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Phase Ib, 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 Lymphoma, Chronic Lymphocytic Leukemia, and Waldenstrom's Macroglobulinemia
|Leukemia, Chronic Lymphocytic (CLL)
|Lymphoma, Non - Hodgkin
|Bruton's Tyrosine Kinase Inhibitor
- Primary Objectives
- To evaluate the safety, tolerability, and dose limiting toxicities (DLTs) of AVL-292 when administered orally (PO) QD or BID as monotherapy to subjects with relapsed or refractory B-Non Hodgkin Leukemia (B-NHL), chronic lymphocytic leukemia (CLL), or Waldenstrom's macroglobulinemia (WM)
- To establish the recommended Phase 2 dose (RP2D) of AVL-292 when administered QD or BID to such subjects
- Secondary Objectives
- To evaluate the pharmacokinetics PK of AVL-292 in subjects with relapsed and/or refractory B-NHL, CLL, or WM
- To evaluate the pharmacodynamic PD of AVL-292 in these subjects by measurement of free Bruton's tyrosine kinase (Btk) in lysates prepared from peripheral blood mononuclear cells (PBMC)
- To characterize preliminary anti-tumor efficacy of AVL-292 against relapsed and/or refractory B-NHL, CLL, and WM
- Exploratory Objectives
- To assess the effects of AVL-292 on the Btk signaling and related pathways/cell surface markers in tumor tissue and peripheral blood B cells
- To assess the effects of AVL-292 on serum levels of soluble markers, such as chemokine (C-C motif) ligands 3 and 4 (CCL3 and CCL4)
- To assess directly in tumor tissue, eg, lymph nodes, the degree of occupancy of Btk by AVL-292
- Women and men ≥ 18 years of age willing and able to participate in all AVL-292-003 clinical study directed activities as defined in the protocol.
- Willing and able to sign written informed consent.
- Body weight ≥ 50 kg.
- Confirmed diagnosis of B-NHL (according to the World Health Organization [WHO] classification) including CLL/SLL (International Workshop), or WM (Second International Workshop) by investigator assessment.
- The original diagnostic biopsy and/or other diagnostic datasets (eg, cell marker data) will ordinarily suffice. However, current re-biopsy is mandatory in those situations where new clinical features such as marked acceleration of tumor growth or new appearance of severe B symptoms suggest a possibility of histological transformation.
- Subjects with low grade B-NHL, CLL, or WM which has transformed into high grade lymphoma of the diffuse large cell type (Richter's transformation) are eligible to enroll provided they meet all of the other inclusion/exclusion criteria including Easterm Cooperative Oncology Group Performance Scale (ECOG PS) ≤ 2 and expected 3 month life expectancy. These subjects should enroll as DLBCL.
- For subjects with DLBCL, submission of a Formalin-Fixed Paraffin Embedded (FFPE) tumor block or 20 unstained slides from a fresh biopsy or an archival specimen of their lymphoma is required. These samples are required for all DLBCL subjects. During screening site must confirm the existence of pathology material. Within 86 weeks the pathology sample must be provided to LabCorp Clinical Trials (as described in the study-specific lab manual). These samples must be submitted even if the subject is already discontinued from the study.
- B cell NHL with bi-dimensional measurable disease ≥ 2 cm diameter; or CLL with ≥ 5000 leukemia cells/mm3: CD5+; CD19+; CD20 dim; CD23+; sIg dim; or WM with monoclonal serum IgM ≥ 2x upper limit of normal (ULN) and with lymphoplasmacytic marrow cell infiltrate: sIgM+; CD19+; CD20+; CD22+; CD79+
- Note for subjects with CLL: Variations of the intensity of expression of these lymphocyte surface markers may exist and do not prevent inclusion of a subject in this clinical trial. For example, CD23 may be variably positive. If CD23 is negative, mantle cell lymphoma must be ruled out by negative t(11;14) or absence of cyclin D1 staining by IHC.
- Note for subjects with WM: Eligible subjects must meet consensus panel criteria to treat (Appendix F). Some cases of WM may express CD5, CD10, or CD23; care should be taken to differentiate from CLL and mantle cell lymphoma.
- Note for subjects with mantle cell lymphoma (MCL): MCL are typically CD5+, CD10-, and CD23- (but not all cases are CD23-); demonstration of over-expression of cyclin D1 or the presence of a t(11;14)(q13;q32) translocation is necessary to support the diagnosis.
- Have failed ≥ 1 previous treatment for B-NHL/CLL/WM, and have relapsed or refractory disease following last prior treatment. Subjects with diffuse large B cell lymphoma must have failed, refused, be ineligible, or not otherwise appropriate, per the Investigator's judgment, for autologous stem cell transplant.
- Eastern Cooperative Oncology Group performance status (Appendix B) of ≤ 2 and a life expectancy of at least 3 months.
- All subjects with preserved reproductive potential must agree to practice abstinence or employ contraceptive measures for the duration of treatment and for 4 weeks following final dosing.
- All male subjects are considered to have reproductive potential.
- Female subjects of reproductive potential are those who: 1) are not at least 50 years old and have no menses for 24 consecutive months; or 2) have not been rendered surgically sterile (having undergone hysterectomy and/or bilateral salpingooophorectomy).
- Female subjects of reproductive potential must have a negative serum pregnancy test (minimum sensitivity 25IU/L or equivalent units of human chorionic gonadotropin [hCG]) within 7 days of first day of drug dosing.
- Ability to swallow oral capsules without difficulty.
- Have an echocardiogram or multigated acquisition scan of the heart demonstrating left ventricular ejection fraction (LVEF) ≥ 50% or ≥ the institution's lower limit of normal.
- Has recovered from adverse, toxic effects of prior therapies to Grade ≤ 1 (NCI CTCAE v4) except for alopecia and peripheral neuropathy. This requirement will be subordinate to specific clinical and laboratory criteria that are otherwise specifically addressed in these inclusion/exclusion criteria. Peripheral neuropathy must have recovered to ≤ Grade 2 except for subjects with WM, who may enroll with Grade 3 peripheral neuropathy if due to the underlying WM.
- Meet the following clinical laboratory requirements:
- Creatinine clearance by Cockcroft-Gault formula of ≥ 30 mL/min
- Total bilirubin ≤ 1.5 x ULN (unless indirect bilirubin is elevated from Gilbert's syndrome or hemolysis)
- AST and ALT ≤ 3 x ULN
- For subjects with NHL and WM:
- Platelet count ≥ 50,000/uL, without transfusion for 7 days before the laboratory test
- ANC ≥ 1000/uL, with or without chronic granulocyte growth factor support; if requiring chronic granulocyte growth factor support, then the subject must have been on a stable growth factor dose and regimen for at least 3 weeks prior to C1D1 and have an ANC ≥ 1000/uL for at least 3 weeks prior to C1D1; growth factor support for ANC is allowed only for subjects whose neutropenia is due to marrow infiltration by the underlying B-NHL or WM; if there is diagnostic uncertainty regarding the cause of the neutropenia, bone marrow examination must be performed.
- Hemoglobin ≥ 8 g/dL without transfusion within 7 days before the laboratory test.
- For subjects with CLL:
- Platelet count ≥ 30,000/uL, without transfusion within 7 days before the laboratory test
- ANC ≥ 1000/uL, with or without chronic granulocyte growth factor support; if requiring chronic granulocyte growth factor support, then the subject must have been on a stable growth factor dose and regimen for at least 3 weeks prior to C1D1 and have an ANC ≥ 1000/uL for at least 3 weeks prior to C1D1; growth factor support for ANC is allowed only for subjects whose neutropenia is due to marrow infiltration by disease; if there is diagnostic uncertainty regarding the cause of the neutropenia, bone marrow examination must be performed.
- Hemoglobin ≥ 8 g/dL without transfusion for 7 days before the laboratory test.
- Subjects enrolling in Part 1 under AVL-292-003 Protocol Amendment 2.0 will be required to undergo lymph node core biopsy while on treatment, if the subject has safely accessible tumor as determined by the clinical judgment of the investigator. Lymph node core biopsies for subjects enrolling in Part 2 will be covered under an optional separate consent. Subjects must additionally meet the following criteria on the day of the biopsy:
- Have accessible tumor tissue that is 1) suitable for core needle biopsy (18 gauge or larger) with acceptable clinical risk as judged by the investigator (eg, palpable peripheral lymph node masses); and 2) which is distinct from index lesions to be followed to assess tumor response.
- A single fresh tissue biopsy to be performed on C1 Day 15, will be required for all subjects enrolling into Part 1 under AVL-292-003 Protocol Amendment 2.0 if the subject has safely accessible nodal tissue as determined in the clinical judgment of the investigator. The fresh tumor tissue core biopsy should be collected as close to 4 hours after the C1D15 dose administration as possible, and in all cases within 2-6 hours from dosing. Safely accessible tissue is generally understood to mean a peripheral lymph node group that is superficial and readily palpable, not closely adjacent to nearby critical structures (eg, arterial vessels, nerves), and is non-ulcerated, non-inflamed, and non-infected. The investigator will make this determination during the screening physical examination and declare whether the subject is to undergo the biopsy procedure. As a condition for enrollment, the subject must consent to the biopsy if declared by the investigator to be suitable for this procedure. The suitability of the subject for the biopsy must be re-assessed immediately prior to the performance of the biopsy in case the lesion has rapidly shrunken away (which negates the need for biopsy) or has become ulcerated or infected.
- Have at least 1 measurable index lesion anatomically separate and distinct from the tumor lesion to be biopsied.
- Have a normal INR and PTT; platelet count at least 75,000/mm3; and ANC at least 1000/mm3. (Although these tests must be submitted to the designated central laboratory, locally obtained laboratory results may be used to precede with the biopsy.)
- Not be taking oral or injectable anticoagulants, and be judged not to have any bleeding diathesis by the investigator.
- Prior allogeneic bone marrow transplant.
- Autologous stem cell transplant within 3 months of screening date.
- Active central nervous system (CNS) involvement by lymphoma, including untreated symptomatic epidural disease.
- Subjects with autoimmune hemolytic anemia or immune thrombocytopenia requiring ongoing active immunotherapy at study entry other than systemic corticosteroids less than or equal to prednisone equivalent 20 mg/day.
- Subjects with WM with symptoms of acute hyperviscosity syndrome; these subjects must be stabilized with plasmapheresis prior to consideration for enrollment.
- Immunotherapy, chemotherapy, radiotherapy or investigational therapy within 3 weeks (within 4 weeks for monoclonal antibodies; within 6 weeks for nitrosoureas; within 12 weeks for iodine-131 tositumomab and ibritumomab tiuxetan) prior to study drug dosing.
- Prior treatment with a Btk inhibitor.
- Use of systemic corticosteroids in doses greater than prednisone equivalent 20 mg/day within 3 weeks prior to study drug dosing.
- Allergy or intolerance to AVL-292 or any of its excipients.
- Active uncontrolled infection.
- History of malabsorption.
- Uncontrolled illness including but not limited to: symptomatic congestive heart failure (New York Heart Association [NYHA] Class III or IV heart failure) (Appendix G), unstable angina pectoris, uncontrolled cardiac arrhythmia, and psychiatric illness that would limit compliance with study requirements.
- History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty and/or stenting within 6 months prior to study drug dosing.
- History of another currently active cancer or any other cancer ≤ 2 years prior to study drug dosing, except for adequately treated basal cell or squamous cell carcinoma of the skin, cervical cancer in situ, or other adequately treated in situ carcinomas.
- Treatment-related myelodysplastic syndrome (MDS).
- Subjects with a history of major surgery within 4 weeks or minor surgery within 1 week of AVL-292 administration. Major surgery includes, for example, any open or laparoscopic entry into a body cavity, or operative repair of fracture; minor surgery includes, for example, open surgical biopsy of palpable/superficial lymph node, or placement of vascular access device.
- Other medical or psychiatric illness or organ dysfunction, including ophthalmologic conditions, which, in the opinion of the investigator, would either compromise the subject's safety or interfere with the evaluation of the safety of the study agent.
- Corrected QT interval (QTc) prolongation (defined as a QTc ≥ 450 msec for males and ≥ 470 msec for females [Fridericia's correction]) or other clinically significant ECG abnormalities as assessed by the investigator.
- Human immunodeficiency virus (HIV) positive.
- Subjects positive for Hepatitis B surface antigen (HBsAg) or Hepatitis C-virus ribonucleic acid (HCV RNA), unless both AST and ALT ≤ 1.25 x ULN and no known history of chronic active hepatitis.
- Women who are pregnant or breastfeeding.
- Treatment with proton pump inhibitors, H2 antagonists or antacids. Subjects with chronic gastroesophageal reflux disease, dyspepsia, and peptic ulcer disease, should be carefully evaluated for their suitability for this treatment prior to enrollment in this study. These medications are prohibited concomitant medications throughout the study.
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