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Randomized Phase II Trial of Pentostatin, Cyclophosphamide, and Rituximab With or Without Concurrent Avastin® for Previously Untreated B-Chronic Lymphocytic Leukemia (CLL)


Phase 2
18 Years
N/A
Open (Enrolling)
Both
Leukemia, Lymphoma

Thank you

Trial Information

Randomized Phase II Trial of Pentostatin, Cyclophosphamide, and Rituximab With or Without Concurrent Avastin® for Previously Untreated B-Chronic Lymphocytic Leukemia (CLL)


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.

Inclusion 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:

- ECOG 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)

- SGOT ≤ 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

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Primary Purpose: Treatment

Outcome Measure:

Complete response rate

Safety Issue:

No

Principal Investigator

Tait D. Shanafelt, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Mayo Clinic

Authority:

United States: Food and Drug Administration

Study ID:

CDR0000630491

NCT ID:

NCT00816595

Start Date:

June 2009

Completion Date:

Related Keywords:

  • Leukemia
  • Lymphoma
  • 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
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Lymphoma

Name

Location

Mayo ClinicRochester, Minnesota  55905
Mayo Clinic in ArizonaScottsdale, Arizona  85259-5404