Pentostatin, Cyclophosphamide, and Rituximab With or Without Bevacizumab in Treating Patients With B-Cell Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

• ClinicalTrials.gov Identifier: NCT00816595
• Recruitment Status: Completed
• First Posted: January 1, 2009
• Results First Posted: May 9, 2014
• Last Update Posted: June 15, 2017
• Sponsor: Mayo Clinic
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Mayo Clinic

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Leukemia; Lymphoma	Biological: bevacizumab; Biological: pegfilgrastim; Biological: rituximab; Drug: cyclophosphamide; Drug: pentostatin	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 68 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: February 2009
• Actual Primary Completion Date: July 2013
• Actual Study Completion Date: November 29, 2016

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm A: Pentostatin, Cyclophosphamide, Rituximab, and Avastin; Patients receive 15 mg/kg bevacizumab IV over 30-90 minutes on day 1 of courses 1-5 and on days 1, 22, and 43 of course 6; 375 mg/m^2 rituximab IV over 2-4 hours on days 2 and 3 of course 1 and on day 1 of courses 2-6; and 2 mg/m^3 pentostatin IV over 30 minutes and 600 mg/m^2 cyclophosphamide IV over 30 minutes on day 2 of course 1 and on day 1 of courses 2-6. Patients also receive 6 mg 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.	Biological: bevacizumab; Given IV; Other Name: Avastin; Biological: pegfilgrastim; Given subcutaneously; Biological: rituximab; Given IV; Drug: cyclophosphamide; Given IV; Drug: pentostatin; Given IV
Experimental: Arm B: Pentostatin, Cyclophosphamide, and Rituximab; Patients receive 100 mg rituximab IV over 2-4 hours on day 1 and 375 mg/m^2 on day 2 of course 1 and 375 mg/m^2 on day 1 of courses 2-6. They receive 2 mg/m^2 pentostatin IV over 30 minutes and 600 mg/m^2 cyclophosphamide IV over 30 minutes on day 1. Patients also receive 6 mg pegfilgrastim SC on day 2. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.	Biological: pegfilgrastim; Given subcutaneously; Biological: rituximab; Given IV; Drug: cyclophosphamide; Given IV; Drug: pentostatin; Given IV

Outcome Measures

Primary Outcome Measures :

1. Complete and Overall Response Rate [ Time Frame: Evaluated after 6 cycles (up to 196 days) ]

   A Complete Response (CR) requires all of the following for 2 months:

   • Absence of lymphadenopathy by physical examination (PE)
   • No hepato- or splenomegaly by PE
   • Neutrophils >1500/ul, Platelets >100,000/ul. Hemoglobin >11.0 gm/dl, Peripheral blood lymphocytes <4000/uL

   Nodular Partial Response (nPR) is defined as a patient qualified for a CR, but regenerative nodules are histologically present on bone marrow samples.

   A Clinical Complete Response (CCR) is defined as a patient qualified for a CR, but bone marrow samples are not available.

   A Partial Response (PR) requires 50% reduction in 2 of the following: peripheral blood lymphocytes, or the sum of the products of the maximal perpendicular diameters, or the size of liver and/or spleen; and a 50% increase in neutrophils, platelets, or hemoglobin.

   Overall response rate is calculated as the number of patients receiving CR, CCR, nPR, or PR as their objective status divided by the total number of evaluable patients.

Secondary Outcome Measures :

1. Overall Survival [ Time Frame: Assessed up to 5 years from registration ]
   The Kaplan-Meier method will be used to estimate overall survival distributions Overall survival is measured as the time from registration to the time of death due to any cause.
2. Progression-free Survival [ Time Frame: Assessed up to 5 years from registration ]
   The Kaplan-Meier method will be used to estimate progression-free survival distribution. Progression-free survival is defined as the time from registration to the time of progression or death, whichever occurs first.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 120 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, Arizona

Mayo Clinic in Arizona

Scottsdale, Arizona, United States, 85259

United States, Minnesota

Mayo Clinic

Rochester, Minnesota, United States, 55905

Sponsors and Collaborators

Mayo Clinic

National Cancer Institute (NCI)

Investigators

• Study Chair: Tait D. Shanafelt, MD; Mayo Clinic
• Principal Investigator: Jose F. Francisco, M.D.; Mayo Clinic

More Information

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT00816595
• Other Study ID Numbers: CDR0000630491; P30CA015083 ( U.S. NIH Grant/Contract ); RC0783 ( Registry Identifier: Mayo Clinic Cancer Center ); 08-002080 ( Other Identifier: Mayo Clinic IRB ); AVF4491s ( Other Identifier: Genentech protocol ); NCI-2009-01225 ( Registry Identifier: NCI CTRP )
• First Posted: January 1, 2009
• Results First Posted: May 9, 2014
• Last Update Posted: June 15, 2017
• Last Verified: May 2017

Keywords provided by Mayo Clinic:

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

Additional relevant MeSH terms:

Lymphoma; Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, B-Cell; Cyclophosphamide; Bevacizumab; Rituximab; Pentostatin; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Adenosine Deaminase Inhibitors