States	St. Agnes - Medical Center	Baltimore	Maryland
United States	Mamie McFadden Ward Center	Beaumont	Texas
United States	Center for Cancer And Blood Disorders	Bethesda	Maryland
United States	Center for Cancer Research CAMC	Bethesda	Maryland
United States	Tufts Medical Center	Boston	Massachusetts
United States	Minnesota Oncology Hematology, PA	Burnsville	Minnesota
United States	Hematology Oncology Assoc. of IL Orchard Research LLC	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	Taussig Cancer Center Cleveland Clinic Foundation	Cleveland	Ohio
United States	Methodist Charlton Cancer Center	Dallas	Texas
United States	UT Southwestern Medical Center Simmons Comprehensive Cancer Center	Dallas	Texas
United States	Henry Ford Hospital	Detroit	Michigan
United States	El Paso Cancer Treatment Center	El Paso	Texas
United States	Texas Oncology, P.A.-Fort Worth	Fort Worth	Texas
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	UT MD Anderson Cancer Center	Houston	Texas
United States	Moore UCSD Cancer Center	La Jolla	California
United States	UCLA Division of Hematology Oncology	Los Angeles	California
United States	Consultants in Blood Disorders and Cancer	Louisville	Kentucky
United States	Central Georgia Cancer Care	Macon	Georgia
United States	Accelerated Community Oncology Research Network Inc ACORN	Memphis	Tennessee
United States	Allison Cancer Center	Midland	Texas
United States	Yale University	New Haven	Connecticut
United States	Columbia University Medical Center	New York	New York
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Weill Cornell Medical College	New York	New York
United States	Nebraska Cancer Specialists	Omaha	Nebraska
United States	Cancer Centers of Florida, PA	Orlando	Florida
United States	US Oncology	Plano	Texas
United States	Northwest Cancer Specialists, P.C.	Portland	Oregon
United States	St. Joseph Oncology, Inc	Saint Joseph	Missouri
United States	Arch Medical Services	Saint Louis	Missouri
United States	HOAST	San Antonio	Texas
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	University of California, San Francisco	San Francisco	California
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington
United States	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida
United States	Tyler Cancer Center	Tyler	Texas
United States	Texas Oncology, PA	Waco	Texas
United States	Georgetown University IRB	Washington	District of Columbia
United States	Washington Hospital Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Celgene

Countries where clinical trial is conducted

United States,  Australia,  Czechia,  France,  Germany,  Poland,  Spain,  Sweden,  Ukraine,  United Kingdom, 

References & Publications (4)

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 st — View 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. — View 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 ¹8fluoro-deoxyglucose positron emission tomography for prognosis and response — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Complete Response (CR): >75% decrease in size aggregate of nodal index lesions (large and small), complete disappearance of extranodal and non-index lesions; total disappearance of clinical disease including skin involvement; disease-related signs and symptoms, normalization of biochemical abnormalities and reduction in size of spleen or liver so no longer palpable. Unconfirmed CR: all above criteria except all nodal index lesions must have regressed >75% in the sum of the product diameters (SPD) from baseline. Individual nodes previously confluent must have regressed by >75% in their SPD.	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	Percentage of Participants With Objective Disease Response	Objective disease response was defined as patients with a Complete Response, Unconfirmed Complete Response or a Partial Response (PR) according to the IWC 1999 assessed by an independent review committee: CR, Cru defined above, PR defined as =50% decrease in size of 6 largest dominant nodes and/or nodal masses & extranodal index lesions and no increase of non-index lesions, liver, or spleen; no new sites of disease evident; skin lesions decreased by =50%.	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	Duration of Objective Disease Response	Duration of response was defined as the number of days from the date of the first disease response (Complete, Unconfirmed Complete or Partial Response) until the date of progression and was determined using Kaplan-Meier product-limit estimates. Progression was defined as: a =50% increase from the nadir in the individual sum of the products of the diameters of any index lesion; the reappearance of pathology, enlargement of liver/spleen, or unequivocal progression of non-measurable disease or appearance of any new lesions.	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	Duration of Complete Disease Response	Duration of response was defined as the number of days from the date of the first disease response (Complete or Unconfirmed Complete) until the date of progression and was determined using Kaplan-Meier product-limit estimates. Progression was defined as: a =50% increase from the nadir in the individual sum of the products of the diameters of any index lesion; the reappearance of pathology, enlargement of liver/spleen, or unequivocal progression of non-measurable disease or appearance of any new lesions.	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	Time to Disease Progression	Time to progression (=50% increase from the nadir in the individual sum of the products of the diameters of any index lesion; the reappearance of pathology, enlargement of liver/spleen, or unequivocal progression of non-measurable disease or appearance of any new lesions) was defined as the duration from the date of the first study drug dose to the date of relapse or progression as reported by the independent review committee and was determined using Kaplan-Meier product-limit estimates.	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	Change in Eastern Cooperative Oncology Group (ECOG) Performance Status	The ECOG scale is as follows: Grade 0: Fully active, able to perform all pre-disease activities without restriction; Grade 1: Restricted in physically strenuous activity, ambulatory, able to carry out light work; Grade 2: Ambulatory and capable of all self-care but unable to work. Up and about more than 50% of waking hours; Grade 3: Capable of only limited self-care, confined to bed or chair > 50% of waking hours; Grade 4: Completely disabled. Cannot carry on any self-care. Confined to bed or chair. Data reported is the shift from Baseline ECOG score to best on-study assessment score.	From Baseline up until 30 September 2012 (data cutoff for analysis). Maximum duration on study was 1931 days.
Secondary	Number of Participants With Treatment Emergent Adverse Events (TEAEs)	An adverse event or experience (AE) is defined as any untoward medical occurrence, which does not necessarily have to have a causal relationship with this treatment. A serious AE is any untoward medical occurrence that at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is an important medical event or condition. Related AEs are defined as those considered by the Investigator to have a possible, probable, or very likely/certain relationship to the study drug. AEs were graded as mild (1), moderate (2), severe (3), lifethreatening (4), or death (5). TEAEs occurred from the first dose of study medication through the end of the study (30 days post last dose) or any event that was present at baseline but worsened in intensity or was subsequently considered drug-related by the Investigator through end of study.	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.