Clinical trial NCT00980395: Bortezomib, Cladribine, and Rituximab in Treating Patients With Advanced Mantle Cell Lymphoma or Indolent Lymphoma
Official title: A Phase II, Open-Label Study of Bortezomib (Velcade), Cladribine and Rituximab (VCR) in Advanced, Newly Diagnosed and Relapsed/Refractory Mantle Cell and Indolent Lymphomas
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Lymphoma
Mantle Cell Lymphoma
Indolent Lymphoma
SLL
Keywords: recurrent mantle cell lymphoma
stage III mantle cell lymphoma
stage IV mantle cell lymphoma
recurrent marginal zone lymphoma
stage III marginal zone lymphoma
stage IV marginal zone lymphoma
Waldenstrom macroglobulinemia
recurrent small lymphocytic lymphoma
stage III small lymphocytic lymphoma
stage IV small lymphocytic lymphoma
recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
recurrent grade 3 follicular lymphoma
stage III grade 1 follicular lymphoma
stage III grade 2 follicular lymphoma
stage III grade 3 follicular lymphoma
stage IV grade 1 follicular lymphoma
stage IV grade 2 follicular lymphoma
stage IV grade 3 follicular lymphoma
extranodal marginal zone BCL mucosa assoc lymphoid tissue
nodal marginal zone B Cell lymphoma
splenic marginal zone lymphoma
Lead sponsor: University of Arizona
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2009-09-21
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cladribine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving bortezomib together with cladribine and rituximab may kill more cancer cells.

PURPOSE: This phase II trial is studying how well giving bortezomib together with cladribine and rituximab works in treating patients with advanced mantle cell lymphoma or indolent lymphoma.

Detailed description: OBJECTIVES:

Primary

* Determine the 2-year progression-free survival of patients with advanced mantle cell lymphoma or indolent lymphoma treated with bortezomib, cladribine, and rituximab.

Secondary

* Determine the 2-year overall survival of patients treated with this regimen.
* Determine the complete response and overall response rate in patients treated with this regimen.
* Describe the long- and short-term toxicity of this regimen in these patients.
* Determine the prognostic importance of Aurora kinase A in patients treated with this regimen.
* Determine the cytokine profiles for each lymphoma subtype and how they change with this regimen.
* Evaluate the prognostic importance of major carcinogenic pathways using tissue microarray.

OUTLINE: Patients receive bortezomib IV on days 1 and 4, cladribine IV over 2 hours on days 1-5, and rituximab IV on day 1. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Blood samples are collected at baseline and after course 1 for cytokine profile studies. Previously collected tissue samples are obtained for analysis of Aurora kinase A and B, Ki-67, cyclin D, Bcl-2, phosphor-HisH3, c-Met, and VEGF expression by using tissue microarray (IHC staining), reverse transcriptase-PCR, and/or western blotting.

After completion of study therapy, patients are followed up every 3 months for 2 years.

Eligibility criteria: Inclusion Criteria:

* Voluntary consent before performance of any study-related procedure
* Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control
* Male subject agrees to use an acceptable method for contraception for the duration of the study.
* Biopsy-proven mantle cell, marginal zone, lymphoplasmacytic, small lymphocytic lymphoma, or follicular lymphoma
* CD20-positive disease
* Patients with marginal zone, lymphoplasmacytic, small lymphocytic, or follicular lymphoma - at least one criterion for initiation of treatment must be met:

  * Symptomatic disease
  * Cytopenia related to lymphoma
  * Leukemic phase (\> 5,000 malignant lymphocytes/µl)
  * Mass over 5 cm in greatest diameter
  * For lymphoplasmacytic lymphoma: additional treatment criteria are serum viscosity ≥ 4 cp, serum monoclonal protein \> 5 g/L, concurrent primary systemic AL amyloidosis, cold agglutinin disease
* Age over 18
* Prior treatment with bortezomib and/or rituximab is acceptable
* For follicular lymphoma only, at least one prior treatment

Exclusion Criteria:

* Platelet count of \< 100 X10 /L within 14 days before enrollment, unless due to bone marrow infiltration with lymphoma, or due to autoimmune thrombocytopenia because of lymphoma.
* Patient has an absolute neutrophil count of \< 1.0 X 10/L within 14 days before registration, unless due to bone marrow infiltration with lymphoma.
* Patient has a calculated or measured creatinine clearance of \<20 mL/minute within 14 days before registration. (Creatinine Clearance is indicated through the Serum Creatinine. If the Serum Creatinine is abnormal, the physician may then due a 24 hour urine to further clarify Creatinine Clearance. A 24 hour urine test is not required per study.)
* Patient has ≥ Grade 2 peripheral neuropathy within 14 days before registration.
* Myocardial infarction within 6 months prior to registration or has New York Heart Association (NYHA) Class III or IV heart failure. uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
* Hypersensitivity to bortezomib, boron or mannitol.
* Female subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant
* Patient received other investigational drugs with 14 days before registration
* Serious medical or psychiatric illness likely to interfere with study participation
* Diagnosed or treated for another malignancy within 3 years of registration, w/ the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.
* CNS involvement with lymphoma.
* Known HIV-positive.
* History of disease refractory to a purine analog (defined as remission duration of \< 6 months to therapy that included fludarabine, pentostatin, or cladribine).
* History of intolerance of bortezomib, boron, mannitol, cladribine, or rituximab.
* Patient has \> 1.5 X ULN Total Bilirubin
* Radiation therapy within 3 weeks before randomization. Enrollment of subjects who require concurrent radiotherapy (which must be localized in its field size) should be deferred until the radiotherapy is completed and 3 weeks have elapsed since the last date of therapy.

Primary outcomes:
measure: Progression-free Survival at 2 Years
timeFrame: 2 years
Secondary outcomes:
measure: Overall Survival at 2 Years
timeFrame: 2 years
measure: Complete Response Rate
timeFrame: Two years
measure: Partial Response
timeFrame: Two years
Other outcomes:
Locations:
city: Tucson
country: United States
facility: The University of Arizona Cancer Center
state: Arizona
Study officials:
affiliation: University of Arizona
name: Daniel O. Persky, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Puvvada SD, Guillen-Rodriguez J, Kumar A, Inclan L, Heard K, Rivera XI, Anwer F, Schatz JH, Mahadevan D, Persky DO. Phase 2 Open-Label Study of Bortezomib, Cladribine, and Rituximab in Advanced, Newly Diagnosed, and Relapsed/Refractory Mantle-Cell and Indolent Lymphomas. Clin Lymphoma Myeloma Leuk. 2018 Jan;18(1):58-64. doi: 10.1016/j.clml.2017.09.001. Epub 2017 Sep 19.