Efficacy and Safety of R-HAD Alone or in Combination With Bortezomib in Patients With Relapsed or Refractory MCL

Mantle Cell Lymphoma Clinical Trial

— (R-HAD)  

Official title:

Efficacy and Safety of Rituximab, High-dose Ara-C and Dexamethasone (R-HAD) Alone or in Combination With Bortezomib in Patients With Relapsed or Refractory Mantle Cell Lymphoma

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01449344
• Other study ID #: MCL2005-01
• Status: Active, not recruiting
• Phase: Phase 3
• First received: September 28, 2011
• Last updated: March 6, 2017
• Start date: May 9, 2009
• Est. completion date: December 2018

Study information

• Verified date: March 2017
• Source: European Mantle Cell Lymphoma Network
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the efficacy and safety of rituximab, high-dose ara-c and dexamethasone (r-had) alone or in combination with bortezomib in patients with relapsed or refractory mantle cell lymphoma.

Description:

This study is a prospective, randomized, multicenter, open-label phase III clinical trial to compare the efficacy and safety of Bortezomib in combination with Rituximab, high-dose Ara-C and dexamethasone (R-HAD) to R-HAD alone in patients with relapsed or refractory MCL after or not eligible for myeloablative treatment. The primary endpoint is time to treatment failure (TTF). Secondary endpoints are the complete response (CR) rate, the overall response (CR,PR) rate, the progression-free survival (PFS), the progression free survival of responders, the time to next lymphoma treatment, overall survival (OS), safety and tolerability of Rituximab, high-dose Ara-C and dexamethasone alone or in combination with Bortezomib. Study arms will be compared to each other to evaluate the impact of additional Bortezomib. Study arms will also be compared to historical controls.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 128
• Est. completion date: December 2018
• Est. primary completion date: December 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Confirmed pathological diagnosis of MCL according to WHO classification.

• Relapse or progression following 1 to 3 prior lines of anti-neoplastic standard therapy. Therapy in remission after initial induction like intensified chemotherapy for stem cell separation followed by myeloablative therapy or any kind of maintenance therapy is classified as one line of therapy with the induction therapy..

• If Rituximab was part of prior treatment, documented time to progression must be at least 12 weeks after this particular regimen.

• If high-dose Ara-C was part of prior treatment, documented time to progression must be at least 6 months after this particular regimen.

• Patients relapsed after autologous stem cell transplantation or not appropriate for myeloablative treatment.

• At least 1 measurable or assessable site of disease; in case of bone marrow infiltration only, bone marrow aspiration/ biopsy is mandatory for all staging evaluations.

• age > 18 years

• ECOG/WHO Performance Score 0-2 unless lymphoma related.

• The following laboratory values at screening, unless lymphoma related:

• Absolute neutrophil count (ANC) > = 1500 cells/microlitre

• Platelets > = 100,000 cells/microlitre

• Transaminases (AST and ALT) <=3 x upper limit of normal (ULN)

• Total bilirubin <=2 x ULN

• Creatinine <=2 mg/dL or calculated creatinine clearance >=50 mL/min

• Toxic effects of previous therapy or surgery resolved to NCI CTC grade 2 or better.

• Premenopausal fertile females must agree to use a highly effective method of birth control for the duration of the therapy. A highly effective method of birth control is defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, some IUDs, sexual abstinence or vasectomised partner.

• Men must agree not to father a child for the duration of therapy and must agree to advice a female partner to use a highly effective method of birth control.

• Written informed consent before performance of any study-related procedure.

Exclusion Criteria:

• Previous treatment with Bortezomib

• Treatment within another clinical trial within 30 days before trial entry or planned during this trial

• Anti-neoplastic (including radiation and antibody treatment) or experimental therapy within 4 weeks before planed Day 1 of Cycle 1 (Nitrosoureas within 6 weeks ) or radioimmunoconjugates or toxin immunoconjugates such as Ibritumomab tiuxetan (Zevalin™) or Tositumomab (Bexxar®) within 12 weeks before planed Day 1 of Cycle 1

• Known hypersensitivity to Rituximab, boron or mannitol.

• Active malignancy other than MCL within 5 years before Day 1 of Cycle 1, with the exception of complete resection of basal cell carcinoma, squamous cell carcinoma of the skin, or in situ malignancy.

• Active systemic infection requiring treatment.

• HIV, hepatitis B or C

• Patient has >= grade 2 peripheral sensory neuropathy or neuropathic pain defined by the NCI Common Terminology Criteria for Adverse Events (CTCAE).

• Symptomatic degenerative or toxic encephalopathy

• Serious medical condition (such as severe hepatic impairment, pericardial disease, acute diffuse infiltrative pulmonary disease, systemic infections etc) or psychiatric illness likely to interfere with participation in this clinical study

• Female subject is pregnant or breast-feeding (pregnancy testing is mandatory for premenopausal women).

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, Mantle-Cell
• Mantle Cell Lymphoma

Intervention

Drug:
• Rituximab
Rituximab 375mg/m² IV , day 1
• High dose Ara-C
Ara-C 2000 mg/m² (patients >65 years or s/p myeloablative treatment: 1000 mg/m²) IV, d 2 and 3
• Dexamethasone
Dexamethasone 40 mg PO, day 1-4
• Bortezomib
Bortezomib 1.5 mg/m² IV, day 1 and 4

Locations

Country	Name	City	State
France	CH Victor Dupouy, Service hématologie	Argenteuil Cedex
France	Centre Hospitalier de la côte Basque, Service hématologie	Bayonne
France	CH de Blois, Service hématologie	Blois
France	Institut Bergonie, Service Hématologie	Bordeaux
France	CH Sud Francilien de Corbeil, Service hématologie	Corbeil Essonnes
France	Hôpital Henri Mondor, Service hématologie	Créteil
France	Hôpital Albert Michallon, Service hématologie	Grenoble
France	CH du Mans, Service hématologie	Le Mans
France	CH Mulhouse, Service hématologie	Le Mans
France	Clinique Victor Hugo, Service hématologie	Le Mans
France	CHU de Nice, Service hématologie	Nice
France	CHU Necker, Service d'hématologie - adulte	Paris
France	Hôpital Haut Lévêque, Service hématologie	Pessac
France	CHU Lyon Sud, Service hématologie	Pierre Benite
France	Hôpital Jean Bernard, Service hématologie	Poitiers
France	CH René Dubos, Service hématologie	Pontoise
France	CHU Robert Debré, Service hématologie	Reims
France	Hôpital Bretonneau, Service hématologie, Bâtiment H. Kaplan	Tours
France	CHU Brabois, Service hématologie	Vandoeuvre les Nancy
France	CH de Bretagne Atlantique, Service Hématologie	Vannes
France	Institut Gustave ROUSSY	Villejuif
Germany	Kreisklinik Altötting-Burghausen, Sektion Hämatologie/Onkologie und Palliativmedizin	Altötting
Germany	Klinikum St. Marien, Med. Klinik II	Amberg
Germany	Vivantes Klinikum Neukölln, Medizinische Klinik I - Hämatologie und Onkologie	Berlin
Germany	Knappschaftskrankenhaus, Onkologische Ambulanz	Bottrop
Germany	Praxis für Hämatologie/Onkologie,	Burgwedel
Germany	Marien Hospital Düsseldorf	Düsseldorf
Germany	Universitätsklinik Essen, Klinik für Hämatologie	Essen
Germany	Klinikum der J.W. Goethe-Universtität Frankfurt, Medizinische Klinik II, Hämatologie/Onkologie	Frankfurt am Main
Germany	Ernst-Moritz-Arndt-Universität, Hämatologie/Onkologie	Greifswald
Germany	Kath. Krankenhaus Hagen gem. GmbH St.-Marien-Hospital	Hagen
Germany	Asklepios Klinik St. Georg, Abteilung Hämatologie	Hamburg
Germany	St.-Marien-Hopsital Gem. GmbH	Hamm
Germany	Universitätsklinik des Saarlandes	Homburg/Saar
Germany	Westpfalz-Klinikum GmbH, I. Medizinische Klinik	Kaiserslautern
Germany	UKSH im Städt. Krankenhaus Kiel, II. Med. Klinik und Poliklinik im SSK	Kiel
Germany	Klinikum der Universität zu Köln, Klinik I f. Innere Medizin	Köln
Germany	Praxis Dr. Vehling-Kaiser	Landshut
Germany	Klinikum Magdeburg gemeinnützige GmbH, Klinik f. Hämatologie/Onkologie	Magdeburg
Germany	Klinikum d. Phillips-Universität, Klinik für Innere Medizin Hämatol./Onkologie/Immunologie	Marburg
Germany	Kliniken Maria Hilf GmbH (Krankenhaus St. Franziskus)	Mönchengladbach
Germany	LMU München - Klinikum Großhadern Medizinische Klinik III	München
Germany	Klinikum Schwäbisch Gmünd, Zentrum Innere Medizin	Mutlangen
Germany	Klinikum Nord Nürnberg, 5. Med. Klinik, Onkologie/Hämatologie	Nürnberg
Germany	Schlossberg Klinik, Oberstaufen Internistische Onkologie	Oberstaufen
Germany	Diakonie Klinikum Jung Stilling Krankenhaus	Siegen
Germany	Diakonieklinikum Stuttgart, Medizinische Klinik II	Stuttgart
Germany	Robert-Bosch-Krankenhaus, Hämatologie/Onkologie	Stuttgart
Germany	Krankenhaus der Barmherzigen Brüder, 1. Medizinische Abteilung	Trier
Germany	Mutterhaus der Borromäerinnen, Medizinische Abteilung	Trier
Germany	Universitätsklinikum Ulm, Innere Medizin III	Ulm
Germany	Harz-Klinikum Wernigerode-Blankenburg GmbH, Innere Medizin, Hämato-Onkologie und Palliativmedizin	Wernigerode
Germany	Ammerland-Klinik GmbH, Klinik für innere Medizin	Westerstede
Germany	Heinrich-Braun-Krankenhaus, Klinik für Innere Medizin III	Zwickau

Sponsors (4)

Lead Sponsor	Collaborator
Prof. Dr. M. Dreyling (co-chairman)	ClinAssess GmbH, GELARC Service de Pharmacovigilance, Pierre Benite, Klinikum der Universitaet Muenchen, Grosshadern

Countries where clinical trial is conducted

France,  Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change from Baseline of diseased nodes and nodal masses.	Average time frame is three weeks after the first two cycles of trial therapy and 4 to 6 weeks after the end of trial therapy.; Response is always evaluated in comparison to the status before start of trial therapy. The assessment will be done with CT of all known lymphoma manifestations. In case of isolated bone marrow involvement a bone marrow aspiration/ biopsy is mandatory. A minimum of 50 % decrease in SPD (sum of the products of the greatest diameters) of the six largest nodes or nodal masses are necessary, in order to be able to evaluate it as partly remission.	approx. 66 and 126 days after start of therapy