Clinical trial NCT00816595: Pentostatin, Cyclophosphamide, and Rituximab With or Without Bevacizumab in Treating Patients With B-Cell Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
Official title: Randomized Phase II Trial of Pentostatin, Cyclophosphamide, and Rituximab With or Without Concurrent Avastin® for Previously Untreated B-Chronic Lymphocytic Leukemia (CLL)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Leukemia
Lymphoma
Keywords: B-cell chronic lymphocytic leukemia
stage 0 chronic lymphocytic leukemia
stage I chronic lymphocytic leukemia
stage II chronic lymphocytic leukemia
stage III chronic lymphocytic leukemia
stage IV chronic lymphocytic leukemia
stage I small lymphocytic lymphoma
stage III small lymphocytic lymphoma
stage IV small lymphocytic lymphoma
contiguous stage II small lymphocytic lymphoma
noncontiguous stage II small lymphocytic lymphoma
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2009-01-01
Enrollment: 68
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: RATIONALE: Drugs used in chemotherapy, such as pentostatin and cyclophosphamide, 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 and bevacizumab, 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. It is not yet known whether giving pentostatin and cyclophosphamide together with rituximab is more effective with or without bevacizumab in treating patients with B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma.

PURPOSE: This randomized phase II trial is studying the side effects of giving pentostatin and cyclophosphamide together with rituximab with or without bevacizumab and to see how well it works in treating patients with B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma.

Detailed description: OBJECTIVES:

Primary

* To assess the rate of complete and overall response in patients with B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma treated with pentostatin, cyclophosphamide, and rituximab with or without bevacizumab.
* To assess the proportion of patients who achieve a negative minimal residual disease state after treatment with these regimens.
* To monitor and assess the adverse events of these regimens.

Secondary

* To determine if molecular prognostic parameters (ZAP-70, CD38, cytogenetic abnormalities identified by FISH, and IgVH mutation status) relate to response in these patients.
* To determine the progression-free survival of patients treated with these regimens.
* To complete additional correlative studies to gain insight into disease biology and how it influences drug sensitivity.

OUTLINE: Patients are stratified according to Rai risk group (high \[Rai stage III or IV\] vs low \[Rai stage 0\] or intermediate \[Rai stage I or II\]) and FISH prognosis group (favorable \[normal, +12, 13q-, or other\] vs unfavorable \[17p- or 11q-\]). Patients are randomized to 1 of 2 treatment arms.

* Arm I: Patients receive bevacizumab IV over 30-90 minutes on day 1 of courses 1-5 and on days 1, 22, and 43 of course 6; rituximab IV over 2-4 hours on days 2 and 3 of course 1 and on day 1 of courses 2-6; and pentostatin IV over 30 minutes and cyclophosphamide IV over 30 minutes on day 2 of course 1 and on day 1 of courses 2-6. Patients also receive pegfilgrastim subcutaneously (SC) on day 3 of course 1 and on day 2 of courses 2-6. Treatment repeats every 21 days\* for 6 courses in the absence of disease progression or unacceptable toxicity.

NOTE: \*Course 6 is 56 days in duration

* Arm II: Patients receive rituximab IV over 2-4 hours on days 1 and 2 of course 1 and on day 1 of courses 2-6 and pentostatin IV over 30 minutes and cyclophosphamide IV over 30 minutes on day 1. Patients also receive pegfilgrastim SC on day 2. Treatment repeats every 21 days\* for 6 courses in the absence of disease progression or unacceptable toxicity.

NOTE: \*Course 6 is 56 days in duration

Patients undergo blood sample collection and bone marrow biopsy/aspiration periodically for translational research studies. Samples are analyzed by flow cytometry for assessment of minimal residual disease. Molecular prognostic markers (including CD38, ZAP-70, IgVH gene mutation status, and cytogenetic abnormalities by FISH), Tcl-1 and CD49d protein expression, and immunoglobulin heavy chain D and J family gene usage are also analyzed. Plasma samples are stored for future studies evaluating levels of VEGF, bFGF, and thrombospondin by ELISA.

After completion of study therapy, patients are followed periodically for up to 5 years.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Diagnosis of 1 of the following:

  * Biopsy proven small lymphocytic lymphoma (SLL)
  * Chronic lymphocytic leukemia (CLL)\* as evidenced by the following criteria:

    * Peripheral blood lymphocyte count \> 5,000/mm³ consisting of small to moderate size lymphocytes
    * Immunophenotyping consistent with CLL, defined by the following:

      * The predominant population of lymphocytes share both B-cell antigens (CD19, CD20, or CD23) as well as CD-5 in the absence of other pan-T-cell markers (CD-3 or CD-2)
      * Dim surface immunoglobulin expression
      * Exclusively kappa and lambda light chains
    * Negative FISH analysis for t(11;14)(IgH/CCND1) on peripheral blood or tissue biopsy samples NOTE: \*Splenomegaly, hepatomegaly, or lymphadenopathy are not required for the diagnosis of CLL
* Has ≥ 1 of the following indications\*\* for chemotherapy:

  * Evidence of progressive marrow failure as manifested by the development of or worsening anemia (hemoglobin ≤ 11 g/dL) and/or thrombocytopenia (platelet count ≤ 100,000/mm³)
  * Symptomatic or progressive lymphadenopathy, splenomegaly or hepatomegaly
  * Has ≥ 1 of the following disease-related symptoms:

    * Weight loss \> 10% within the past 6 months
    * Extreme fatigue attributed to CLL
    * Fevers \> 100.5\^oF for 2 weeks without evidence of infection
    * Night sweats without evidence of infection
  * Progressive lymphocytosis (not due to the effects of corticosteroids) with an increase of \> 50% over a 2-month period or an anticipated doubling time of \< 6 months NOTE: \*\*Marked hypogammaglobulinemia or the development of a monoclonal protein in the absence of any of the above criteria for active disease are not sufficient indications for study treatment

PATIENT CHARACTERISTICS:

* Eastern Cooperative Oncology Group performance status 0-3
* Life expectancy ≥ 12 months
* Total bilirubin ≤ 3.0 times upper limit of normal (ULN) (unless due to Gilbert's disease)

  * Direct bilirubin \< 1.5 mg/dL (in patients with Gilbert's disease)
* Serum glutamate oxaloacetate transaminase ≤ 3.0 times ULN (unless due to hepatic involvement by CLL)
* Creatinine ≤ 1.5 times ULN
* Urine protein:creatinine ratio \< 1.0 OR \< 1 g of protein by 24-hour urine collection
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception during and for 12 months after completion of study treatment
* Willing to provide mandatory blood and tissue samples
* None of the following cardiovascular conditions:

  * NYHA class III-IV heart disease
  * Myocardial infarction within the past 6 months
  * Unstable angina
  * Stroke, cerebrovascular accident, or transient ischemic attack within the past 6 months
  * Arterial thromboembolic events within the past 12 months
  * Clinically significant peripheral vascular disease
  * Uncontrolled hypertension, defined as systolic BP \> 150 mm Hg or diastolic BP \> 100 mm Hg

    * Hypertension allowed provided it is controlled with a stable anti-hypertensive regimen
  * History of hypertensive crises or hypertensive encephalopathy
  * Deep venous thromboses or pulmonary embolism within the past 12 months
* No evidence of bleeding diathesis or coagulopathy
* No uncontrolled or active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic treatment
* No active or recent history (within the past 30 days) of hemoptysis (≥ ½ teaspoon of bright red blood per episode)
* No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
* No active peptic ulcer disease
* No serious non-healing wound, ulcer, or bone fracture
* No significant traumatic injury within the past 28 days
* No uncontrolled infection
* No active HIV infection
* No other active primary malignancy (except nonmelanoma skin cancer or carcinoma in situ of the cervix) requiring treatment or limiting survival to ≤ 2 years
* No psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude study participation

PRIOR CONCURRENT THERAPY:

* Prior corticosteroids allowed
* More than 4 weeks since prior radiotherapy
* More than 28 days since prior and no concurrent major surgical procedure or open biopsy
* More than 7 days since prior minor surgical procedure, fine needle aspiration, or core biopsy (other than bone marrow biopsy)
* No concurrent therapeutic doses of coumadin-derivative anticoagulants (e.g., warfarin)

  * Doses of ≤ 2 mg daily allowed for prophylaxis of thrombosis
  * Prophylactic doses of low molecular weight heparin allowed
* No other concurrent investigational agents for treatment of CLL or SLL
* No other concurrent specific anticancer treatment except hormonal therapy

Primary outcomes:
measure: Complete and Overall Response Rate
timeFrame: Evaluated after 6 cycles (up to 196 days)
Secondary outcomes:
measure: Overall Survival
timeFrame: Assessed up to 5 years from registration
measure: Progression-free Survival
timeFrame: Assessed up to 5 years from registration
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic in Arizona
state: Arizona
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
Study officials:
affiliation: Mayo Clinic
name: Tait D. Shanafelt, MD
role: STUDY_CHAIR
affiliation: Mayo Clinic
name: Jose F. Francisco, M.D.
role: PRINCIPAL_INVESTIGATOR
References: