Clinical trial NCT01449344: Efficacy and Safety of R-HAD Alone or in Combination With Bortezomib in Patients With Relapsed or Refractory MCL
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Mantle Cell Lymphoma
Keywords: relapsed
refractory
Lead sponsor: European Mantle Cell Lymphoma Network
Sponsor class: OTHER
Collaborators: name: Klinikum der Universitaet Muenchen, Grosshadern
name: ClinAssess GmbH
name: GELARC Service de Pharmacovigilance, Pierre Benite
First posted: 2011-10-10
Enrollment: 128
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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).

Primary outcomes:
measure: Change from Baseline of diseased nodes and nodal masses.
timeFrame: approx. 66 and 126 days after start of therapy
Secondary outcomes:
Other outcomes:
Locations:
city: Argenteuil Cedex
country: France
facility: CH Victor Dupouy, Service hématologie
city: Bayonne
country: France
facility: Centre Hospitalier de la côte Basque, Service hématologie
city: Blois
country: France
facility: CH de Blois, Service hématologie
city: Bordeaux
country: France
facility: Institut Bergonie, Service Hématologie
city: Corbeil Essonnes
country: France
facility: CH Sud Francilien de Corbeil, Service hématologie
city: Créteil
country: France
facility: Hôpital Henri Mondor, Service hématologie
city: Grenoble
country: France
facility: Hôpital Albert Michallon, Service hématologie
city: Le Mans
country: France
facility: CH Mulhouse, Service hématologie
city: Le Mans
country: France
facility: Clinique Victor Hugo, Service hématologie
city: Le Mans
country: France
facility: CH du Mans, Service hématologie
city: Nice
country: France
facility: CHU de Nice, Service hématologie
city: Paris
country: France
facility: CHU Necker, Service d'hématologie - adulte
city: Pessac
country: France
facility: Hôpital Haut Lévêque, Service hématologie
city: Pierre Benite
country: France
facility: CHU Lyon Sud, Service hématologie
city: Poitiers
country: France
facility: Hôpital Jean Bernard, Service hématologie
city: Pontoise
country: France
facility: CH René Dubos, Service hématologie
city: Reims
country: France
facility: CHU Robert Debré, Service hématologie
city: Tours
country: France
facility: Hôpital Bretonneau, Service hématologie, Bâtiment H. Kaplan
city: Vandoeuvre les Nancy
country: France
facility: CHU Brabois, Service hématologie
city: Vannes
country: France
facility: CH de Bretagne Atlantique, Service Hématologie
city: Villejuif
country: France
facility: Institut Gustave ROUSSY
city: Altötting
country: Germany
facility: Kreisklinik Altötting-Burghausen, Sektion Hämatologie/Onkologie und Palliativmedizin
city: Amberg
country: Germany
facility: Klinikum St. Marien, Med. Klinik II
city: Berlin
country: Germany
facility: Vivantes Klinikum Neukölln, Medizinische Klinik I - Hämatologie und Onkologie
city: Bottrop
country: Germany
facility: Knappschaftskrankenhaus, Onkologische Ambulanz
city: Burgwedel
country: Germany
facility: Praxis für Hämatologie/Onkologie,
city: Düsseldorf
country: Germany
facility: Marien Hospital Düsseldorf
city: Essen
country: Germany
facility: Universitätsklinik Essen, Klinik für Hämatologie
city: Frankfurt am Main
country: Germany
facility: Klinikum der J.W. Goethe-Universtität Frankfurt, Medizinische Klinik II, Hämatologie/Onkologie
city: Greifswald
country: Germany
facility: Ernst-Moritz-Arndt-Universität, Hämatologie/Onkologie
city: Hagen
country: Germany
facility: Kath. Krankenhaus Hagen gem. GmbH St.-Marien-Hospital
city: Hamburg
country: Germany
facility: Asklepios Klinik St. Georg, Abteilung Hämatologie
city: Hamm
country: Germany
facility: St.-Marien-Hopsital Gem. GmbH
city: Homburg/Saar
country: Germany
facility: Universitätsklinik des Saarlandes
city: Kaiserslautern
country: Germany
facility: Westpfalz-Klinikum GmbH, I. Medizinische Klinik
city: Kiel
country: Germany
facility: UKSH im Städt. Krankenhaus Kiel, II. Med. Klinik und Poliklinik im SSK
city: Köln
country: Germany
facility: Klinikum der Universität zu Köln, Klinik I f. Innere Medizin
city: Landshut
country: Germany
facility: Praxis Dr. Vehling-Kaiser
city: Magdeburg
country: Germany
facility: Klinikum Magdeburg gemeinnützige GmbH, Klinik f. Hämatologie/Onkologie
city: Marburg
country: Germany
facility: Klinikum d. Phillips-Universität, Klinik für Innere Medizin Hämatol./Onkologie/Immunologie
city: Mutlangen
country: Germany
facility: Klinikum Schwäbisch Gmünd, Zentrum Innere Medizin
city: Mönchengladbach
country: Germany
facility: Kliniken Maria Hilf GmbH (Krankenhaus St. Franziskus)
city: München
country: Germany
facility: LMU München - Klinikum Großhadern Medizinische Klinik III
city: Nürnberg
country: Germany
facility: Klinikum Nord Nürnberg, 5. Med. Klinik, Onkologie/Hämatologie
city: Oberstaufen
country: Germany
facility: Schlossberg Klinik, Oberstaufen Internistische Onkologie
city: Siegen
country: Germany
facility: Diakonie Klinikum Jung Stilling Krankenhaus
city: Stuttgart
country: Germany
facility: Diakonieklinikum Stuttgart, Medizinische Klinik II
city: Stuttgart
country: Germany
facility: Robert-Bosch-Krankenhaus, Hämatologie/Onkologie
city: Trier
country: Germany
facility: Mutterhaus der Borromäerinnen, Medizinische Abteilung
city: Trier
country: Germany
facility: Krankenhaus der Barmherzigen Brüder, 1. Medizinische Abteilung
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm, Innere Medizin III
city: Wernigerode
country: Germany
facility: Harz-Klinikum Wernigerode-Blankenburg GmbH, Innere Medizin, Hämato-Onkologie und Palliativmedizin
city: Westerstede
country: Germany
facility: Ammerland-Klinik GmbH, Klinik für innere Medizin
city: Zwickau
country: Germany
facility: Heinrich-Braun-Krankenhaus, Klinik für Innere Medizin III
Study officials:
affiliation: Klinikum der Universität München, Grosshadern
name: Martin Dreyling, MD
role: PRINCIPAL_INVESTIGATOR
References: