Trial Information

A Randomized Phase II Trial of Maintenance vs Consolidation Bortezomib Therapy Following Aggressive Chemo-Immunotherapy and Autologous Stem Cell Transplant for Previously Untreated Mantle Cell Lymphoma

OBJECTIVES:

Primary

- Determine the 18-month progression-free survival (PFS) of patients with previously
untreated mantle cell lymphoma treated with aggressive chemoimmunotherapy and
autologous stem cell transplantation followed by maintenance therapy versus
consolidation therapy with bortezomib.

Secondary

- Determine the toxicity profiles of maintenance therapy vs consolidation therapy with
bortezomib by evaluating the number of patients able to complete all maintenance or
consolidation therapy.

- Determine the complete response (CR) rate in patients treated with intensive
chemoimmunotherapy plus maintenance therapy vs consolidation therapy with bortezomib.

- Determine time to progression and overall survival (OS) in patients treated with these
regimens.

- Determine the importance of p53 mutation or deletion on patient outcome with respect to
CR rate, PFS, and OS.

- Determine the importance of Ki67, cyclin D1, phosphohistone 3, p27, p21, p16, and PARP
p85 expression in pre-treatment tumor biopsies with respect to CR rate, PFS, and OS.

- Determine the relationship between proliferation signature and clinical outcome using
quantitative real-time reverse-transcriptase polymerase chain reaction (RT-PCR).

- Evaluate the importance of quantitative cyclin D1 expression and expression of cyclin
D1 isoforms in predicting clinical outcome using quantitative real-time RT-PCR.

- To evaluate the prognostic significance of microRNAs in mantle cell lymphoma using
microRNA arrays.

- To explore the correlation of selected microRNA polymorphisms with gene target
expression with clinical outcomes such as response, PFS, and OS.

- Determine changes in gene expression profile from diagnosis to relapse samples to
identify genes differentially silenced or over-expressed with disease recurrence.

- Determine the importance of early PCR negativity (after chemoimmunotherapy) using
bcl-1/IgH junction and/or IgH-chain gene rearrangement with respect to maintained PFS
and the success of maintenance or consolidation therapy to converting patients to
PCR-negative status.

OUTLINE: This is a multicenter, open-label, randomized study.

- Chemoimmunotherapy: Patients receive chemoimmunotherapy comprising rituximab* IV over
4-6 hours on day 1, methotrexate (MTX) IV over 4 hours on day 2, cyclophosphamide IV
over 2 hours, doxorubicin hydrochloride IV, and vincristine IV on day 3, and oral
prednisone on days 3-7. Beginning 24 hours after completion of MTX, patients receive
leucovorin calcium IV every 6 hours until blood levels of MTX are in a safe range.
Patients also receive filgrastim (G-CSF) subcutaneously (SC) once daily beginning on
day 3 and continuing until blood counts recover.

Beginning no sooner than day 22, but no later that day 29 of the first course, patients
receive a second course of chemoimmunotherapy as above. Patients with > 15% persistent bone
marrow involvement may receive a third course of chemoimmunotherapy. Patients are restaged
and those with progressive disease are removed from therapy.

NOTE: *During the first course of chemoimmunotherapy, patients receive rituximab only if the
number of circulating mantle cells is < 10, 000/mm3, otherwise, rituximab is omitted during
the first course of chemoimmunotherapy.

- High-dose consolidation chemoimmunotherapy and peripheral blood stem cell (PBSC)
collection: Approximately 4 weeks after completion of chemoimmunotherapy, patients
receive high-dose consolidation chemoimmunotherapy comprising cytarabine IV over 2
hours and etoposide phosphate IV continuously on days 1-4, and rituximab IV over 4-6
hours on days 5 and 12 OR 6 and 13. Beginning on day 14 and continuing until completion
of PBSC collection, patients receive G-CSF SC once daily. Once blood counts recover,
patients undergo 1-3 leukapheresis procedures for collection of PBSCs on days 22-25.

- High-dose chemotherapy and autologous PBSC transplantation (PBSCT): Beginning 4-6 weeks
after completion of leukapheresis, patients receive carmustine IV over 2 hours on day
-6, etoposide phosphate IV over 4 hours on day -4, and cyclophosphamide IV over 2 hours
on day -2. Patients undergo autologous PBSCT on day 0. Patients also receive G-CSF SC
once daily beginning on day 4 and continuing until blood counts recover.

- Post-transplantation immunotherapy: Approximately 5 weeks after autologous PBSCT,
patients receive rituximab IV over 4-6 hours once weekly for 2 weeks. Approximately 4
weeks after completion of post-transplantation immunotherapy, patients proceed to
maintenance therapy or consolidation therapy with bortezomib.

- Maintenance therapy or consolidation therapy with bortezomib: Patients are randomized
to 1 of 2 treatment arms.

- Arm I (maintenance therapy with bortezomib): Patients receive bortezomib IV on
days 1, 8, 15, and 22. Treatment repeats every 56 days for up to 10 courses in the
absence of disease progression or unacceptable toxicity.

- Arm II (consolidation therapy with bortezomib): Patients receive bortezomib IV on
days 1, 4, 8, and 11. Treatment repeats every 21 days for up to 4 courses in the
absence of disease progression or unacceptable toxicity.

Patients undergo peripheral blood collection and bone marrow aspirates and biopsies
periodically during study participation for biomarker correlative studies and laboratory
analysis.

After completion of study treatment, patients are followed every 3 months for 2 years, every
6 months for 3 years, and then annually for 5 years.

PROJECTED ACCRUAL: A total of 150 patients will be accrued for this study.