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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

Phase 3
18 Years
Open (Enrolling)
Mantle Cell Lymphoma

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Trial Information

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.

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

- 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).

Type of Study:


Study Design:

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Change from Baseline of diseased nodes and nodal masses.

Outcome 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.

Outcome Time Frame:

approx. 66 and 126 days after start of therapy

Safety Issue:


Principal Investigator

Martin Dreyling, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Klinikum der Universität München, Grosshadern


Germany: Federal Institute for Drugs and Medical Devices

Study ID:




Start Date:

November 2011

Completion Date:

September 2016

Related Keywords:

  • Mantle Cell Lymphoma
  • relapsed
  • refractory
  • Lymphoma
  • Lymphoma, Mantle-Cell