Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II, Phase I	Treatment	Active	18 and over	NCI	MSKCC-05103 NCT00295932

Objectives

Primary

1. 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)
2. Determine the frequency and duration of complete and partial responses in patients treated with two different treatment regimes. (phase II)

Secondary

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

Entry Criteria

Disease Characteristics:

• Histologically confirmed diagnosis of 1 of the following:
  • Chronic lymphocytic leukemia (CLL) (phase I)
  • B-cell small lymphocytic leukemia (SLL) (phase I)
  • Any marginal zone lymphoma (phase I)
  • Grade 1-3A follicular lymphoma (phase I and II)
  • Waldenstrom's macroglobulinemia (phase I)
  • Mantle cell lymphoma (phase I)
  • Transformed indolent lymphoma (phase I)



• 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

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

Patient Characteristics:

• Karnofsky performance status > 50%
• Absolute neutrophil count > 1,000/mm³ (more than 500/mm³ if known lymphomatous involvement)
• Platelet count ≥ 50,000/mm³
• 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

Expected Enrollment

A total of 115 patients will be accrued for this study.

Outcomes

Maximum tolerated dose

Progression-free survival
Duration of response (mean and median)
Event-free survival
Overall survival
Toxicity

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 with follicular lymphoma only): 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.

Trial Contact Information

Trial Lead Organizations

Memorial Sloan-Kettering Cancer Center

John Gerecitano, MD, PhD, Protocol chair		Ph: 212-639-3748; 800-525-2225 Email: gerecitj@mskcc.org

U.S.A.
New York
	New York
	Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center
		Clinical Trials Office - Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center	Ph:  212-305-8615
	Memorial Sloan-Kettering Cancer Center
		John Gerecitano, MD, PhD	Ph:  212-639-3748 800-525-2225
			Email: gerecitj@mskcc.org

Registry Information
Official Title		A Phase I/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)
Trial Start Date		2005-12-13
Trial Completion Date		2010-09-27 (estimated)
Registered in ClinicalTrials.gov		NCT00295932
Date Submitted to PDQ		2005-10-26
Information Last Verified		2008-12-14
NCI Grant/Contract Number		CA08748

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