Bortezomib, Rituximab, Cyclophosphamide, and Prednisone in Treating Patients With Relapsed or Refractory Indolent Non-Hodgkin's Lymphoma

Lymphoma Clinical Trial

Official title:

A Phase II Study of the Novel Proteasome Inhibitor Bortezomib in Combination With Rituximab, Cyclophosphamide and Prednisone in Patients With Relapsed/Refractory Indolent B-Cell Lymphoproliferative Disorders and Mantle Cell Lymphoma (MCL)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00295932
• Other study ID #: 05-103
• Secondary ID: MSKCC-05103
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: December 13, 2005
• Est. completion date: March 11, 2018

Study information

• Verified date: March 2018
• Source: Memorial Sloan Kettering Cancer Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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 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 cyclophosphamide, prednisone, and rituximab may be an effective treatment for non-Hodgkin's lymphoma.

PURPOSE: This randomized phase I/II trial is studying the side effects and best dose of bortezomib when given together with cyclophosphamide, prednisone, and rituximab and to see how well it works in treating patients with relapsed or refractory indolent B-cell non-Hodgkin's lymphoma.

Description:

OBJECTIVES:

Primary

• Determine the maximum tolerated dose of bortezomib when given in combination with rituximab, cyclophosphamide, and prednisone (R-CP) in patients with relapsed or refractory indolent B-cell lymphoproliferative disorders or mantle cell lymphoma. (phase I)

• Determine the frequency and duration of complete and partial responses in patients treated with two different treatment regimes. (phase II)

Secondary

• Evaluate the progression-free survival, event-free survival, and overall survival of patients treated with this regimen. (phase II)

• Evaluate the toxicity profile of this regimen.

OUTLINE: This is a phase I dose-escalation study of bortezomib followed by a phase II randomized, multicenter study. Patients in phase II are stratified according to disease (mantle cell lymphoma vs indolent B-cell lymphoproliferative disorder vs transformed lymphoma).

• Phase I: Patients receive cyclophosphamide IV and rituximab IV on day 1, oral prednisone on days 2-6, and bortezomib IV on days 2 and 7. Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of bortezomib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 1 of 3 or 2 of 6 patients experience dose-limiting toxicity.

• Phase II: Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive cyclophosphamide IV and rituximab IV on day 1, oral prednisone on days 2-6, and bortezomib IV (at the MTD determined in phase I) on days 2, 5, 9, and 12. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.

• Arm II: Patients receive cyclophosphamide IV and rituximab IV on day 1, oral prednisone on days 2-6, and bortezomib IV (at the MTD determined in phase I) on days 2 and 8. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed at 1 month, every 4 months for 2 years, and then every 6 months thereafter.

Other known NCT identifiers

• NCT00859443

Recruitment information / eligibility

• Status: Completed
• Enrollment: 79
• Est. completion date: March 11, 2018
• Est. primary completion date: March 11, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

DISEASE CHARACTERISTICS:

• Histologically confirmed diagnosis of 1 of the following:

• Chronic lymphocytic leukemia (CLL)

• B-cell small lymphocytic leukemia (SLL)

• Any marginal zone lymphoma

• Grade 1-3A follicular lymphoma

• Waldenstrom's macroglobulinemia

• Mantle cell lymphoma

• No transformed indolent lymphoma

• Assessable disease (phase I)

• Measurable disease (phase I and II), defined as = one lesion that can be accurately measured in = 1 dimension as = 2 cm by conventional techniques OR = 1 cm by spiral CT scan

• Lymph nodes measuring = 1 cm in the short axis are considered normal

• Relapsed or refractory disease

• Must have received at least 1 prior therapeutic regimen but no more than 3 prior conventional cytotoxic therapy regimens

• No known brain metastases or meningeal disease

PATIENT CHARACTERISTICS:

• Karnofsky performance status > 50%

• Absolute neutrophil count > 1,000/mcl (more than 500/mcl if known lymphomatous involvement)

• Platelet count = 50,000/mcl

• Total bilirubin < 1.5 times upper limit of normal (ULN) (less than 5 mg/dL if known history of Gilbert's disease)

• AST and ALT = 2.5 times ULN (4 times ULN if liver involvement)

• Creatinine < 1.5 times ULN OR creatinine clearance > 50 mL/min

• Patients may have febrile episodes up to 38.5ºC without evidence of active infection

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• No New York Heart Association class III or IV congestive heart failure

• No uncontrolled intercurrent illness, including any of the following:

• Ongoing or active infection

• Cerebrovascular accident or transient ischemic attack within 6 months of study entry

• Unstable angina pectoris

• Cardiac arrhythmia

• EKG evidence of acute ischemia

• Psychiatric illness/social situations that would limit compliance with study requirements

• No uncontrolled hypertension requiring active manipulation of antihypertensive medications

• No known or active HIV infection

• No history of hypersensitivity to bortezomib, boron, or mannitol

• No peripheral neuropathy > grade 2

• No other malignancy within the past 5 years except curatively treated non life-threatening malignancies, such as cutaneous basal cell or squamous cell carcinoma or carcinoma in situ of the cervix

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• Recovered from prior therapy

• Prior stem cell transplantation allowed

• Preparative cytoreductive and high-dose therapies considered 1 prior therapy

• At least 4 weeks since prior cytotoxic chemotherapy (6 weeks since prior nitrosoureas or mitomycin C)

• At least 12 weeks since prior radioimmunotherapy

• One prior course comprising tositumomab or ibritumomab tiuxetan allowed

• At least 1 week since prior palliative steroids for NHL

• No therapeutic monoclonal antibodies (e.g., rituximab, tositumomab, ibritumomab, alemtuzumab, etc.) within 3 months of study entry

• Patients treated with monoclonal antibodies within 3 months allowed provided disease progressed on this therapy AND no treatment received 7 days prior to study entry

• Seven days since prior rituximab (for patients enrolled in phase I portion)

• No major surgery within 4 weeks of study entry

• No other concurrent investigational agents

• No other concurrent anticancer therapy

Related Conditions & MeSH terms

• Leukemia
• Lymphoma
• Lymphoma, Mantle-Cell
• Lymphoproliferative Disorders

Intervention

Biological:
• rituximab
Given IV

Drug:
• bortezomib
Given IV
• cyclophosphamide
Given IV
• prednisone
Given orally

Locations

Country	Name	City	State
United States	Winship Cancer Institute of Emory University	Atlanta	Georgia
United States	Memorial Sloan-Kettering at Basking Ridge	Basking Ridge	New Jersey
United States	Memorial Sloan-Kettering Cancer Center @ Suffolk	Commack	New York
United States	Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School	New Brunswick	New Jersey
United States	Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center	New York	New York
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Memorial Sloan-Kettering at Mercy Medical Center	Rockville Centre	New York
United States	Memoral Sloan Kettering Cancer Center@Phelps	Sleepy Hollow	New York

Sponsors (5)

Lead Sponsor	Collaborator
Memorial Sloan Kettering Cancer Center	Columbia University, Emory University, National Cancer Institute (NCI), Rutgers Cancer Institute of New Jersey

Country where clinical trial is conducted

United States, 

References & Publications (1)

Gerecitano J, Portlock C, Hamlin P, Moskowitz CH, Noy A, Straus D, Schulman P, Dumitrescu O, Sarasohn D, Pappanicholaou J, Iasonos A, Zhang Z, Mo Q, Horanlli E, Rojas CN, Zelenetz AD, O'Connor OA. Phase I trial of weekly and twice-weekly bortezomib with r — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum Tolerated Dose	Maximum tolerated dose of Bortezomib in combination with Rituximab, Cyclophosphamide and Prednisone in Phase I participants	2 years
Secondary	Progression-free Survival		2 years
Secondary	Duration of Response (Mean and Median)		2 years
Secondary	Event-free Survival		2 years
Secondary	Overall Survival		2 years
Secondary	Toxicity of Participants Receiving Bortezomib, Rituximab, Cyclophosphamide, and Prednisone for Treatment of Non-Hodgkin's Lymphoma	Toxicity assessed using NCI-CTC v. 3.0	2 years

External Links

•   Memorial Sloan Kettering Cancer Center