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

Primary Purpose

Mantle Cell Lymphoma

Status
Unknown status
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Rituximab
High dose Ara-C
Dexamethasone
Bortezomib
Sponsored by
Prof. Dr. M. Dreyling (co-chairman)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Mantle Cell Lymphoma focused on measuring relapsed, refractory

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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).

Sites / Locations

  • CH Victor Dupouy, Service hématologie
  • Centre Hospitalier de la côte Basque, Service hématologie
  • CH de Blois, Service hématologie
  • Institut Bergonie, Service Hématologie
  • CH Sud Francilien de Corbeil, Service hématologie
  • Hôpital Henri Mondor, Service hématologie
  • Hôpital Albert Michallon, Service hématologie
  • CH Mulhouse, Service hématologie
  • Clinique Victor Hugo, Service hématologie
  • CH du Mans, Service hématologie
  • CHU de Nice, Service hématologie
  • CHU Necker, Service d'hématologie - adulte
  • Hôpital Haut Lévêque, Service hématologie
  • CHU Lyon Sud, Service hématologie
  • Hôpital Jean Bernard, Service hématologie
  • CH René Dubos, Service hématologie
  • CHU Robert Debré, Service hématologie
  • Hôpital Bretonneau, Service hématologie, Bâtiment H. Kaplan
  • CHU Brabois, Service hématologie
  • CH de Bretagne Atlantique, Service Hématologie
  • Institut Gustave ROUSSY
  • Kreisklinik Altötting-Burghausen, Sektion Hämatologie/Onkologie und Palliativmedizin
  • Klinikum St. Marien, Med. Klinik II
  • Vivantes Klinikum Neukölln, Medizinische Klinik I - Hämatologie und Onkologie
  • Knappschaftskrankenhaus, Onkologische Ambulanz
  • Praxis für Hämatologie/Onkologie,
  • Marien Hospital Düsseldorf
  • Universitätsklinik Essen, Klinik für Hämatologie
  • Klinikum der J.W. Goethe-Universtität Frankfurt, Medizinische Klinik II, Hämatologie/Onkologie
  • Ernst-Moritz-Arndt-Universität, Hämatologie/Onkologie
  • Kath. Krankenhaus Hagen gem. GmbH St.-Marien-Hospital
  • Asklepios Klinik St. Georg, Abteilung Hämatologie
  • St.-Marien-Hopsital Gem. GmbH
  • Universitätsklinik des Saarlandes
  • Westpfalz-Klinikum GmbH, I. Medizinische Klinik
  • UKSH im Städt. Krankenhaus Kiel, II. Med. Klinik und Poliklinik im SSK
  • Klinikum der Universität zu Köln, Klinik I f. Innere Medizin
  • Praxis Dr. Vehling-Kaiser
  • Klinikum Magdeburg gemeinnützige GmbH, Klinik f. Hämatologie/Onkologie
  • Klinikum d. Phillips-Universität, Klinik für Innere Medizin Hämatol./Onkologie/Immunologie
  • Klinikum Schwäbisch Gmünd, Zentrum Innere Medizin
  • Kliniken Maria Hilf GmbH (Krankenhaus St. Franziskus)
  • LMU München - Klinikum Großhadern Medizinische Klinik III
  • Klinikum Nord Nürnberg, 5. Med. Klinik, Onkologie/Hämatologie
  • Schlossberg Klinik, Oberstaufen Internistische Onkologie
  • Diakonie Klinikum Jung Stilling Krankenhaus
  • Diakonieklinikum Stuttgart, Medizinische Klinik II
  • Robert-Bosch-Krankenhaus, Hämatologie/Onkologie
  • Mutterhaus der Borromäerinnen, Medizinische Abteilung
  • Krankenhaus der Barmherzigen Brüder, 1. Medizinische Abteilung
  • Universitätsklinikum Ulm, Innere Medizin III
  • Harz-Klinikum Wernigerode-Blankenburg GmbH, Innere Medizin, Hämato-Onkologie und Palliativmedizin
  • Ammerland-Klinik GmbH, Klinik für innere Medizin
  • Heinrich-Braun-Krankenhaus, Klinik für Innere Medizin III

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

R-HAD + Bortezomib

R-HAD

Arm Description

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Full Information

First Posted
September 28, 2011
Last Updated
March 6, 2017
Sponsor
Prof. Dr. M. Dreyling (co-chairman)
Collaborators
Klinikum der Universitaet Muenchen, Grosshadern, ClinAssess GmbH, GELARC Service de Pharmacovigilance, Pierre Benite
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1. Study Identification

Unique Protocol Identification Number
NCT01449344
Brief Title
Efficacy and Safety of R-HAD Alone or in Combination With Bortezomib in Patients With Relapsed or Refractory MCL
Acronym
(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
Study Type
Interventional

2. Study Status

Record Verification Date
March 2017
Overall Recruitment Status
Unknown status
Study Start Date
May 9, 2009 (Actual)
Primary Completion Date
December 2018 (Anticipated)
Study Completion Date
December 2018 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Prof. Dr. M. Dreyling (co-chairman)
Collaborators
Klinikum der Universitaet Muenchen, Grosshadern, ClinAssess GmbH, GELARC Service de Pharmacovigilance, Pierre Benite

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Mantle Cell Lymphoma
Keywords
relapsed, refractory

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
128 (Actual)

8. Arms, Groups, and Interventions

Arm Title
R-HAD + Bortezomib
Arm Type
Experimental
Arm Title
R-HAD
Arm Type
Active Comparator
Intervention Type
Drug
Intervention Name(s)
Rituximab
Other Intervention Name(s)
Rituximab:Rituxan
Intervention Description
Rituximab 375mg/m² IV , day 1
Intervention Type
Drug
Intervention Name(s)
High dose Ara-C
Other Intervention Name(s)
Ara-C: Cytarabine
Intervention Description
Ara-C 2000 mg/m² (patients >65 years or s/p myeloablative treatment: 1000 mg/m²) IV, d 2 and 3
Intervention Type
Drug
Intervention Name(s)
Dexamethasone
Other Intervention Name(s)
Dexamethasone: none
Intervention Description
Dexamethasone 40 mg PO, day 1-4
Intervention Type
Drug
Intervention Name(s)
Bortezomib
Other Intervention Name(s)
Bortezomib: Velcade
Intervention Description
Bortezomib 1.5 mg/m² IV, day 1 and 4
Primary Outcome Measure Information:
Title
Change from Baseline of diseased nodes and nodal masses.
Description
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.
Time Frame
approx. 66 and 126 days after start of therapy

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Martin Dreyling, MD
Organizational Affiliation
Klinikum der Universität München, Grosshadern
Official's Role
Principal Investigator
Facility Information:
Facility Name
CH Victor Dupouy, Service hématologie
City
Argenteuil Cedex
ZIP/Postal Code
95107
Country
France
Facility Name
Centre Hospitalier de la côte Basque, Service hématologie
City
Bayonne
ZIP/Postal Code
64109
Country
France
Facility Name
CH de Blois, Service hématologie
City
Blois
ZIP/Postal Code
41016
Country
France
Facility Name
Institut Bergonie, Service Hématologie
City
Bordeaux
ZIP/Postal Code
33076
Country
France
Facility Name
CH Sud Francilien de Corbeil, Service hématologie
City
Corbeil Essonnes
ZIP/Postal Code
91106
Country
France
Facility Name
Hôpital Henri Mondor, Service hématologie
City
Créteil
ZIP/Postal Code
94010
Country
France
Facility Name
Hôpital Albert Michallon, Service hématologie
City
Grenoble
ZIP/Postal Code
38043
Country
France
Facility Name
CH Mulhouse, Service hématologie
City
Le Mans
ZIP/Postal Code
68070
Country
France
Facility Name
Clinique Victor Hugo, Service hématologie
City
Le Mans
ZIP/Postal Code
72015
Country
France
Facility Name
CH du Mans, Service hématologie
City
Le Mans
ZIP/Postal Code
72037
Country
France
Facility Name
CHU de Nice, Service hématologie
City
Nice
ZIP/Postal Code
06202
Country
France
Facility Name
CHU Necker, Service d'hématologie - adulte
City
Paris
ZIP/Postal Code
75015
Country
France
Facility Name
Hôpital Haut Lévêque, Service hématologie
City
Pessac
ZIP/Postal Code
33604
Country
France
Facility Name
CHU Lyon Sud, Service hématologie
City
Pierre Benite
ZIP/Postal Code
69495
Country
France
Facility Name
Hôpital Jean Bernard, Service hématologie
City
Poitiers
ZIP/Postal Code
86021
Country
France
Facility Name
CH René Dubos, Service hématologie
City
Pontoise
ZIP/Postal Code
95301
Country
France
Facility Name
CHU Robert Debré, Service hématologie
City
Reims
ZIP/Postal Code
51092
Country
France
Facility Name
Hôpital Bretonneau, Service hématologie, Bâtiment H. Kaplan
City
Tours
ZIP/Postal Code
37044
Country
France
Facility Name
CHU Brabois, Service hématologie
City
Vandoeuvre les Nancy
ZIP/Postal Code
54511
Country
France
Facility Name
CH de Bretagne Atlantique, Service Hématologie
City
Vannes
ZIP/Postal Code
56017
Country
France
Facility Name
Institut Gustave ROUSSY
City
Villejuif
ZIP/Postal Code
94805
Country
France
Facility Name
Kreisklinik Altötting-Burghausen, Sektion Hämatologie/Onkologie und Palliativmedizin
City
Altötting
ZIP/Postal Code
84503
Country
Germany
Facility Name
Klinikum St. Marien, Med. Klinik II
City
Amberg
ZIP/Postal Code
92224
Country
Germany
Facility Name
Vivantes Klinikum Neukölln, Medizinische Klinik I - Hämatologie und Onkologie
City
Berlin
ZIP/Postal Code
12351
Country
Germany
Facility Name
Knappschaftskrankenhaus, Onkologische Ambulanz
City
Bottrop
ZIP/Postal Code
46242
Country
Germany
Facility Name
Praxis für Hämatologie/Onkologie,
City
Burgwedel
ZIP/Postal Code
30938
Country
Germany
Facility Name
Marien Hospital Düsseldorf
City
Düsseldorf
ZIP/Postal Code
40479
Country
Germany
Facility Name
Universitätsklinik Essen, Klinik für Hämatologie
City
Essen
ZIP/Postal Code
45147
Country
Germany
Facility Name
Klinikum der J.W. Goethe-Universtität Frankfurt, Medizinische Klinik II, Hämatologie/Onkologie
City
Frankfurt am Main
ZIP/Postal Code
60590
Country
Germany
Facility Name
Ernst-Moritz-Arndt-Universität, Hämatologie/Onkologie
City
Greifswald
ZIP/Postal Code
17475
Country
Germany
Facility Name
Kath. Krankenhaus Hagen gem. GmbH St.-Marien-Hospital
City
Hagen
ZIP/Postal Code
58095
Country
Germany
Facility Name
Asklepios Klinik St. Georg, Abteilung Hämatologie
City
Hamburg
ZIP/Postal Code
20099
Country
Germany
Facility Name
St.-Marien-Hopsital Gem. GmbH
City
Hamm
ZIP/Postal Code
59071
Country
Germany
Facility Name
Universitätsklinik des Saarlandes
City
Homburg/Saar
ZIP/Postal Code
66421
Country
Germany
Facility Name
Westpfalz-Klinikum GmbH, I. Medizinische Klinik
City
Kaiserslautern
ZIP/Postal Code
67653
Country
Germany
Facility Name
UKSH im Städt. Krankenhaus Kiel, II. Med. Klinik und Poliklinik im SSK
City
Kiel
ZIP/Postal Code
24116
Country
Germany
Facility Name
Klinikum der Universität zu Köln, Klinik I f. Innere Medizin
City
Köln
ZIP/Postal Code
50924
Country
Germany
Facility Name
Praxis Dr. Vehling-Kaiser
City
Landshut
ZIP/Postal Code
84028
Country
Germany
Facility Name
Klinikum Magdeburg gemeinnützige GmbH, Klinik f. Hämatologie/Onkologie
City
Magdeburg
ZIP/Postal Code
39130
Country
Germany
Facility Name
Klinikum d. Phillips-Universität, Klinik für Innere Medizin Hämatol./Onkologie/Immunologie
City
Marburg
ZIP/Postal Code
35033
Country
Germany
Facility Name
Klinikum Schwäbisch Gmünd, Zentrum Innere Medizin
City
Mutlangen
ZIP/Postal Code
73557
Country
Germany
Facility Name
Kliniken Maria Hilf GmbH (Krankenhaus St. Franziskus)
City
Mönchengladbach
ZIP/Postal Code
41063
Country
Germany
Facility Name
LMU München - Klinikum Großhadern Medizinische Klinik III
City
München
ZIP/Postal Code
81377
Country
Germany
Facility Name
Klinikum Nord Nürnberg, 5. Med. Klinik, Onkologie/Hämatologie
City
Nürnberg
ZIP/Postal Code
90419
Country
Germany
Facility Name
Schlossberg Klinik, Oberstaufen Internistische Onkologie
City
Oberstaufen
ZIP/Postal Code
87534
Country
Germany
Facility Name
Diakonie Klinikum Jung Stilling Krankenhaus
City
Siegen
ZIP/Postal Code
57074
Country
Germany
Facility Name
Diakonieklinikum Stuttgart, Medizinische Klinik II
City
Stuttgart
ZIP/Postal Code
70176
Country
Germany
Facility Name
Robert-Bosch-Krankenhaus, Hämatologie/Onkologie
City
Stuttgart
ZIP/Postal Code
70376
Country
Germany
Facility Name
Mutterhaus der Borromäerinnen, Medizinische Abteilung
City
Trier
ZIP/Postal Code
54219
Country
Germany
Facility Name
Krankenhaus der Barmherzigen Brüder, 1. Medizinische Abteilung
City
Trier
ZIP/Postal Code
54292
Country
Germany
Facility Name
Universitätsklinikum Ulm, Innere Medizin III
City
Ulm
ZIP/Postal Code
89081
Country
Germany
Facility Name
Harz-Klinikum Wernigerode-Blankenburg GmbH, Innere Medizin, Hämato-Onkologie und Palliativmedizin
City
Wernigerode
ZIP/Postal Code
38855
Country
Germany
Facility Name
Ammerland-Klinik GmbH, Klinik für innere Medizin
City
Westerstede
ZIP/Postal Code
26655
Country
Germany
Facility Name
Heinrich-Braun-Krankenhaus, Klinik für Innere Medizin III
City
Zwickau
ZIP/Postal Code
08060
Country
Germany

12. IPD Sharing Statement

Learn more about this trial

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

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