A Study of ME-401 in Subjects With CLL/SLL, FL, and B-cell Non Hodgkin's Lymphoma

Study Overview
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Brief Summary
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A Three-Arm Study of ME-401 in Subjects with Relapsed/Refractory CLL/SLL or FL, of ME-401 in Combination with Rituximab in Subjects with Relapsed/Refractory CLL/SLL or B-cell NHL, and of ME-401 in Combination with Zanubrutinib in Subjects with Relapsed/Refractory CLL/SLL or B-cell NHL

Detailed Description
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This is a three-arm study of ME-401 alone, of ME-401 in combination with rituximab, and of ME-401 in combination with zanubrutinib in subjects with relapsed/refractory CLL/SLL or B cell NHL. The 3 arms of the study will be conducted in parallel, with subject allocation to ME-401 alone, ME-401 plus rituximab, or ME-401 plus zanubrutinib based on disease type and availability of an open enrollment slot.

Official Title
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A Three-Arm Study of ME-401 Monotherapy in Subjects With Relapsed/Refractory CLL, SLL, or FL, of ME-401 in Combination With Rituximab in Subjects With Relapsed/Refractory CLL/SLL or B-cell NHL, and of ME-401 in Combination With Zanubrutinib in Subjects With Relapsed/Refractory CLL/SLL or B-cell NHL

Conditions
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Small Lymphocytic Lymphoma (SLL), Follicular Lymphoma (FL), Marginal Zone B Cell Lymphoma, Diffuse Large B-cell Lymphoma (DLBCL), High Grade Non-Hodgkin's Lymphoma, Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Leukemia (CLL)

Intervention / Treatment
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* Drug: ME-401
* Drug: Rituximab
* Drug: Zanubrutinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria MEI-401 Alone: Diagnosis of relapsed/refractory CLL and/or relapsed/refractory SLL or FL No prior therapy with PI3Kd inhibitors No prior therapy with Bruton tyrosine kinase (BTK) inhibitors unless the subject was intolerant of BTK therapy or subject had disease progression Subjects with CLL/SLL must have prior treatment with BTK inhibitor and must have had progression or recurrence while on treatment of within 12 mos from BTK treatment Subject must have failed at least 1 prior systemic therapy QT-interval corrected according to Fridericia's formula (QTcF) ≤ 450 milliseconds (ms) Left ventricular ejection fraction > 50% For subjects, except those with CLL, must have at least one bi-dimensionally measurable nodal lesion >1.5 cm, as defined by Lugano Classification Willingness to participate in collection of pharmacokinetic samples A negative serum pregnancy test within 14 days of study Day 0, for females of childbearing potential Inclusion Criteria ME-401 in Combination with Rituximab Diagnosis of relapsed/refractory CLL SLL or FL, MZL, DLBCL and high-grade B-cell lymphoma. Subjects must meet the following criteria for relapsed or refractory disease: No prior therapy with PI3Kδ inhibitors No prior therapy with Bruton tyrosine kinase (BTK) inhibitors unless the subject was intolerant of BTK therapy or subject had disease progression Subjects with CLL, SLL, FL, and MZL must have a failure of at least 1 prior systemic therapy and be considered by the investigator a candidate for therapy with a rituximab-based regimen; subjects with DLBCL and high-grade B-cell lymphoma must have a failure of at least 2 prior therapies. QT-interval corrected according to Fridericia's formula (QTcF) ≤450 milliseconds (ms) Left ventricular ejection fraction > 50% For subjects, except those with CLL, must have at least one bi-dimensionally measurable nodal lesion >1.5 cm, as defined by Lugano Classification Willingness to participate in collection of pharmacokinetic samples A negative serum pregnancy test within 14 days of study Day 0 for females of childbearing potential Inclusion Criteria ME-401 in Combination with Zanubrutinib Diagnosis of relapsed/refractory CLL or histologically-confirmed relapsed/refractory SLL or FL, MZL, MCL, DLBCL NOS (germinal center B-cell type or activated B-cell type) No prior therapy with PI3Kδ inhibitors No prior therapy with BTK inhibitors Subjects with CLL, SLL, FL, MCL, and MZL must have a failure of at least 1 prior systemic therapy, require treatment in the opinion of the investigator, and be considered by the investigator a candidate for therapy subjects with DLBCL and high-grade B-cell lymphoma must have a failure of at least 2 prior therapies For subjects with SLL, FL, MZL, MCL, DLBCL: At least one bi dimensionally measurable nodal lesion > 1.5 cm in its longest diameter by CT scan or MRI QT-interval corrected according to Fridericia's formula (QTcF) ≤ 450 milliseconds (msec) Left ventricular ejection fraction > 50% as measured by echocardiogram or multigated acquisition (MUGA) scan Willingness to participate in collection of pharmacokinetic samples For females of childbearing potential, a negative serum pregnancy test within 14 days of study Day 0 Exclusion Criteria: Known histological transformation from CLL to an aggressive lymphoma Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia Subjects who have tested positive for hepatitis B surface antigen and/or hepatitis B core antibody Positive for hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) antibody Ongoing drug-induced pneumonitis History of clinically significant cardiovascular abnormalities History of severe bleeding disorders (ME-401 plus zanubrutinib arm only) Known central nervous system (CNS) hemorrhage or stroke within 6 months prior to start of study drugs (ME-401 plus zanubrutinib arm only)

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a three-arm study of ME-401 alone, of ME-401 in combination with rituximab, and of ME-401 in combination with zanubrutinib in subjects with relapsed/refractory CLL/SLL or B cell NHL. The 3 arms of the study will be conducted in parallel, with subject allocation to ME 401 alone, ME-401 plus rituximab, or ME 401 plus zanubrutinib based on disease type and availability of an open enrollment slot.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ME-401 Alone<br>This arm is an open-label, dose escalation study to determine the safety, efficacy and pharmacokinetics of ME-401 along with the mBED, MTD, and DLTs. There are 4 planned cohorts which may enroll up to 61 subjects. | Drug: ME-401<br>* 60 mg<br>|
| Experimental: ME-401 in Combination with Rituximab<br>The second arm is an open label study to evaluate the safety, efficacy, and pharmacokinetics of ME-401 in combination with rituximab in subjects with various B-cell malignancies. There are two planned cohorts which may enroll up to 30 subjects. | Drug: ME-401<br>* 60 mg<br>Drug: Rituximab<br>* IV infusion 375 mg/m2<br>* Other names: Rituxan;|
| Experimental: ME-401 in Combination with Zanubrutinib<br>The third arm is an open label study evaluating the safety, efficacy, MTD, DLT and pharmacokinetics of ME-401 in combination with zanubrutinib in subjects with various B-cell malignancies. This arm will include 2 stages: a safety evaluation stage (cohort of 6-12 subjects) and a disease-specific expansion cohort stage (up to 74 subjects). | Drug: ME-401<br>* 60 mg<br>Drug: Zanubrutinib<br>* 80 and 160 mg bid<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Minimum Biologically Effective Dose (mBED) of ME-401 alone | The mBED will be defined as the dose that is safe and that achieves an objective response rate that is not less than 30%. | 1 year | 
| Maximally Tolerated Dose (MTD) of ME-401 alone | The MTD will be determined as the maximum dose that is safe. DLT rate closest to .25 and not to exceed 2 DLTs in 6 subjects | 1 year | 
| Dose Limiting Toxicities (DLTs) of ME-401 alone | DLTs will be measured by the number of treatment related AEs that occur within the first 56 days of ME-401 administration, is considered clinically significant by the P.I. and occurs in the presence of supportive care | within the first 56 days | 
| Evaluate the safety and tolerability of ME-401 plus rituximab | Safety and tolerability will be measured by the number of treatment related AEs | 1 year | 
| Determine the MTD of ME-401 plus zanubrutinib | The MTD of ME-401 is defined as the dose level with a DLT rate closest to 0.25. | 1 year | 
| Determine the DLTs of ME-401 plus zanubrutinib | DLTs will be measured by the number of treatment related AEs that occur within the first 56 days of ME-401 plus zanubrutinib | within the first 56 days | 
| Evaluate the safety and tolerability of ME-401 plus zanubrutinib | Safety and tolerability will be measured by the number of treatment related AEs | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety profile of ME-401 alone | Safety profile will be measured by number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | 1 year | 
| Efficacy of ME-401 alone as assessed by (OR) | The efficacy of ME-401 alone will be assessed by the overall response (OR) of subjects which is calculated as the percent of subjects achieving complete response (CR), minimal disease negativity (MRD), duration of response (DOR) and progression free survival (PFS). | 2 years | 
| Evaluate the (AUC) PK of ME-401 alone | Determined by the Area Under the Concentration time curve (AUC) | 2 years | 
| Evaluate the PK (Cmax) of ME-401 alone | Determined by Peak Plasma Concentration (Cmax) | 2 years | 
| Efficacy of ME-401 with rituximab | The efficacy of ME-401 with Rituximab will be determined by the overall response (OR) of subjects calculated as the percent of subjects achieving a complete remission (CR), duration of response (DOR) or Progression Free survival (PFS) according to the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) | 2 years | 
| Evaluate the PK (AUC) of ME-401 with rituximab | Determined by the Area Under the Concentration time curve (AUC) | 2 years | 
| Evaluate the PK (Cmax) of ME-401 with rituximab | Determined by Peak Plasma Concentration (Cmax) | 2 years | 
| Efficacy of ME-401 with zanubrutinib | The efficacy of ME-401 with zanubrutinib will be assessed by the overall response (OR) of subjects calculated as the percent of subjects achieving a complete remission (CR), Duration of response (DOR) and progression free survival (PFS) | 2 years | 
| Evaluate the PK (AUC) of ME-401 in combination with zanubrutinib | Determined by the Area Under the Concentration time curve (AUC) | 2 years | 
| Evaluate the PK (Cmax) of ME-401 in combination with zanubrutinib | Determined by Peak Plasma Concentration (Cmax) | 2 years |