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

Sponsor

MEI Pharma, Inc. (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT02914938

Collaborator

(none)

177

Enrollment

Locations

Arms

Duration (Months)

7.4

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Chronic Lymphocytic Leukemia (CLL) 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)	Drug: ME-401 Drug: Rituximab Drug: Zanubrutinib	Phase 1

Detailed Description

Study Design

Study Type:

Interventional

Anticipated Enrollment :

177 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Intervention 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.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)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Oct 1, 2016

Anticipated Primary Completion Date :

Aug 1, 2023

Anticipated Study Completion Date :

Dec 1, 2023

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Minimum Biologically Effective Dose (mBED) of ME-401 alone [1 year]
The mBED will be defined as the dose that is safe and that achieves an objective response rate that is not less than 30%.
Maximally Tolerated Dose (MTD) of ME-401 alone [1 year]
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
Dose Limiting Toxicities (DLTs) of ME-401 alone [within the first 56 days]
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
Evaluate the safety and tolerability of ME-401 plus rituximab [1 year]
Safety and tolerability will be measured by the number of treatment related AEs
Determine the MTD of ME-401 plus zanubrutinib [1 year]
The MTD of ME-401 is defined as the dose level with a DLT rate closest to 0.25.
Determine the DLTs of ME-401 plus zanubrutinib [within the first 56 days]
DLTs will be measured by the number of treatment related AEs that occur within the first 56 days of ME-401 plus zanubrutinib
Evaluate the safety and tolerability of ME-401 plus zanubrutinib [1 year]
Safety and tolerability will be measured by the number of treatment related AEs

Secondary Outcome Measures

Safety profile of ME-401 alone [1 year]
Safety profile will be measured by number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Efficacy of ME-401 alone as assessed by (OR) [2 years]
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).
Evaluate the (AUC) PK of ME-401 alone [2 years]
Determined by the Area Under the Concentration time curve (AUC)
Evaluate the PK (Cmax) of ME-401 alone [2 years]
Determined by Peak Plasma Concentration (Cmax)
Efficacy of ME-401 with rituximab [2 years]
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)
Evaluate the PK (AUC) of ME-401 with rituximab [2 years]
Determined by the Area Under the Concentration time curve (AUC)
Evaluate the PK (Cmax) of ME-401 with rituximab [2 years]
Determined by Peak Plasma Concentration (Cmax)
Efficacy of ME-401 with zanubrutinib [2 years]
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)
Evaluate the PK (AUC) of ME-401 in combination with zanubrutinib [2 years]
Determined by the Area Under the Concentration time curve (AUC)
Evaluate the PK (Cmax) of ME-401 in combination with zanubrutinib [2 years]
Determined by Peak Plasma Concentration (Cmax)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Arizona	Tucson	Arizona	United States	85724
2	Compassionate Care	Corona	California	United States	92708
3	Sylvester Comprehensive Cancer Center (Univ of Miami School of Med)	Miami	Florida	United States	33136
4	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
5	Dana Farber	Boston	Massachusetts	United States	02215
6	Memorial Sloan Kettering	Basking Ridge	New Jersey	United States	07920
7	Memorial Sloan Kettering	Middletown	New Jersey	United States	07748
8	Memorial Sloan Kettering	Montvale	New Jersey	United States	07645
9	Memorial Sloan Kettering	Commack	New York	United States	11725
10	Memorial Sloan Kettering	Harrison	New York	United States	10604
11	NYU Langone Laura & Isaac - Perlmutter Cancer Center	New York	New York	United States	10016
12	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
13	Stony Brook	Stony Brook	New York	United States	11794
14	Memorial Sloan Kettering	Uniondale	New York	United States	11553
15	Cleveland Clinic	Cleveland	Ohio	United States	44195
16	Stephenson Cancer Center	Oklahoma City	Oklahoma	United States	73104
17	Vanderbilt	Nashville	Tennessee	United States	37240
18	University of Southwestern Medical Center	Dallas	Texas	United States	75390
19	MD Anderson Cancer Center	Houston	Texas	United States	77030
20	Swedish Cancer Institute	Edmonds	Washington	United States	98026
21	Swedish Cancer Institute	Issaquah	Washington	United States	98029
22	Swedish Cancer Center	Seattle	Washington	United States	98104
23	Carbone Cancer Center	Madison	Wisconsin	United States	53792
24	lstituto Oncologico della Svizzera ltaliana Ospedale Regionale Bellinzona e Valli CH	Bellinzona		Switzerland