Clinical trial NCT00295932: Bortezomib, Rituximab, Cyclophosphamide, and Prednisone in Treating Patients With Relapsed or Refractory Indolent Non-Hodgkin's Lymphoma
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Leukemia
Lymphoma
Keywords: recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
recurrent grade 3 follicular lymphoma
recurrent small lymphocytic lymphoma
recurrent marginal zone lymphoma
Waldenstrom macroglobulinemia
recurrent mantle cell lymphoma
refractory chronic lymphocytic leukemia
B-cell chronic lymphocytic leukemia
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
nodal marginal zone B-cell lymphoma
splenic marginal zone lymphoma
Lead sponsor: Memorial Sloan Kettering Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
name: Rutgers Cancer Institute of New Jersey
name: Columbia University
name: Emory University
First posted: 2006-02-24
Enrollment: 79
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Maximum Tolerated Dose
timeFrame: 2 years
Secondary outcomes:
measure: Progression-free Survival
timeFrame: 2 years
measure: Duration of Response (Mean and Median)
timeFrame: 2 years
measure: Event-free Survival
timeFrame: 2 years
measure: Overall Survival
timeFrame: 2 years
measure: Toxicity of Participants Receiving Bortezomib, Rituximab, Cyclophosphamide, and Prednisone for Treatment of Non-Hodgkin's Lymphoma
timeFrame: 2 years
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Winship Cancer Institute of Emory University
state: Georgia
city: Basking Ridge
country: United States
facility: Memorial Sloan-Kettering at Basking Ridge
state: New Jersey
city: New Brunswick
country: United States
facility: Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School
state: New Jersey
city: Commack
country: United States
facility: Memorial Sloan-Kettering Cancer Center @ Suffolk
state: New York
city: New York
country: United States
facility: Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Rockville Centre
country: United States
facility: Memorial Sloan-Kettering at Mercy Medical Center
state: New York
city: Sleepy Hollow
country: United States
facility: Memoral Sloan Kettering Cancer Center@Phelps
state: New York
Study officials:
affiliation: Memorial Sloan Kettering Cancer Center
name: Carol Portlock, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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 rituximab, cyclophosphamide, and prednisone in relapsed or refractory non-Hodgkin lymphoma. Clin Cancer Res. 2011 Apr 15;17(8):2493-501. doi: 10.1158/1078-0432.CCR-10-1498. Epub 2011 Feb 23.