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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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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

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

Intervention / Treatment
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* Drug: AVL-292


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AVL-292<br> | Drug: AVL-292<br>* 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<br>* Other names: Btk inhibitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lymphoma, non-hodgkin's lymphoma, leukemia, chronic lymphocytic leukemia, b-cell malignancies, Btk inhibitor, Phase 1b, Avila Therapeutics, Waldenstrom Macroglobulinemia