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Escalating Dose Study in Subjects With Relapsed or Refractory B Cell Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, and Waldenstrom's Macroglobulinemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01351935
Recruitment Status : Completed
First Posted : May 11, 2011
Last Update Posted : November 8, 2019
The Leukemia and Lymphoma Society
Information provided by (Responsible Party):

Brief Summary:
The purpose of this study is to evaluate the safety and tolerability of AVL-292 as monotherapy in subjects with relapsed or refractory B cell non-Hodgkin lymphoma (B-NHL), chronic lymphocytic leukemia (CLL) or Waldenstrom's macroglobulinemia (WM).

Condition or disease Intervention/treatment Phase
B Cell Non-Hodgkin's Lymphoma Chronic Lymphocytic Leukemia Waldenstrom Macroglobulinemia Drug: AVL-292 Phase 1

Detailed Description:
Bruton's tyrosine kinase (Btk) is non-receptor tyrosine kinase with restricted cellular expression largely limited to B-lymphocytes, monocytes, and mast cells or basophils. Btk is a critical component of the B cell receptor (BCR) signaling network and is crucial for B cell development. Investigation has revealed that some B cell lymphomas and CLL depend on BCR signaling, suggesting that interruption of such signaling could be a promising therapeutic opportunity in B-NHL, CLL and WM.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 113 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1b, Escalating Dose Study of AVL-292, a Bruton's Tyrosine Kinase (Btk) Inhibitor, as Monotherapy in Subjects With Relapsed and/or Refractory B Cell Non-Hodgkin's Lymphoma, Chronic Lymphocytic Leukemia, and Waldenstrom's Macroglobulinemia
Actual Study Start Date : July 18, 2011
Actual Primary Completion Date : June 26, 2015
Actual Study Completion Date : June 26, 2015

Arm Intervention/treatment
Experimental: AVL-292 Drug: AVL-292
125 mg to 625 mg orally, once a day, for 28 days (28 days equals 1 cycle). Number of cycles: until progression or unacceptable toxicity develops
Other Name: Btk inhibitor

Primary Outcome Measures :
  1. Safety, tolerability,and dose limiting toxicities will be determined using AEs,PE,ophthalmologic examinations,clinical laboratory tests,vital signs, ECGs and echocardiograms/MUGA scans. [ Time Frame: with in the first 28 days after initiation of once daily oral dosing ]

Secondary Outcome Measures :
  1. Establish recommended Phase 2 dose, after completing dose escalation in Part 1 and evaluating accumulated safety,PK,and PD data from the dose escalation phase (Part1) [ Time Frame: Completion of Part 1 dose escalation phase of study ]
    After completion of observation for dose limiting toxicities in Part 1 of the study, the accumulated safety, PK, and PD data from Part 1 will be evaluated by the investigators and Sponsor to select a preliminary RP2D for administration to additional subjects to be enrolled into 1 of 3 independent and non-randomized diagnosis-specific expansion cohorts in Part 2 of the study

  2. Evaluate the Pharmacokinetic parameters of AVL-292 [ Time Frame: First 28 days of dosing ]
    Serial blood sampling to enable PK characterization of AVL-292 will be performed for the Cycle1 Day 1 (C1D1) and Cycle 1Day 15 dose administrations. Additional samples will be obtained on C1D8 and C1D22.A non-compartmental model will be evaluated for all subjects.

  3. Evaluate the Pharmacodynamics of AVL-292 by measurement of free Btk [ Time Frame: First 28 days of dosing ]
    The PD activity of AVL-292 will be studied with a quantitative assay using a covalent probe to directly assess free Btk in PBMC lysates.

  4. Characterize preliminary anti-tumor efficacy of AVL-292 in relapsed and/or refractory B-NHL, CLL and WM [ Time Frame: After completion of 28 day cycle of treatment ]
    Efficacy response assessments will be formally assessed within 7 days preceding C2D1, C3D1, C5D1, C7D1, and EOT

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Women and men ≥18 years of age
  • Body weight ≥50 kg.
  • Confirmed diagnosis of B cellNon-Hodgkin Lymphoma(according to World Health Organization [WHO] classification)including Chronic Lymphocytic Leukemia/Small cell Lymphocytic Leukemia (International Workshop),or Waldenstrom's Macroglobulinemia(Second International Workshop)
  • Have failed ≥1 previous treatment for B-NHL/CLL/WM, and have relapsed or refractory disease following last prior treatment.
  • Eastern Cooperative Oncology Group performance status of ≤ 2 and a life expectancy of at least 3 months.
  • Ability to swallow oral capsules without difficulty
  • Has recovered from adverse toxic effects of prior therapies
  • Meet the following clinical laboratory requirements:

    • Creatinine ≤ 1.5 × upper limit of normal (ULN)
    • Total bilirubin ≤ 1.5 x ULN
    • AST and ALT ≤ 3 × ULN
    • Platelet count ≥ 50,000/µL (non-hodgkin & Waldenstrom's)
    • Platelet count ≥ 30,000/µL (chronic lymphocytic leukemia)
    • Absolute Neutrophil count ≥ 1000/µL

Exclusion Criteria:

  • Prior allogeneic bone marrow transplant
  • Autologous stem cell transplant within 3 months of screening
  • Active central nervous system involvement
  • Subjects with autoimmune hemolytic anemia or immune thrombocytopenia
  • Prior treatment with a Btk inhibitor
  • Active uncontrolled infection
  • History of malabsorption
  • Uncontrolled illness, i.e cardiac, endocrine, respiratory, etc.
  • History of myocardial infarction, acute coronary syndromes, coronary angioplasty and/or stenting with in the previous 6 months
  • History of another currently active cancer
  • History of major surgery within 4 weeks or minor surgery within 1 week
  • Other medical or psychiatric illness or organ dysfunction
  • HIV positive
  • Positive for Hepatitis B surface antigen or Hepatitis C-virus

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01351935

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United States, Alabama
Clearview Cancer Institute Oncology Specialties, P.C
Huntsville, Alabama, United States, 35805
United States, Arizona
University of Arizona SPORE
Tucson, Arizona, United States, 85719
United States, California
University of California San Diego
La Jolla, California, United States, 92093-0960
United States, Florida
Mayo Clinic Jacksonville
Jacksonville, Florida, United States, 32224
United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611
United States, Indiana
Horizon Oncology Center
Lafayette, Indiana, United States, 47905
United States, Massachusetts
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02115
United States, New York
Mount Sinai School of Medicine and Mount Sinai Graduate School of Biological Sciences
New York, New York, United States, 10029
University of Rochester Medical Center
Rochester, New York, United States, 14642
United States, Ohio
Cleveland Clinic
Cleveland, Ohio, United States, 44195
United States, Texas
The University of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030
University of Texas Health Sciences Center
San Antonio, Texas, United States, 78229
US Oncology
The Woodlands, Texas, United States, 77380
Sponsors and Collaborators
The Leukemia and Lymphoma Society
Additional Information:
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Responsible Party: Celgene Identifier: NCT01351935    
Other Study ID Numbers: AVL-292-003
First Posted: May 11, 2011    Key Record Dates
Last Update Posted: November 8, 2019
Last Verified: November 2019
Keywords provided by Celgene:
non-hodgkin's lymphoma
chronic lymphocytic leukemia
b-cell malignancies
Btk inhibitor
Phase 1b
Avila Therapeutics
Waldenstrom Macroglobulinemia
Additional relevant MeSH terms:
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Lymphoma, Non-Hodgkin
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, B-Cell
Waldenstrom Macroglobulinemia
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Neoplasms, Plasma Cell
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders