Sorafenib in Treating Patients With Relapsed Chronic Lymphocytic Leukemia

Phase 2

Terminated

Conditions: Stage III Chronic Lymphocytic Leukemia
Refractory Chronic Lymphocytic Leukemia
Stage II Chronic Lymphocytic Leukemia
Stage IV Chronic Lymphocytic Leukemia
Stage I Chronic Lymphocytic Leukemia

Interventions: Drug: sorafenib tosylate

Registration Number: NCT00303966

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: Sorafenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the cancer. This phase II trial is studying how well sorafenib works in treating patients with relapsed chronic lymphocytic leukemia.

Detailed Description: PRIMARY OBJECTIVES:

I. Determine the objective response rate in patients with recurrent chronic lymphocytic leukemia (CLL) treated with sorafenib.

II. Determine the toxicity in patients treated with sorafenib.

SECONDARY OBJECTIVES:

I. Correlate bone marrow angiogenesis, CLL tumor cell expression of vascular endothelial growth factor (VEGF), VEGF receptors (flt-1, KDR, flt-4 and neuropilin-1), basic fibroblast growth factor, and plasma interleukin-8 levels with response.

OUTLINE: This is a multicenter study.

Patients receive oral sorafenib twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

PROJECTED ACCRUAL: Approximately 40 patients will be accrued for this study.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 5

Inclusion Criteria

Histologically or cytologically confirmed chronic lymphocytic leukemia (CLL) by NCI-WG immunophenotype and blood criteria
- Documentation of current or prior peripheral blood (PB) or bone marrow (BM) immunophenotype compatible with CLL
  - Patients who currently do not have > 5,000/mm³ absolute lymphocytosis are eligible if they have previously met PB lymphocytosis criteria and have a current immunophenotype documenting monoclonal B lymphocytosis morphologically and immunophenotypically compatible with CLL
Intermediate-risk (Rai stage I or II) or high-risk (Rai stage III or IV) disease, including any of the following:
- Rai stage I disease with lymphocytosis and enlarged nodes
- Rai stage II disease with lymphocytosis plus splenomegaly and/or hepatomegaly (nodes positive or negative)
- Rai stage III disease with lymphocytosis plus anemia
- Rai stage IV disease with lymphocytosis and thrombocytopenia
Must require treatment with active disease, experiencing disease related symptoms, or having deterioration of blood counts, meeting ≥ 1 of the following criteria:
- Presence of ≥ 1 of the following disease-related symptoms:
  - Weight loss > 10% within the past 6 months
  - Extreme fatigue (i.e., ECOG performance status 2: cannot work or unable to perform usual activities)
  - Fever > 100.5°F for 2 weeks without evidence of infection
  - Night sweats without evidence of infection
- Evidence of progressive marrow failure, as manifested by worsening of anemia (hemoglobin < 10 g/dL), thrombocytopenia (platelet count < 100,000/mm³), and/or neutropenia (neutrophil count < 2,000/mm³)
- Massive (i.e., > 6 cm below left costal margin) or progressive splenomegaly or discomfort from splenomegaly
- Massive nodes or clusters (i.e., > 10 cm in longest diameter), progressive adenopathy, or discomfort from lymphadenopathy
- Deterioration of blood counts and/or progressive lymphocytosis, with an increase of ≥ 10% documented over a 2-month period OR an anticipated doubling time < 6 months
Relapsed disease
- Must receive at least 1, but no more than 3, prior chemotherapy regimens with any cytotoxic agent or antibody therapy
  - No fludarabine refractory disease
    - Responded to prior fludarabine without relapse or disease progression for at least 6 months
Patients with a history of Coombs-positive hemolytic anemia are eligible provided recovery from treatment of hemolysis and off steroids
No stage 0 CLL
No known CNS involvement
Life expectancy > 6 months
ECOG performance status 0-2 OR Karnofsky performance status 70-100%
Absolute neutrophil count ≥ 1,000/mm³
Platelets ≥ 30,000/mm³
Bilirubin ≤ 2 mg/dL
AST/ALT ≤ 2.5 times upper limit of normal (ULN)
Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min (for patients with creatinine levels above normal)
No currently active second malignancy
Not pregnant or nursing
Negative pregnancy test
Fertile patient must use effective contraception prior to and during study participation
No uncontrolled hypertension, defined as blood pressure (BP) > 150/100 mm Hg on 2 different measurements at least 1 day apart with either systolic or diastolic number meeting this definition
- Patients may later enter the study, if they have achieved stable BP (i.e., < 140/90 mm Hg) on a regimen of ≤ 2 drugs after 6-8 weeks of therapy
No history of allergic reactions attributed to compounds of similar chemical or biologic composition to sorafenib
No uncontrolled intercurrent illness including, but not limited to, any of the following:
- Symptomatic congestive heart failure
- Unstable angina pectoris
- Cardiac arrhythmia
- Psychiatric illness or social situations that would limit compliance with the study requirements
No active infection requiring systemic antibiotics
No evidence of bleeding diathesis
No evidence of bowel perforation or obstruction risk
No swallowing dysfunction leading to difficulty taking the study drug
See Disease Characteristics
Recovered from prior therapy
At least 2 weeks since prior antibiotic therapy
At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C) or radiotherapy
At least 12 weeks since prior monoclonal antibody
Concurrent warfarin for anticoagulation allowed provided all of the following are met:
- On a stable therapeutic dose
- INR ≤ 3
- No active bleeding or pathological condition that carries high-risk of bleeding
No prior MAPK signaling inhibitor agents or anti-angiogenesis agents
No concurrent combination anti-retroviral therapy for HIV-positive patients
No concurrent cytochrome P450 enzyme-inducing antiepileptic drugs (phenytoin, carbamazepine, or phenobarbital), rifampin, or Hypericum perforatum (St. John's wort)
No other concurrent investigational agents

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (sorafenib tosylate)	sorafenib tosylate	Patients receive oral sorafenib twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Objective Response Rate	Up to week 25	Objective response is defined as a complete (CR) or partial (PR) remission. Complete remission is defined as no evidence of chronic lymphocytic leukemia (CLL) in marrow with normal hematopoiesis and no palpable lymphadenopathy. Partial remission is defined as improvement in blood counts from baseline with \>50% reduction in lymph nodes on examination. These are definitions from the CLL International Working Group (IWG).
Time to Disease Progression	Up to 5.5 years	Time to disease progression will be defined as the time from treatment start until disease progression and will be evaluated using the Kaplan-Meier estimator. Those who do not progress will be censored at the time that they were last known to be progression free.
Overall Survival	Up to 5.5 years	Overall survival will be defined as time from the start of treatment until death from any cause and will be evaluated using the Kaplan-Meier estimator.

Secondary Outcome Measures

Name	Time	Method
Changes in Mean Microvessel Density From Baseline to Week 25	Baseline and week 25	Mean microvessel density will serve as a marker of angiogenesis (other markers includes hot spot density). Will be examined using random-effects linear models.
Changes in Vascular Endothelial Growth Factor (VEGF) From Baseline to Week 25	Baseline and week 25	Changes in VEGF levels (post-pretreatment) will be assessed. A negative value indicates a decrease with treatment.
Changes in Plasma Level of Interleukin-8 (IL-8) From Baseline to Week 25	Baseline and week 25	The change (post-pretreatment) will be calculated and tested using a paired t test. A negative value indicates a decrease with treatment.