B Cell Non-Hodgkin's Lymphoma, Chronic Lymphocytic Leukemia, Waldenstrom Macroglobulinemia
Conditions
Keywords
non-hodgkin's lymphoma, lymphoma, leukemia, chronic lymphocytic leukemia, b-cell malignancies, Btk inhibitor, Phase 1b, Avila Therapeutics, Waldenstrom Macroglobulinemia
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).
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.
Interventions
DRUGAVL-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
Sponsors
The Leukemia and Lymphoma Society
Celgene
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | 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
| Measure | Time frame | Description |
|---|---|---|
| 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) | 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 |
| Evaluate the Pharmacokinetic parameters of AVL-292 | 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. |
| Evaluate the Pharmacodynamics of AVL-292 by measurement of free Btk | 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. |
| Characterize preliminary anti-tumor efficacy of AVL-292 in relapsed and/or refractory B-NHL, CLL and WM | 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 |
Countries
United States
Outcome results
None listed