Clinical trial NCT00428142: Bortezomib, Combination Chemotherapy, and Rituximab as First-Line Therapy in Treating Patients With Stage III or Stage IV Follicular Non-Hodgkin's Lymphoma
Official title: A Multi-Centre Phase II Trial Investigating the Efficacy and Tolerability of Bortezomib Added to Cyclophosphamide, Vincristine, Prednisone, and Rituximab (BCVP-R) for Patients With Advanced Stage Follicular Non-Hodgkin's Lymphoma Requiring Systemic First-Line Treatment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Lymphoma
Keywords: 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
Lead sponsor: Canadian Cancer Trials Group
Sponsor class: NETWORK
First posted: 2007-01-29
Enrollment: 95
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
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 cyclophosphamide, vincristine, and prednisone, 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 combination chemotherapy and rituximab may kill more cancer cells.

PURPOSE: This phase II trial is studying the side effects and how well giving bortezomib together with combination chemotherapy and rituximab works when given as first-line therapy in treating patients with stage III or stage IV follicular non-Hodgkin's lymphoma.

Detailed description: OBJECTIVES:

Primary

* Assess the efficacy of systemic first-line treatment comprising bortezomib, cyclophosphamide, vincristine, prednisone, and rituximab, in terms of complete response rate, in patients with stage III or IV follicular non-Hodgkin's lymphoma.
* Assess the incidence of severe neurotoxicity (defined as grade 3 or 4 neuropathy or neuropathic pain during the first 4 courses of treatment) in patients treated with this regimen.

Secondary

* Assess the overall response rate and response duration in patients treated with this regimen.
* Determine progression-free and overall survival of patients treated with this regimen.
* Evaluate the tolerability and characterize the toxicity profile of this regimen in these patients.
* Assess quality of life, with particular focus on neurotoxicity-related changes, of patients treated with this regimen.

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

Patient receive cyclophosphamide IV over 15-45 minutes, vincristine IV over 3-5 seconds and rituximab IV over 1½-6 hours on day 1, oral prednisone daily on days 1-5, and bortezomib IV over 3-5 seconds on days 1 and 8. Treatment repeats every 3 weeks for up to 8 courses in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline, at the end of each course of treatment, and on day 42 at the post treatment visit.

After completion of study treatment, patients are followed at 3 and 6 weeks and then every 3-6 months thereafter.

PROJECTED ACCRUAL: A total of 90 patients will be accrued for this study.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed follicular non-Hodgkin's lymphoma meeting the following criteria:

  * Stage III or IV disease
  * Grade 1, 2, or 3 disease requiring systemic first-line treatment
  * No transformation to diffuse large cell lymphoma
* At least 1 bidimensionally measurable lesion meeting 1 of the following criteria:

  * Lymph nodes \> 1.5 cm x 1.0 cm by physical exam or CT scan
  * Other non-nodal lesion ≥ 1.0 cm x 1.0 cm by MRI or CT scan OR ≥ 1.0 cm x 1.0 cm (e.g., skin lesions or nodules) by physical exam
* Must have a medical indication for treatment, as indicated by 1 of the following:

  * Presence of constitutional symptoms that are attributed to lymphoma (e.g., B symptoms, including night sweats, fever, weight loss, fatigue, or pain)
  * Lymphadenopathy that requires treatment based on presence of associated symptoms, potential threat to organ function (e.g., ureteric compromise from retroperitoneal disease), or degree of enlargement (i.e., \> 5 cm)
  * Impairment of normal organ function (e.g., impaired hematopoiesis due to marrow involvement by lymphoma or from splenomegaly and hypersplenism)
  * Immune-related complications of lymphoma that require therapy
  * Rate of disease progression for which observation is deemed inappropriate
* No history of any other lymphoproliferative disorder or evidence of transformation to an aggressive histology lymphoma
* No known CNS involvement by lymphoma

PATIENT CHARACTERISTICS:

* ECOG performance status 0-2
* Life expectancy ≥ 12 weeks
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* Platelet count ≥ 75,000/mm\^3\*
* Absolute neutrophil count ≥ 1,000/mm\^3\*
* Creatinine ≤ 1.5 times upper limit of normal (ULN)
* Bilirubin ≤ 1.5 times ULN
* AST or ALT ≤ 2.5 times ULN (5 times ULN if liver involvement with lymphoma)
* Able (i.e., sufficiently fluent) and willing to complete the quality of life questionnaires in either English or French

  * Inability (illiteracy in English or French, loss of sight, or other equivalent reason) to complete the questionnaires will not make the patient ineligible for the study
* No history of other malignancies, except for the following:

  * Adequately treated nonmelanoma skin cancer
  * Curatively treated in situ cancer of the cervix
  * Ductal carcinoma in situ of the breast (as long as radiation limitation is not exceeded)
  * Other solid tumors curatively treated with no evidence of disease for \> 5 years
* No history of allergic reactions attributed to compounds containing boron or mannitol
* No history of an unusual or severe allergic reaction to rituximab or similar agent
* No pre-existing neuropathy ≥ grade 2
* No known HIV infection
* No other serious illness or medical condition that would preclude study participation, including any of the following:

  * Active, uncontrolled bacterial, fungal, or viral infection
  * Significant cardiac dysfunction
  * Cardiovascular disease NOTE: \*Exceptions will be allowed for values below these thresholds in patients with marrow involvement by lymphoma or lymphoma-related hypersplenism

PRIOR CONCURRENT THERAPY:

* No prior systemic therapy for lymphoma
* No prior bortezomib, cyclophosphamide, or vincristine
* At least 4 weeks since prior radiotherapy that involved ≤ 25% of functioning bone marrow and recovered

  * Exceptions may be made for low-dose, nonmyelosuppressive radiotherapy or if the irradiated field is not a significant marrow-bearing area
* At least 2 weeks since prior major surgery
* No other concurrent anticancer therapy, investigational agents, corticosteroids (except for physiologic replacement or antiemesis), cytotoxic chemotherapy, or immunotherapy

Primary outcomes:
measure: Complete response rate
timeFrame: 5 years
measure: Incidence of severe grade 3 or 4 neurotoxicity or neuropathic pain during the first 4 courses of treatment
timeFrame: 5 years
Secondary outcomes:
measure: Overall response rate
timeFrame: 5 years
measure: Response duration in patients with observed responses
timeFrame: 5 years
measure: Time to progression
timeFrame: 5 years
measure: Overall survival
timeFrame: 5 years
measure: Toxicity
timeFrame: 5 years
measure: Quality of life
timeFrame: 5 years
Other outcomes:
Locations:
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Surrey
country: Canada
facility: BCCA - Fraser Valley Cancer Centre
state: British Columbia
city: Vancouver
country: Canada
facility: BCCA - Vancouver Cancer Centre
state: British Columbia
city: Victoria
country: Canada
facility: BCCA - Vancouver Island Cancer Centre
state: British Columbia
city: Winnipeg
country: Canada
facility: CancerCare Manitoba
state: Manitoba
city: Moncton
country: Canada
facility: The Moncton Hospital
state: New Brunswick
city: Halifax
country: Canada
facility: QEII Health Sciences Center
state: Nova Scotia
city: London
country: Canada
facility: London Regional Cancer Program
state: Ontario
city: Mississauga
country: Canada
facility: Credit Valley Hospital
state: Ontario
city: Sudbury
country: Canada
facility: Regional Cancer Program of the Hopital Regional
state: Ontario
city: Thunder Bay
country: Canada
facility: Thunder Bay Regional Health Science Centre
state: Ontario
city: Toronto
country: Canada
facility: Odette Cancer Centre
state: Ontario
city: Toronto
country: Canada
facility: Univ. Health Network-Princess Margaret Hospital
state: Ontario
city: Toronto
country: Canada
facility: Humber River Regional Hospital
state: Ontario
city: Greenfield Park
country: Canada
facility: Hopital Charles LeMoyne
state: Quebec
city: Montreal
country: Canada
facility: CHUM - Hopital Notre-Dame
state: Quebec
city: Montreal
country: Canada
facility: McGill University - Dept. Oncology
state: Quebec
city: Quebec City
country: Canada
facility: CHA-Hopital Du St-Sacrement
state: Quebec
city: Regina
country: Canada
facility: Allan Blair Cancer Centre
state: Saskatchewan
Study officials:
affiliation: British Columbia Cancer Agency
name: Laurie Sehn
role: STUDY_CHAIR
affiliation: Princess Margaret Hospital, Canada
name: Michael R. Crump, MD, FRCPC
role: STUDY_CHAIR
References:
citation: Sehn LH, Macdonald DA, Rubin SH, et al.: Tolerability and efficacy of bortezomib added to CVP-R for previously untreated advanced stage follicular fymphoma: interim analysis of a phase II study by the NCIC Clinical Trials Group. [Abstract] Blood 112 (11): A-1576, 2008.
citation: Sehn LH, MacDonald D, Rubin S, Cantin G, Rubinger M, Lemieux B, Basi S, Imrie K, Gascoyne RD, Sussman J, Chen BE, Djurfeldt M, Shepherd L, Couban S, Crump M. Bortezomib ADDED to R-CVP is safe and effective for previously untreated advanced-stage follicular lymphoma: a phase II study by the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2011 Sep 1;29(25):3396-401. doi: 10.1200/JCO.2010.33.6594. Epub 2011 Aug 1.