AZD2171 in Treating Patients With Relapsed or Refractory B-Cell Chronic Lymphocytic Leukemia

A Phase II Trial of AZD2171 in Relapsed/Refractory B-Cell Chronic Lymphocytic Leukemia Patients

This phase II trial is studying how well AZD2171 works in treating patients with relapsed or refractory B-cell chronic lymphocytic leukemia. AZD2171 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 cells

Study Overview

• Status: Completed
• Conditions: B-cell Chronic Lymphocytic Leukemia; Refractory Chronic Lymphocytic Leukemia
• Intervention / Treatment: Other: laboratory biomarker analysis; Drug: cediranib maleate

Detailed Description

OBJECTIVES:

I. Evaluate the response rate in patients with relapsed or refractory B-cell chronic lymphocytic leukemia (B-CLL) treated with AZD2171.

II. Evaluate the toxicity of AZD2171 in patients with relapsed or refractory B-CLL.

III. Evaluate the complete response rate, progression-free and overall survival distributions, and duration of response in patients with relapsed or refractory B-CLL treated with AZD2171.

IV. Assess vascular endothelial growth factor receptor-2 (VEGFR-2) protein and phosphorylation levels in B-CLL cells using pretreatment samples and evaluate the association between Rai stage at study entry and clinical response to AZD2171.

V. Perform preclinical testing of AZD2171 in the induction of B-CLL cell apoptosis/cell death using pretreatment samples, and evaluate the ability to downregulate the phosphorylation status of VEGFR-2 of B-CLL cells by comparing in vitro samples with and without AZD2171.

VI. Study the differences in in vitro levels of B-CLL cell apoptosis/cell death and alteration of VEGFR-2 phosphorylation using pretreatment samples with and without AZD2171 and how these differences correlate with clinical outcomes.

VII. Assess if the clinical responses are associated with changes in bone marrow vascularity.

OUTLINE: This is a multicenter study.

Patients receive oral AZD2171 once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients undergo blood sampling and biopsies at baseline and periodically throughout study for biomarker and correlative studies.

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

• Study Type: Interventional
• Enrollment (Anticipated): 35
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • North Central Cancer Treatment Group

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histological confirmation of B-cell chronic lymphocytic leukemia (B-CLL)

  • Peripheral blood lymphocyte count > 5,000/mm³
  • Small to moderate peripheral blood lymphocytes with ≤ 55% prolymphocytes
  • Bone marrow aspirate with ≥ 30% lymphoid cells

  • Monoclonality of B lymphocytes by immunophenotyping, demonstrating all of the following:

    • B-cell markers with CD5 antigen in the absence of other pan-T-cell markers (CD3, CD2, etc.)
    • CD19 and/or CD20
    • Expression of CD23 on the CLL cells OR dim B-cell expression of kappa or lambda light chains
• Disease must be refractory to or progressive after treatment with at least 1 course containing a purine nucleoside analog (e.g., fludarabine, cladribine, or pentostatin)
• Life expectancy > 6 months
• ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 50,000/mm³
• Hemoglobin ≥ 8 g/dL

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)

  • Patients with Gilbert's syndrome may have a bilirubin ≥ 1.5 times ULN
• AST and ALT ≤ 2.5 times ULN
• Creatinine ≤ 1.5 times ULN
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No history of allergies to compounds similar to AZD2171
• QTc prolongation < 500 msec
• No other significant ECG abnormality
• No history of familial long QT syndrome
• Proteinuria < 1+ by dipstick OR protein < 1 g/24 hr urine collection
• No known HIV positivity

• No New York Heart Association (NYHA) class III or IV disease

  • NYHA class II disease controlled with treatment and monitoring allowed

• No other uncontrolled illness including, but not limited to, the following:

  • Hypertension
  • Ongoing or active infection
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Psychiatric illness or social situations that would limit compliance
• See Disease Characteristics
• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C), radiotherapy, anti-vascular endothelial growth factor (VEGF) treatment, or major surgery and recovered
• More than 30 days since prior investigational agents
• No concurrent drugs or biologics with proarrhythmic potential
• No other concurrent investigational agents
• No other concurrent anticancer therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (cediranib maleate); Patients receive oral AZD2171 once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Other: laboratory biomarker analysis; Correlative studies; Drug: cediranib maleate; Given orally; Other Names: AZD2171; Recentin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Confirmed response defined to be an objective status of complete remission [CR], nodular partial remission [nPR], and partial remission [PR]	Ninety percent confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner.	Up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete response rate estimated by the number of confirmed complete responses (CR) observed in the trial divided by the total number of evaluable patients	Exact binomial 95% confidence intervals for the true complete response rate will be calculated.	Up to 5 years
Overall survival	Estimated using the Kaplan-Meier method.	From the date of registration to the date of death, assessed up to 5 years
Time to progression as estimated by Kaplan-Meier method	Estimated using the Kaplan-Meier method.	From the date of registration to the date of disease progression, assessed up to 5 years
Duration of response	Estimated using the Kaplan-Meier method.	From the date at which the patient's objective status is first noted to be a response to the date that progression or death is documented, assessed up to 5 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Neil Kay, North Central Cancer Treatment Group

Study record dates

Study Major Dates

• Study Start: May 1, 2006
• Primary Completion (Actual): May 1, 2007

Study Registration Dates

• First Submitted: May 2, 2006
• First Submitted That Met QC Criteria: May 2, 2006
• First Posted (Estimate): May 4, 2006

Study Record Updates

• Last Update Posted (Estimate): January 15, 2013
• Last Update Submitted That Met QC Criteria: January 14, 2013
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, B-Cell; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Cediranib
• Other Study ID Numbers: NCI-2012-01825; U10CA025224 (U.S. NIH Grant/Contract); NCCTG-N048F; CDR0000467560 (Registry Identifier: PDQ (Physician Data Query))