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A Phase I/II Study of the Novel Proteasome Inhibitor Bortezomib in Combination With Rituxamib, Cyclophosphamide and Prednisone in Patients With Relapsed/Refractory Indolent B-Cell Lymphoproliferative Disorders and Mantle Cell Lymphoma (MCL)

Phase 1/Phase 2
18 Years
Not Enrolling
Follicular Lymphoma (Grade I, II, III), Small Lymphocytic Lymphoma, Chronic Lymphocytic Leukemia, Marginal Zone Lymphoma, Waldenstrom's Macroglobulinemia, Mantle Cell Lymphoma

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Trial Information

A Phase I/II Study of the Novel Proteasome Inhibitor Bortezomib in Combination With Rituxamib, Cyclophosphamide and Prednisone in Patients With Relapsed/Refractory Indolent B-Cell Lymphoproliferative Disorders and Mantle Cell Lymphoma (MCL)

This is a Phase I/II study to evaluate the safety and efficacy of bortezomib for patients
with indolent and mantle cell lymphomas. The primary objective in Phase I is to determine
the maximum tolerated dose (MTD) of bortezomib when given in combination with rituximab,
cyclophosphamide, and prednisone (RCP). The primary objective in Phase II is to determine
the frequency and duration of complete and partial responses in patients treated with
bortezomib + RCP (RCB or P) administered every 21 days for a total of 68 cycles.

Inclusion Criteria:

- Patients must have histologically confirmed (using the WHO Classification): chronic
lymphocytic leukemia/B cell small lymphocytic lymphoma, any marginal zone lymphoma,
follicular lymphoma, grade I, II, III, Waldenstrom's macroglobulinemia (all in cohort
1 of the phase II portion of the study), or mantle cell lymphoma (cohort 2 of the
phase II portion of the study). Patients with transformed indolent lymphomas will be
enrolled on the phase I portion, but not the phase II portion of the study.

- For the phase I portion of this study, all patients must have assessable disease. For
the phase II portion all NHL patients (except SLL/CLL and Waldenstrom's
macroglobulinemia, discussed below) must have measurable disease defined as at least
one lesion that can be accurately measured in at least one dimension (longest
diameter to be recorded as >2 cm with conventional techniques or as >1 cm with spiral
CT scan). Lymph nodes measuring < 1 cm in the short axis are considered normal. For
chronic lymphocytic leukemia, patients must have an absolute lymphocytosis > 5 x
109/L with a B cell phenotype (CD19 or CD20 co expression with CD5, CD 23 +/), with >
30% bone marrow lymphocytes. Staging will be made according to the modified Rai as

- Patients must have received at least one but no more than three prior regimens of
conventional cytotoxic therapy, and must be off all cytotoxic chemotherapy for at
least four weeks prior to study enrollment (6 weeks for BCNU or mitomycin C, 12 weeks
with recovery to baseline counts for radioimmunotherapy). Patients are allowed to
have received one course of prior radioimmunotherapy (RIT: either tositumomab or
ibritumomab). Prior recipients of stem cell transplantation will be included, with
the preparative cytoreductive and high dose therapies counted collectively as one
prior therapy.

- Patients must not have received any therapeutic monoclonal antibodies (e.g.
rituximab, tositumomab, ibritumomab alemtuzumab, etc.) within 3 months of enrollment
(except for patients enrolled on the phase I portion, who may have received rituximab
up to 7 days prior to enrollment). Patients who have been treated with monoclonal
antibodies within 3 months may be enrolled if they show progression of disease on
this therapy, as long as they have not received the treatment within 7 days of

- Age greater than or equal to 18 years. Because no dosing or adverse event data are
currently available on the use of bortezomib in patients <18 years of age, children
are excluded from this study but will be eligible for future pediatric single agent
trials, if applicable.

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C, 12 weeks or lack of recovery to baseline counts for RIT)
prior to entering the study or those who have not recovered from adverse events due
to agents administered more than 4 weeks earlier. Patients who have received a
therapeutic monoclonal antibody within 3 months (except those with objective evidence
of PD).

- Patients may not be receiving any other investigational agents.

- Patients with known brain metastases or meningeal disease will be excluded from this
clinical trial because of their poor prognosis and because they often develop
progressive neurologic dysfunction that would confound the evaluation of neurologic
and other adverse events.

- Patients who have had any major surgery within four weeks of study entry.

- Patients with uncontrolled intercurrent illness including, but not limited to,
ongoing or active infection, symptomatic congestive heart failure, cerebrovascular
accident (CVA) or transient ischemic attack within 6 months of study enrollment,
unstable angina pectoris, cardiac arrhythmia, EKG evidence of acute ischemia, or
psychiatric illness/social situations that would limit compliance with study

- Pregnant women are excluded from this study because bortezomib is a novel agent that
may have the potential for teratogenic or abortifacient effects. Because there is an
unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with bortezomib, breastfeeding should be discontinued if the
mother is treated with this agent.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Phase I: Maximum Tolerated Dose

Outcome Time Frame:

3 months

Safety Issue:


Principal Investigator

Owen A O'Connor, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Columbia University


United States: Institutional Review Board

Study ID:




Start Date:

September 2007

Completion Date:

December 2013

Related Keywords:

  • Follicular Lymphoma (Grade I, II, III)
  • Small Lymphocytic Lymphoma
  • Chronic Lymphocytic Leukemia
  • Marginal Zone Lymphoma
  • Waldenstrom's Macroglobulinemia
  • Mantle Cell Lymphoma
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Lymphoma
  • Lymphoma, Follicular
  • Lymphoproliferative Disorders
  • Waldenstrom Macroglobulinemia
  • Lymphoma, B-Cell, Marginal Zone
  • Lymphoma, Mantle-Cell



Columbia University Medical Center New York, New York  10032