Efficacy and Safety of Romidepsin CHOP vs CHOP in Patients With Untreated Peripheral T-Cell Lymphoma

Phase 3

Completed

• Conditions: Peripheral T-cell Lymphoma
• Interventions: Drug: Romidepsin + CHOP; Drug: CHOP

• Registration Number: NCT01796002
• Lead Sponsor: The Lymphoma Academic Research Organisation

Brief Summary

Primary objective of the study is to compare the efficacy of romidepsin when administered with CHOP versus CHOP alone in subjects with previously untreated peripheral T-cell lymphoma (PTCL) in terms of progression-free survival (PFS) assessed according to Response criteria for malignant lymphoma 1999 by a Response Adjudication Committee (RAC).

Detailed Description

This is a randomized multi-center phase III study, to compare efficacy and safety of Ro-CHOP with standard CHOP regimen in patients with previously untreated, histologically proven PTCL. Given the nature of the experimental agent, this study is an open-label study. Patients are randomized 1:1 to receive either (Arm A) cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) administered in 3 week cycles for 6 cycles \[22\] or (Arm B) romidepsin CHOP (Ro-CHOP) administered in 3 week cycles for 6 cycles. In the Ro-CHOP arm, romidepsin will be administered at a dose of 12 mg/m² IV on day 1 and day 8 every 3 weeks. In this study, patients will advance through three phases of the study: screening phase, treatment phase and follow-up phase. Patients will receive study drug(s) for up to 6 cycles, or until unacceptable toxicity will develop or progression or voluntary withdrawal. Patients will be followed for survival until the earliest of either 80% of patients have died or 3 years from the last patient randomized. Three years after the primary analysis an update of the database will be done and a rerun of the analysis will be performed.

Study Timeline

• Study Start: 2013-01
• Study First Submitted: 2013-01-31
• Study First Submitted QC: 2013-02-20
• Study First Posted: 2013-02-21
• Primary Completion: 2019-12-13
• Study Completion: 2022-12-13
• Status Verified: 2023-01
• Last Update Submitted: 2023-01-09
• Last Update Posted: 2023-01-10

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 421

Inclusion Criteria

1. Males and females of 18 years of age to 80 years of age.

2. Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures are conducted.

3. Able to adhere to the study visit schedule and other protocol requirements.

4. Patients with histologically proven peripheral T-cell lymphoma (PTCL), not previously treated; the following subtypes as defined by the World Health Organization (WHO) classification (2008;2011) may be included, whatever the Ann Arbor stage (I - IV):

   a. Nodal types: i. PTCL, not otherwise specified ii. Angioimmunoblastic T-cell lymphoma iii. Anaplastic large cell lymphoma, anaplastic lymphoma kinase (ALK)-negative type

   b. Extra-nodal types: i. Enteropathy-associated T-cell lymphoma ii. Hepato-splenic T-cell lymphoma iii. Subcutaneous panniculitis-like T-cell lymphoma iv. Primary cutaneous gamma-delta T-cell lymphoma v. Primary cutaneous cluster of differentiation 8 positive (CD8+) aggressive epidermotropic lymphoma vi. Primary cutaneous cluster of differentiation 4 positive (CD4+) small/medium T-cell lymphoma

   c. Other non classifiable peripheral T-cell lymphoma

5. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2

6. Negative pregnancy test for Females of ChildBearing Potential (FCBP)

7. Female patients of child bearing potential must use an effective method of birth control (i.e. hormonal contraceptive, intrauterine device, diaphragm with spermicide, condom with spermicide or abstinence) during treatment period and 1 month thereafter; Males must use an effective method of birth control during treatment period and 3 months thereafter.

8. Life expectancy of ≥ 90 days (3 months).

Exclusion Criteria

1. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from participating in the study.

2. Any condition that confounds the ability to interpret data from the study.

3. Other types of lymphomas, e.g. B-cell lymphoma

4. The following types of T cell lymphomas:

   1. Adult T-cell lymphoma/leukemia (HTLV-1 related T-cell lymphoma)
   2. Extranodal T-cell/Natural Killer (NK)-cell lymphoma, nasal type
   3. Anaplastic large cell lymphoma, ALK-positive type
   4. Cutaneous T cell lymphoma (mycosis fungoid, Sézary syndrome)
   5. Primary cutaneous cluster of differentiation antigen 30 positive (CD30+) T-cell lymphoproliferative disorder
   6. Primary cutaneous anaplastic T-cell lymphoma

5. Previous treatment for PTCL with immunotherapy or chemotherapy except for short-term corticosteroids (duration of ≤ 8 days) before randomization

6. Previous radiotherapy for PTCL except if localized to one lymph node area

7. Patients planned for autologous or allogeneic transplant as consolidation in first line

8. Central nervous system -meningeal involvement

9. Contraindication to any drug contained in the chemotherapy regimen,

10. Subjects with HIV positivity

11. Subjects with active hepatitis B or C. Chronic carriers of Hepatitis B virus (HBV) without HBV DNA positive blood are eligible. Subjects with non-active hepatitis C (with normal transaminases) are eligible.

12. Any of the following laboratory abnormalities, except if secondary to the lymphoma:

    1. Absolute neutrophil count (ANC) < 1,500 cells/mm3 (1.5 x 109/L),
    2. Platelet count < 100,000/mm3 (100 x 109/L), or < 75,000/mm3 if bone marrow is involved,
    3. Serum Aspartate Aminotransferase (ASAT/AST) or Alanine Aminotransferase (ALAT/ALT) ≥ 3.0 x Upper Limit of Normal (ULN),
    4. Serum total bilirubin > 2 x ULN, except in case of hemolytic anemia,
    5. K+ and Mg2+ levels < Lower Limit of Normal (LLN), except if corrected per protocol guidance before beginning the romidepsin infusion

13. Serum creatinine > 2.0 x ULN

14. Prior history of malignancies other than lymphoma (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast or untreated prostatic cancer without any plan for a treatment) unless the patient has been free of the disease for ≥ 3 years

15. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from signing the informed consent form

16. Any known cardiac abnormalities such as:

    1. Patients with congenital long QT syndrome
    2. Corrected QT interval > 480 msec (using the Fridericia formula)
    3. Myocardial infarction within 6 months of cycle 1 day 1
    4. History of or concomitant significant cardiovascular disease
    5. Ejection fraction <45% by multigated acquisition (MUGA) scan or by echocardiogram;

17. Concomitant use of drugs that may cause a significant prolongation of the corrected QT interval (QTc)

18. Patients who have received more than 200 mg/m2 doxorubicin

19. Concomitant use of strong CYP3A4 inhibitors

20. Concomitant use of therapeutic warfarin due to a potential drug interaction. Use of a low dose of warfarin or another anticoagulant to maintain patency of venous access port and cannulas is permitted.

21. Clinically significant active infection

22. Use of any standard or experimental anti-cancer drug therapy within 28 days of the initiation (Day 1) of study drug

23. Pregnant or lactating females or women of childbearing potential not willing to use an adequate method of birth control for the duration of the study.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Experimental: Romidepsin plus CHOP	Romidepsin + CHOP	Patients in experimental arm receive romidepsin plus CHOP (Ro-CHOP) administered in 3 week cycles for 6 cycles. Romidepsin is administered at a dose of 12 mg/m² IV on day 1 and day 8 every 3 weeks.
Standard: CHOP	CHOP	Patients in control Arm receive cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) administered in 3 week cycles for 6 cycles.

Primary Outcome Measures

Name	Time	Method
The primary efficacy endpoint is Progression Free Survival	60 months	The primary efficacy endpoint is Progression Free Survival (PFS) using the response criteria for malignant lymphoma (1999) by a Response Adjudication Committee

Trial Locations

Locations (131)

CH de Annecy; 🇫🇷 Annecy, France

CH Henri Duffaut; 🇫🇷 Avignon, France

CH Sud Francilien de Corbeil; 🇫🇷 Corbeil Essonnes, France

CHRU de Lille - Hôpital Claude Hurriez; 🇫🇷 Lille, France

ULB - Hôpital Erasme; 🇧🇪 Bruxelles, Belgium

CHU Mont Godinne; 🇧🇪 Yvoir, Belgium

CHU de Dijon; 🇫🇷 Dijon, France

CH de Dunkerque; 🇫🇷 Dunkerque, France

Hôpital Pasteur; 🇫🇷 Colmar, France

CHU Estaing; 🇫🇷 Clermont-Ferrand, France

Centre Hospitalier de Versailles - André Mignot; 🇫🇷 Le Chesnay, France

CHU de Limoges; 🇫🇷 Limoges, France

Chi Poissy /Saint- Germain-En-Laye; 🇫🇷 Mantes-la-Jolie, France

Institut Paoli Calmettes; 🇫🇷 Marseille, France

CHD La Roche sur Yon; 🇫🇷 La Roche sur Yon, France

Hôpital Saint Vincent de Paul; 🇫🇷 Lille, France

Charité Medical School Campus Virchow-Klinikum; 🇩🇪 Berlin, Germany

CHC - Clinique Saint Joseph; 🇧🇪 Liege, Belgium

Institut Jules Bordet; 🇧🇪 Bruxelles, Belgium

AZ Groeninge; 🇧🇪 Kortrijk, Belgium

UCL Louvain Saint Luc; 🇧🇪 Bruxelles, Belgium

CHU Henri Mondor; 🇫🇷 Créteil, France

Hôpital Kremlin Bicêtre; 🇫🇷 Le Kremlin Bicêtre, France

Clinique Victor Hugo; 🇫🇷 Le Mans, France

Hôpital Saint Eloi; 🇫🇷 Montpellier, France

Hôpital Jolimont; 🇧🇪 Haine Saint Paul, Belgium

ZNA Stuivenberg; 🇧🇪 Antwerpen, Belgium

A.Z. Sint Jan AV; 🇧🇪 Brugge, Belgium

Grand Hôpital de Charleroi; 🇧🇪 Charleroi, Belgium

AZ VUB; 🇧🇪 Jette, Belgium

CHU de Liege; 🇧🇪 Liege, Belgium

CHU d'Amiens; 🇫🇷 Amiens, France

CHU d'Angers; 🇫🇷 Angers, France

CH Côte Basque; 🇫🇷 Bayonne, France

CHU Jean Minjoz; 🇫🇷 Besançon, France

Polyclinique Bordeaux Nord Aquitaine; 🇫🇷 Bordeaux, France

CHU de Bordeaux - Hôpital Haut Lévêque - Centre François Magendie; 🇫🇷 Bordeaux, France

Institut Bergonié; 🇫🇷 Bordeaux, France

CH de Bourg en Bresse; 🇫🇷 Bourg en Bresse, France

CH du Dr Duchenne; 🇫🇷 Boulogne-sur-mer, France

CH de Béziers; 🇫🇷 Béziers, France

Institut d'Hématologie de Basse-Normandie; 🇫🇷 Caen, France

Centre François Baclesse; 🇫🇷 Caen, France

CH de Chalon sur Saône; 🇫🇷 Chalon sur Saône, France

CH de Chambéry; 🇫🇷 Chambéry, France

Hôpital Antoine Béclère; 🇫🇷 Clamart, France

CHU de Grenoble; 🇫🇷 Grenoble, France

CH du Mans; 🇫🇷 Le Mans, France

CH de Lens; 🇫🇷 Lens, France

CH de Saint Quentin; 🇫🇷 Lille, France

CH de Saint Germain; 🇫🇷 Mantes-La-Jolie, France

Centre Léon Bérard; 🇫🇷 Lyon, France

UniversitätsKrebszentrum Göttingen - G-CCC; 🇩🇪 Göttingen, Germany

CH de Meaux; 🇫🇷 Meaux, France

CHR de Metz; 🇫🇷 Metz, France

CHU Nancy Brabois; 🇫🇷 Nancy, France

CHU de Mulhouse; 🇫🇷 Mulhouse, France

CHU Hôtel Dieu Nantes; 🇫🇷 Nantes, France

CHU de Nîmes - Caremeau; 🇫🇷 Nimes, France

Centre Antoine Lacassagne; 🇫🇷 Nice, France

CHU de Nice; 🇫🇷 Nice, France

Hôpital de la Pitié Salpétrière; 🇫🇷 Paris, France

Hôpital Necker; 🇫🇷 Paris, France

Hôpital Saint Antoine; 🇫🇷 Paris, France

Hôpital Saint Louis; 🇫🇷 Paris, France

Institut Curie; 🇫🇷 Paris, France

Centre François Magendie; 🇫🇷 Pessac, France

CH de Perpignan; 🇫🇷 Perpignan, France

Centre Hospitalier Lyon Sud; 🇫🇷 Pierre Bénite, France

CHU de Poitiers; 🇫🇷 Poitiers, France

CH de Roubaix; 🇫🇷 Roubaix, France

CHU Robert Debré; 🇫🇷 Reims, France

CHU Pontchaillou; 🇫🇷 Rennes, France

Centre Henri Becquerel; 🇫🇷 Rouen, France

Institut Curie - Centre René Huguenin; 🇫🇷 Saint Cloud, France

CHU de Toulouse; 🇫🇷 Toulouse, France

CHU Bretonneau; 🇫🇷 Tours, France

CH Valence; 🇫🇷 Valence, France

CH de Valenciennes; 🇫🇷 Valenciennes, France

Institut Gustave Roussy; 🇫🇷 Villejuif, France

Charité Medical School Campus Benjamin Franklin; 🇩🇪 Berlin, Germany

CH de Bretagne Atlantique; 🇫🇷 Vannes, France

HELIOS Hospital Berlin-Buch; 🇩🇪 Berlin, Germany

St Johannes-Hospital; 🇩🇪 Dortmund, Germany

Vivantes Klinikum Neukölln; 🇩🇪 Berlin, Germany

Klinik Universitätsklinikum Düsseldorf; 🇩🇪 Düsseldorf, Germany

Universitätsklinikum Carl Gustav Carus der TU Dresden; 🇩🇪 Dresden, Germany

University of Duisburg-Essen; 🇩🇪 Essen, Germany

Krankenhaus Nordwest; 🇩🇪 Frankfurt am Main, Germany

Universitätklinikum Freiburg Klinik für Innere medizin I; 🇩🇪 Freiburg, Germany

Universitätsmedizin Greifswald; 🇩🇪 Greifswald, Germany

Asklepios Klinik St. Georg; 🇩🇪 Hamburg, Germany

Universitätsklinikum des Saarlandes; 🇩🇪 Homburg, Germany

Uniklinik Köln; 🇩🇪 Köln, Germany

Klinikum St. Georg gGmbH; 🇩🇪 Leipzig, Germany

Klinikum Oldenburg gGmbH; 🇩🇪 Oldenburg, Germany

Azienda Ospedaliera Spedali Civili di Brescia; 🇮🇹 Brescia, Italy

Universitätsklinikum Ulm; 🇩🇪 Ulm, Germany

Istituto di Ematologia "Saragnoli" Policlinico San'Orsola-Malpighi, Bologna; 🇮🇹 Bologna, Italy

Azienda Sanitaria Ospedaliera S.Croce e Carle Cuneo; 🇮🇹 Cuneo, Italy

Ospedale Ferrarotto; 🇮🇹 Catania, Italy

Azienda Ospedaliera universitaria Careggi; 🇮🇹 Firenze, Italy

Ematologia Oncologica Istituto Pascale; 🇮🇹 Napoli, Italy

Azienda Ospedaliera Bianchi Melacrino Morelli; 🇮🇹 Reggio Calabria, Italy

Ematologia Università La Sapienza; 🇮🇹 Roma, Italy

AOU San Giovanni Battista; 🇮🇹 Torino, Italy

Dong-A Univ. Hospital; 🇰🇷 Busan, Korea, Republic of

Clinica Ematologica di Udine; 🇮🇹 Udine, Italy

National Cancer Center; 🇰🇷 Goyang-si, Korea, Republic of

Hospital de la Santa Creu i Sant Pau; 🇪🇸 Barcelone, Spain

Samsung Medical Center; 🇰🇷 Seoul, Korea, Republic of

Asian Medical Center; 🇰🇷 Seoul, Korea, Republic of

Korean Cancer Center Hospital; 🇰🇷 Seoul, Korea, Republic of

Severance Hospital Yonsei University; 🇰🇷 Seoul, Korea, Republic of

Hospital Clínic de Barcelona; 🇪🇸 Barcelona, Spain

Instituto Português Oncologia; 🇵🇹 Lisbon, Portugal

National University Cancer Hospital; 🇸🇬 Singapore, Singapore

National Cancer Centre Singapore; 🇸🇬 Singapore, Singapore

Hospital del Mar; 🇪🇸 Barcelona, Spain

Singapore General Hospital; 🇸🇬 Singapore, Singapore

ICO l'Hospitalet; 🇪🇸 Barcelona, Spain

Hospital de Jerez de la Frontera; 🇪🇸 Jerez de la Frontera, Spain

ICO - Institut Català d'Oncologia - Hospital Doctor Josep Trueta; 🇪🇸 Girona, Spain

Hospital Universitario 12 de Octubre; 🇪🇸 Madrid, Spain

H. Morales Messeguer; 🇪🇸 Murcia, Spain

Hospital Clínico Universitario de Salamanca; 🇪🇸 Salamanca, Spain

Hospital Universitario Central de Asturias; 🇪🇸 Oviedo, Spain

H. Virgen del Rocío; 🇪🇸 Sevilla, Spain

Hospital Universitario Dr. Peset de Valencia; 🇪🇸 Valencia, Spain

Hospital Arnau de Vilanova de Valencia; 🇪🇸 Valencia, Spain

Hospital Clinico Universitario de Valladolid; 🇪🇸 Valladolid, Spain