Sorafenib in Treating Patients With Relapsed Chronic Lymphocytic Leukemia

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT00303966
• Collaborator: (none)
• Enrollment: 5
• Location: 1
• Arm: 1
• Duration (Months): 65.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Refractory Chronic Lymphocytic Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage II Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage IV Chronic Lymphocytic Leukemia	Drug: sorafenib tosylate	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

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

2. Determine the toxicity in patients treated with sorafenib.

SECONDARY OBJECTIVES:

1. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 5 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of BAY 43-9006 in Relapsed Chronic Lymphocytic Leukemia
• Study Start Date: Nov 1, 2005
• Actual Primary Completion Date: May 1, 2011
• Actual Study Completion Date: May 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (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.	Drug: sorafenib tosylate; Given orally; Other Names: BAY 43-9006 BAY 43-9006 Tosylate Salt BAY 54-9085 Nexavar SFN

Outcome Measures

Primary Outcome Measures

1. 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).

2. 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.

3. 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

1. 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.

2. 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.

3. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637-1470

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Wendy Stock, University of Chicago Comprehensive Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00303966
• Other Study ID Numbers: NCI-2012-02688; 14194B; UCCRC-14194B; NCI-7071; CDR0000462339; N01CM62201
• First Posted: Mar 17, 2006
• Last Update Posted: May 7, 2014
• Last Verified: Jan 1, 2014

• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Sorafenib

Study Results

Participant Flow

Arm/Group Title	Treatment (Sorafenib Tosylate)
Arm/Group Description	Patients receive oral sorafenib twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	5
COMPLETED	5
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (Sorafenib Tosylate)
Arm/Group Description	Patients receive oral sorafenib twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Overall Participants	5
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.3 (5.9)
Sex: Female, Male (Count of Participants)
Female	3 60%
Male	2 40%
Region of Enrollment (participants) [Number]
United States	5 100%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate
Description	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 Frame	Up to week 25

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Sorafenib Tosylate)
Arm/Group Description	Patients receive oral sorafenib twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	5
Number (95% Confidence Interval) [percentage of participants]	0 0%

2. Primary Outcome

Title	Time to Disease Progression
Description	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.
Time Frame	Up to 5.5 years

Outcome Measure Data

Analysis Population Description

Study terminated early and only 5 patients were enrolled.

Arm/Group Title	Treatment (Sorafenib Tosylate)
Arm/Group Description	Patients receive oral sorafenib twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	5
Median (Standard Error) [months]	4.6 (1.2)

3. Primary Outcome

Title	Overall Survival
Description	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.
Time Frame	Up to 5.5 years

Outcome Measure Data

Analysis Population Description

Study terminated early and only 5 patients were enrolled.

Arm/Group Title	Treatment (Sorafenib Tosylate)
Arm/Group Description	Patients receive oral sorafenib twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	5
Median (Standard Error) [months]	32.8 (10.5)

4. Secondary Outcome

Title	Changes in Mean Microvessel Density From Baseline to Week 25
Description	Mean microvessel density will serve as a marker of angiogenesis (other markers includes hot spot density). Will be examined using random-effects linear models.
Time Frame	Baseline and week 25

Outcome Measure Data

Analysis Population Description

Study terminated early with only 5 patients. Data wasn't collected for this outcome.

Arm/Group Title	Treatment (Sorafenib Tosylate)
Arm/Group Description	Patients receive oral sorafenib twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	0

5. Secondary Outcome

Title	Changes in Vascular Endothelial Growth Factor (VEGF) From Baseline to Week 25
Description	Changes in VEGF levels (post-pretreatment) will be assessed. A negative value indicates a decrease with treatment.
Time Frame	Baseline and week 25

Outcome Measure Data

Analysis Population Description

Study terminated early after enrolling only 5 patients. Data wasn't collected for this outcome.

Arm/Group Title	Treatment (Sorafenib Tosylate)
Arm/Group Description	Patients receive oral sorafenib twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	0

6. Secondary Outcome

Title	Changes in Plasma Level of Interleukin-8 (IL-8) From Baseline to Week 25
Description	The change (post-pretreatment) will be calculated and tested using a paired t test. A negative value indicates a decrease with treatment.
Time Frame	Baseline and week 25

Outcome Measure Data

Analysis Population Description

Study terminated early and enrolled only 5 patients. Data wasn't collected for this outcome.

Arm/Group Title	Treatment (Sorafenib Tosylate)
Arm/Group Description	Patients receive oral sorafenib twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	0

Adverse Events

Time Frame	up to 6 months
Adverse Event Reporting Description	Grade 3 or higher adverse events are reported.
Arm/Group Title	Treatment (Sorafenib Tosylate)
Arm/Group Description	Patients receive oral sorafenib twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
All Cause Mortality
	Treatment (Sorafenib Tosylate)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Sorafenib Tosylate)
	Affected / at Risk (%)	# Events
Total	1/5 (20%)
Hepatobiliary disorders
Cholecystitis	1/5 (20%)
Infections and infestations
Lung infection	1/5 (20%)
Investigations
Platelet count decreased	1/5 (20%)
Other (Not Including Serious) Adverse Events
	Treatment (Sorafenib Tosylate)
	Affected / at Risk (%)	# Events
Total	4/5 (80%)
Blood and lymphatic system disorders
Anemia	1/5 (20%)
General disorders
Fatigue	1/5 (20%)
Metabolism and nutrition disorders
Hyperkalemia	2/5 (40%)
Hypocalcemia	1/5 (20%)
Hyponatremia	1/5 (20%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/5 (20%)
Arthritis	1/5 (20%)

Limitations/Caveats

Early termination leading to small number of subjects

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.