Bortezomib, Combination Chemotherapy, and Rituximab as First-Line Therapy in Treating Patients With Stage III or Stage IV Follicular Non-Hodgkin's Lymphoma

Sponsor

NCIC Clinical Trials Group (Other)

Overall Status

Completed

CT.gov ID

NCT00428142

Collaborator

(none)

Enrollment

Locations

Arm

Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma	Biological: rituximab Drug: bortezomib Drug: cyclophosphamide Drug: prednisone Drug: vincristine sulfate	Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

95 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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 Start Date :

Dec 1, 2006

Actual Primary Completion Date :

Apr 1, 2011

Actual Study Completion Date :

Jan 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Bortezomib + BCVP-R BCVP-R - q 21 days x 4 cycles Bortezomib: 1.3 mg/m2 Days 1 & 8 Cyclophosphamide: 750 mg/m2 IV Day 1 Vincristine: 1.4 mg/m2 IV Day 1 (dose capped at 2 mg) Prednisone: 40 mg/m2 po Days 1-5 Rituximab: 375 mg/m2 IV Day 1	Biological: rituximab 375mg/m2 day 1 Drug: bortezomib 1.3mg/m2 days 1 & 8 Drug: cyclophosphamide 750mg/m2 day 1 Drug: prednisone 40mg/m2 days 1-5 Drug: vincristine sulfate 1.4mg/m2 day 1 (dose capped at 2mg)

Arm

Intervention/Treatment

Experimental: Bortezomib + BCVP-R

BCVP-R - q 21 days x 4 cycles Bortezomib: 1.3 mg/m2 Days 1 & 8 Cyclophosphamide: 750 mg/m2 IV Day 1 Vincristine: 1.4 mg/m2 IV Day 1 (dose capped at 2 mg) Prednisone: 40 mg/m2 po Days 1-5 Rituximab: 375 mg/m2 IV Day 1

Biological: rituximab

375mg/m2 day 1

Drug: bortezomib

1.3mg/m2 days 1 & 8

Drug: cyclophosphamide

750mg/m2 day 1

Drug: prednisone

40mg/m2 days 1-5

Drug: vincristine sulfate

1.4mg/m2 day 1 (dose capped at 2mg)

Outcome Measures

Primary Outcome Measures

Complete response rate [5 years]
Incidence of severe grade 3 or 4 neurotoxicity or neuropathic pain during the first 4 courses of treatment [5 years]

Secondary Outcome Measures

Overall response rate [5 years]
Response duration in patients with observed responses [5 years]
Time to progression [5 years]
Overall survival [5 years]
Toxicity [5 years]
Quality of life [5 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cross Cancer Institute	Edmonton	Alberta	Canada	T6G 1Z2
2	BCCA - Fraser Valley Cancer Centre	Surrey	British Columbia	Canada	V3V 1Z2
3	BCCA - Vancouver Cancer Centre	Vancouver	British Columbia	Canada	V5Z 4E6
4	BCCA - Vancouver Island Cancer Centre	Victoria	British Columbia	Canada	V8R 6V5
5	CancerCare Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
6	The Moncton Hospital	Moncton	New Brunswick	Canada	E1C 6Z8
7	QEII Health Sciences Center	Halifax	Nova Scotia	Canada	B3H 1V7
8	London Regional Cancer Program	London	Ontario	Canada	N6A 4L6
9	Credit Valley Hospital	Mississauga	Ontario	Canada	L5M 2N1
10	Regional Cancer Program of the Hopital Regional	Sudbury	Ontario	Canada	P3E 5J1
11	Thunder Bay Regional Health Science Centre	Thunder Bay	Ontario	Canada	P7B 6V4
12	Odette Cancer Centre	Toronto	Ontario	Canada	M4N 3M5
13	Univ. Health Network-Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2M9
14	Humber River Regional Hospital	Toronto	Ontario	Canada	M9N 1N8
15	Hopital Charles LeMoyne	Greenfield Park	Quebec	Canada	J4V 2H1
16	CHUM - Hopital Notre-Dame	Montreal	Quebec	Canada	H2L 4M1
17	McGill University - Dept. Oncology	Montreal	Quebec	Canada	H2W 1S6
18	CHA-Hopital Du St-Sacrement	Quebec City	Quebec	Canada	G1S 4L8
19	Allan Blair Cancer Centre	Regina	Saskatchewan	Canada	S4T 7T1