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

Chronic Lymphocytic Leukemia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01351935
• Other study ID #: AVL-292-003
• Status: Completed
• Phase: Phase 1
• Start date: July 18, 2011
• Est. completion date: June 26, 2015

Study information

• Verified date: November 2019
• Source: Celgene
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 113
• Est. completion date: June 26, 2015
• Est. primary completion date: June 26, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• B Cell Non-Hodgkin's Lymphoma
• Chronic Lymphocytic Leukemia
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Non-Hodgkin
• Waldenstrom Macroglobulinemia

Intervention

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

Locations

Country	Name	City	State
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Northwestern University	Chicago	Illinois
United States	Cleveland Clinic	Cleveland	Ohio
United States	The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	Clearview Cancer Institute Oncology Specialties, P.C	Huntsville	Alabama
United States	Mayo Clinic Jacksonville	Jacksonville	Florida
United States	University of California San Diego	La Jolla	California
United States	Horizon Oncology Center	Lafayette	Indiana
United States	Mount Sinai School of Medicine and Mount Sinai Graduate School of Biological Sciences	New York	New York
United States	University of Rochester Medical Center	Rochester	New York
United States	University of Texas Health Sciences Center	San Antonio	Texas
United States	US Oncology	The Woodlands	Texas
United States	University of Arizona SPORE	Tucson	Arizona

Sponsors (2)

Lead Sponsor	Collaborator
Celgene	The Leukemia and Lymphoma Society

Country where clinical trial is conducted

United States, 

References & Publications (1)

Arnason JE, Brown JR. B cell receptor pathway in chronic lymphocytic leukemia: specific role of CC-292. Immunotargets Ther. 2014 Jan 24;3:29-38. doi: 10.2147/ITT.S37419. eCollection 2014. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety, tolerability,and dose limiting toxicities will be determined using AEs,PE,ophthalmologic examinations,clinical laboratory tests,vital signs, ECGs and echocardiograms/MUGA scans.		with in the first 28 days after initiation of once daily oral dosing
Secondary	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)	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	Completion of Part 1 dose escalation phase of study
Secondary	Evaluate the Pharmacokinetic parameters of AVL-292	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.	First 28 days of dosing
Secondary	Evaluate the Pharmacodynamics of AVL-292 by measurement of free Btk	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.	First 28 days of dosing
Secondary	Characterize preliminary anti-tumor efficacy of AVL-292 in relapsed and/or refractory B-NHL, CLL and WM	Efficacy response assessments will be formally assessed within 7 days preceding C2D1, C3D1, C5D1, C7D1, and EOT	After completion of 28 day cycle of treatment

External Links

•   Leukemia & Lymphoma Society