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

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

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

Study Overview

• Status: Terminated
• Conditions: Chronic Lymphocytic Leukemia (CLL); Small Lymphocytic Lymphoma (SLL); Mantle Cell Lymphoma (MCL); Diffuse Large B-cell Lymphoma (DLBCL); Follicular Lymphoma (FL); Marginal Zone B Cell Lymphoma; High Grade Non-Hodgkin's Lymphoma
• Intervention / Treatment: Drug: ME-401; Drug: Rituximab; Drug: Zanubrutinib

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 97
• Phase: Phase 1

Contacts and Locations

Study Locations

• Switzerland
  • Bellinzona, Switzerland
    • lstituto Oncologico della Svizzera ltaliana Ospedale Regionale Bellinzona e Valli CH
• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona
  • California
    • Corona, California, United States, 92708
      • Compassionate Care
  • Florida
    • Miami, Florida, United States, 33136
      • Sylvester Comprehensive Cancer Center (Univ of Miami School of Med)
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Cancer Center
  • New Jersey
    • Basking Ridge, New Jersey, United States, 07920
      • Memorial Sloan Kettering
    • Middletown, New Jersey, United States, 07748
      • Memorial Sloan Kettering
    • Montvale, New Jersey, United States, 07645
      • Memorial Sloan Kettering
  • New York
    • Commack, New York, United States, 11725
      • Memorial Sloan Kettering
    • Harrison, New York, United States, 10604
      • Memorial Sloan Kettering
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10016
      • NYU Langone Laura & Isaac - Perlmutter Cancer Center
    • Stony Brook, New York, United States, 11794
      • Stony Brook
    • Uniondale, New York, United States, 11553
      • Memorial Sloan Kettering
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Stephenson Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37240
      • Vanderbilt
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Southwestern Medical Center
    • Houston, Texas, United States, 77030
      • Md Anderson Cancer Center
  • Washington
    • Edmonds, Washington, United States, 98026
      • Swedish Cancer Institute
    • Issaquah, Washington, United States, 98029
      • Swedish Cancer Institute
    • Seattle, Washington, United States, 98104
      • Swedish Cancer Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • Carbone Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ME-401 Alone; 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; 60 mg
Experimental: ME-401 in Combination with Rituximab; 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; 60 mg; Drug: Rituximab; IV infusion 375 mg/m2; Other Names: Rituxan
Experimental: ME-401 in Combination with Zanubrutinib; 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; 60 mg; Drug: Zanubrutinib; 80 and 160 mg bid

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: MEI Pharma, Inc.

Publications and helpful links

General Publications

• Pagel JM, Soumerai JD, Reddy N, Jagadeesh D, Stathis A, Asch A, Salman H, Kenkre VP, Iasonos A, Llorin-Sangalang J, Li J, Zelenetz AD. Zandelisib with continuous or intermittent dosing as monotherapy or in combination with rituximab in patients with relapsed or refractory B-cell malignancy: a multicentre, first-in-patient, dose-escalation and dose-expansion, phase 1b trial. Lancet Oncol. 2022 Aug;23(8):1021-1030. doi: 10.1016/S1470-2045(22)00333-3. Epub 2022 Jul 11.

Study record dates

Study Major Dates

• Study Start: October 1, 2016
• Primary Completion (Actual): March 29, 2023
• Study Completion (Actual): March 29, 2023

Study Registration Dates

• First Submitted: September 12, 2016
• First Submitted That Met QC Criteria: September 23, 2016
• First Posted (Estimate): September 26, 2016

Study Record Updates

• Last Update Posted (Actual): May 9, 2023
• Last Update Submitted That Met QC Criteria: May 5, 2023
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, Lymphoid; Leukemia; Leukemia, B-Cell; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Lymphoma, Mantle-Cell; Lymphoma, B-Cell, Marginal Zone; Leukemia, Lymphocytic, Chronic, B-Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Rituximab; Zanubrutinib
• Other Study ID Numbers: ME-401-002