A Study of Voruciclib Alone or in Combination With Venetoclax in Subjects With B-Cell Malignancies or AML

Study Overview
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Brief Summary
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This is a Phase 1, open-label, dose escalation study to determine the safety and preliminary efficacy of voruciclib monotherapy in subjects with relapsed/refractory B cell malignancies or AML after failure of standard therapies or voruciclib in combination with venetoclax in subjects with relapsed or refractory AML

Detailed Description
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This is a Phase 1, open-label, 3 + 3 dose escalation and expansion study to determine the safety and preliminary efficacy of voruciclib monotherapy in subjects with relapsed/refractory B cell malignancies or AML after failure of prior standard therapies or voruciclib in combination with venetoclax in subjects with relapsed or refractory AML. Escalation to the next higher dose level will depend on demonstrated safety and tolerability at each dose level.

Official Title
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Phase 1, Open-label, Study of Voruciclib in Subjects With Relapsed and/or Refractory B Cell Malignancies or AML After Failure of Prior Standard Therapies and Voruciclib in Combination With Venetoclax in Subjects With Relapsed/Refractory AML

Conditions
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Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), Marginal Zone Lymphoma (MZL), Small Lymphocytic Lymphoma (SLL), Chronic Lymphocytic Leukemia (CLL), Diffuse Large B-cell Lymphoma (DLBCL), Acute Myeloid Leukemia (AML)

Intervention / Treatment
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* Drug: voruciclib monotherapy
* Drug: voruciclib and venetoclax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years Histologically-confirmed diagnosis of Follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), small lymphocytic lymphoma (SLL), chronic lymphocytic leukemia(CLL), diffuse large B-cell lymphoma (DLBCL), or AML a. Subjects must have disease that has relapsed or is refractory to 2 or more prior regimens and in need of treatment due to progressive disease Presence of measurable disease defined per the 2008 International workshop on CLL guidelines, or by 2014 Lugano criteria for non-Hodgkin lymphoma (does not apply for AML subjects) Adequate hematologic parameters unless clearly due to the disease under study Adequate renal and hepatic function, per laboratory reference range at screening Exclusion Criteria: History of pneumonitis of any cause For CLL subjects: only known histological transformation to an aggressive lymphoma For AML subjects: Acute promyelocytic leukemia Peripheral blast count > 25 × 10 9/L Known central nervous system involvement Significant cardiovascular disease Significant screening ECG abnormalities Subjects who require warfarin, anti-cancer therapeutics or investigational agents Evidence of an ongoing systemic bacterial, fungal, or viral infection (including upper respiratory tract infections) at the time of start of voruciclib therapy Prior solid organ transplantation Receipt of an allogeneic transplant within 6 months or an autologous transplant within the preceding 3 months; evidence of ongoing graft-versus-host disease (GVHD) Prior therapy with a cyclin-dependent kinase (CDK9) inhibitor Symptomatic/uncontrolled HIV infection/AIDS, or currently taking contraindicated medications for HIV control Ongoing immunosuppressive treatment including calcineurin inhibitors at the time of the start of study treatment, including systemic or enteric corticosteroids except as follows: Prior to the start of study treatment, subjects may be using systemic corticosteroids (≤20 mg/day of prednisone or equivalent), topical, or inhaled corticosteroids During study therapy, subjects may use systemic, topical, or enteric corticosteroids, if needed

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
Interventional Model Description: This is a Phase 1, open-label, 3 + 3 dose escalation study to determine the safety and preliminary efficacy of voruciclib alone or in combination with venetoclax.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: voruciclib monotherapy and voruciclib in combination with venetoclax<br>voruciclib monotherapy - Open-label, 3 + 3 dose escalation study which may enroll up to 6 subjects at each dose level and disease type (AML or B-cell malignancies) voruciclib and venetoclax - Open-label, 3 + 3 dose escalation study which may enroll up to 6 subjects at each dose level for AML subjects | Drug: voruciclib monotherapy<br>* Voruciclib will be administered orally<br>* Other names: ME-522;Drug: voruciclib and venetoclax<br>* Voruciclib and Venetoclax will be administered orally<br>* Other names: ME-522;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the safety and tolerability of voruciclib | Safety will be measured by the incidence of all AEs and SAEs, timing, grade [CTCAE v4.03] severity, seriousness, relatedness. Tolerability will be measured by the incidence of DLTs (dose limiting toxicities) | 2 years | 
| Determine the safety and tolerability of voruciclib in combination with venetoclax in subjects with AML. | Safety will be measured by the incidence of all AEs and SAEs, timing, grade [CTCAE v4.03] severity, seriousness, relatedness. Tolerability will be measured by the incidence of DLTs (dose limiting toxicities) | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | defined as the sum of complete response (CR), complete remission with incomplete marrow recovery (CRi) and partial response (PR) for B-cell malignancies, or for AML the sum of CR/CRi rate by the 2017 European LeukemiaNet (ELN) criteria | 2 years | 
| Duration of Response (DOR) | defined as the time from the initial determination of response to the time of disease progression or death on study, which ever occurs first | 2 years | 
| Progression Free Survival (PFS) | defined as the time from the first dose of study drug administration (Cycle 1 Day 1) to disease recurrence or progression as defined by IWG criteria, or death on study | 2 years | 
| Evaluate the PK of voruciclib | Determined by the Area Under the Concentration time curve (AUC) | 2 years | 
| Evaluate the PK of voruciclib Cmax in combination with venetoclax Determined by the Area Under the Concentration time curve (AUC) | Determined by the Area Under the Concentration time curve (AUC) | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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B-Cell Malignancies, AML, voruciclib, venetoclax, CDK Inhibitor