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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


Phase 2
18 Years
70 Years
Open (Enrolling)
Both
Lymphoma

Thank you

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.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Histologically confirmed mantle cell lymphoma, meeting the following criteria:

- Stage I-IV disease

- Patients with nodular histology must have stage III or IV disease

- Co-expression of CD20 (or CD19) and CD5 AND lack of CD23 expression by
immunophenotyping

- At least 1 of the following confirmatory tests:

- Positive immunostaining for cyclin D1

- Presence of t(11;14) on cytogenetic analysis

- Molecular evidence of bcl-1/IgH rearrangement

- Previously untreated disease OR ≤ 1 prior course of chemotherapy and/or rituximab

- No mantle zone histology

- No Waldenstrom's macroglobulinemia

- No active CNS disease defined as symptomatic meningeal lymphoma

- No known CNS parenchymal lymphoma

PATIENT CHARACTERISTICS:

- LVEF ≥ 45% by MUGA or echocardiogram

- Creatinine ≤ 2.0 mg/dL

- Patients testing positive for hepatitis B surface antigen or hepatitis C antibody are
eligible provided all of the following criteria are met:

- Bilirubin ≤ 2 times upper limit of normal (ULN)

- AST ≤ 3 times ULN

- Fibrosis ≤ grade 2 fibrosis AND no cirrhosis by liver biopsy

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No known hypersensitivity to murine products

- No medical condition requiring chronic use of oral corticosteroids

- No known HIV positivity

- No currently active second malignancy other than nonmelanoma skin cancer

- Patients are not considered to have a currently active malignancy if they have
completed anticancer therapy and are considered to have < 30% risk of relapse

PRIOR CONCURRENT THERAPY:

- At least 2 weeks since prior major surgery

- At least 3 weeks since prior chemotherapy

- No prior radiotherapy for mantle cell lymphoma

- No other concurrent hormonal therapy or chemotherapy except for the following:

- Corticosteroids for adrenal failure, diffuse alveolar hemorrhage, or carmustine
pneumonitis

- Dexamethasone as an antiemetic or premedication for rituximab

- Hormones for nonlymphoma-related conditions (e.g., insulin for diabetes)

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression-free survival at 18 months

Safety Issue:

No

Principal Investigator

Lawrence D. Kaplan, MD

Investigator Role:

Study Chair

Investigator Affiliation:

University of California, San Francisco

Authority:

United States: Federal Government

Study ID:

CDR0000466167

NCT ID:

NCT00310037

Start Date:

June 2006

Completion Date:

Related Keywords:

  • Lymphoma
  • contiguous stage II mantle cell lymphoma
  • noncontiguous stage II mantle cell lymphoma
  • stage I mantle cell lymphoma
  • stage III mantle cell lymphoma
  • stage IV mantle cell lymphoma
  • recurrent mantle cell lymphoma
  • Lymphoma
  • Lymphoma, Mantle-Cell

Name

Location

Roswell Park Cancer InstituteBuffalo, New York  14263
University of Chicago Cancer Research CenterChicago, Illinois  60637
CCOP - North Shore University HospitalManhasset, New York  11030
CCOP - Illinois Oncology Research AssociationPeoria, Illinois  61602
Methodist Medical Center of IllinoisPeoria, Illinois  61636
Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical CenterLebanon, New Hampshire  03756-0002
Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel HillChapel Hill, North Carolina  27599-7570
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer InstituteBoston, Massachusetts  02115
Long Island Jewish Medical CenterNew Hyde Park, New York  11040
SUNY Upstate Medical University HospitalSyracuse, New York  13210
Wake Forest University Comprehensive Cancer CenterWinston-Salem, North Carolina  27157-1096
UCSF Helen Diller Family Comprehensive Cancer CenterSan Francisco, California  94115
Siteman Cancer Center at Barnes-Jewish Hospital - Saint LouisSt. Louis, Missouri  63110
Don Monti Comprehensive Cancer Center at North Shore University HospitalManhasset, New York  11030
St. Joseph Medical CenterBloomington, Illinois  61701
Graham HospitalCanton, Illinois  61520
Memorial HospitalCarthage, Illinois  62321
Eureka Community HospitalEureka, Illinois  61530
Mason District HospitalHavana, Illinois  62644
McDonough District HospitalMacomb, Illinois  61455
BroMenn Regional Medical CenterNormal, Illinois  61761
Community Cancer CenterNormal, Illinois  61761
Community Hospital of OttawaOttawa, Illinois  61350
Oncology Hematology Associates of Central Illinois, PC - OttawaOttawa, Illinois  61350
Oncology Hematology Associates of Central Illinois, PC - PeoriaPeoria, Illinois  61615
OSF St. Francis Medical CenterPeoria, Illinois  61637
Proctor HospitalPeoria, Illinois  61614
Illinois Valley Community HospitalPeru, Illinois  61354
Perry Memorial HospitalPrinceton, Illinois  61356
Monter Cancer Center of the North Shore-LIJ Health SystemLake Success, New York  11042
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer CenterColumbus, Ohio  43210-1240
Dana-Farber/Brigham and Women's Cancer CenterBoston, Massachusetts  02115
Galesburg Clinic, PCGalesburg, Illinois  61401
Illinois CancerCare - BloomingtonBloomington%, Illinois  61701
Illinois CancerCare - CantonCanton, Illinois  61520
Illinois CancerCare - CarthageCarthage, Illinois  62321
Illinois CancerCare - EurekaEureka, Illinois  61530
Illinois CancerCare - GalesburgGalesburg, Illinois  61401
Illinois CancerCare - HavanaHavana, Illinois  62644
Illinois CancerCare - Kewanee ClinicKewanee, Illinois  61443
Illinois CancerCare - MacombMacomb, Illinois  61455
OSF Holy Family Medical CenterMonmouth, Illinois  61462
Illinois CancerCare - MonmouthMonmouth, Illinois  61462
Illinois CancerCare - Community Cancer CenterNormal, Illinois  61761
Illinois CancerCare - PekinPekin, Illinois  61603
Illinois CancerCare - PeruPeru, Illinois  61354
Illinois CancerCare - PrincetonPrinceton, Illinois  61356
Illinois CancerCare - Spring ValleySpring Valley, Illinois  61362