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

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.

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.

• Drug: Rituximab
  Rituximab 375mg/m² IV , day 1
  Other Name: Rituximab:Rituxan
• Drug: 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
  Other Name: Ara-C: Cytarabine
• Drug: Dexamethasone
  Dexamethasone 40 mg PO, day 1-4
  Other Name: Dexamethasone: none
• Drug: Bortezomib
  Bortezomib 1.5 mg/m² IV, day 1 and 4
  Other Name: Bortezomib: Velcade

• Experimental: R-HAD + Bortezomib
  Interventions:

  • Drug: Rituximab
  • Drug: High dose Ara-C
  • Drug: Dexamethasone
  • Drug: Bortezomib
• Active Comparator: R-HAD
  Interventions:

  • Drug: Rituximab
  • Drug: High dose Ara-C
  • Drug: Dexamethasone

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).

• Klinikum der Universitaet Muenchen, Grosshadern
• ClinAssess GmbH
• GELARC Service de Pharmacovigilance, Pierre Benite