Clinical Trials /

BTK Inhibitor in B Cell Malignancies

NCT02825836

Description:

M7583 is an investigational drug that is being evaluated for the treatment of patients with B-cell malignancies, which are cancers that form in B cells (cells that are part of the immune system). This study has been designed to assess the use of the study drug in patients with B-cell lymphomas who have tried and did not respond well (or the B-cell lymphoma came back) to at least one but not more than three types of treatment for cancer. This is a Phase I/II study, which means that it is looking at several dose levels of an investigational medication in terms of its safety and how well it is tolerated in multiple doses. The final selected dose will be tested for activity against the tumor in specific populations of lymphoma (Mantle cell lymphoma and Diffuse Large B Cell Lymphoma)

Related Conditions:
  • Chronic Lymphocytic Leukemia
  • Diffuse Large B-Cell Lymphoma
  • Follicular Lymphoma
  • Lymphoplasmacytic Lymphoma
  • Mantle Cell Lymphoma
  • Small Lymphocytic Lymphoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title:BTK Inhibitor in B Cell Malignancies
  • Official Title:Phase I/II, First in Human, Dose Escalation Trial of the Bruton's Tyrosine Kinase Inhibitor M7583 in Patients With Relapsed/Refractory B Cell Malignancies and Expansion Cohorts in Patients With Mantle Cell Lymphoma and Diffuse Large B Cell Lymphoma (ABC Subtype) That Have Progressed After at Least 1 But Not More Than 3 Prior Lines of Therapy

Clinical Trial IDs

  • ORG STUDY ID: MS200662_0001
  • SECONDARY ID: 2016-000286-23
  • NCT ID: NCT02825836

Trial Conditions

  • Relapsed/Refractory B Cell Malignancies
  • Mantle Cell Lymphoma and Diffuse Large B Cell Lymphoma

Trial Interventions

DrugSynonymsArms
M7583M7538 (Part 1): Dose escalation

Trial Purpose

M7583 is an investigational drug that is being evaluated for the treatment of patients with B-cell malignancies, which are cancers that form in B cells (cells that are part of the immune system). This study has been designed to assess the use of the study drug in patients with B-cell lymphomas who have tried and did not respond well (or the B-cell lymphoma came back) to at least one but not more than three types of treatment for cancer. This is a Phase I/II study, which means that it is looking at several dose levels of an investigational medication in terms of its safety and how well it is tolerated in multiple doses. The final selected dose will be tested for activity against the tumor in specific populations of lymphoma (Mantle cell lymphoma and Diffuse Large B Cell Lymphoma)

Detailed Description

Trial Arms

NameTypeDescriptionInterventions
M7538 (Part 1): Dose escalationExperimental
  • M7583
M7538 (Part 2): Dose expansionExperimental
  • M7583

Eligibility Criteria

Inclusion Criteria:

- Patient population In the dose escalation cohorts: Patients with pathologically confirmed B cell malignancy (i.e. DLBCL, CLL, small lymphocytic lymphoma [SLL], follicular lymphoma [FL], mantle cell lymphoma (MCL), Morbus Waldenström), with at least 1, but not more than 3 prior lines of therapy.

In the dose expansion cohort: Patients with relapsed/refractory DLBCL (ABC subtype) histo-pathologically confirmed by gene expression profiling (GEP) tested at a central laboratory or MCL with documented overexpression of either cyclin D1 or t(11;14), with at least 1, but not more than 3 prior lines of therapy, and measurable disease according to the Cheson criteria.

- Life expectancy of greater than 4 months from the first dose of M7583 and Eastern Cooperative Oncology Group (ECOG) performance status of less than equal to (<=) 2 at Screening

- Adequate hematological function in the absence of transfusions defined (within 6 weeks prior to first dose of study medication) defined by white blood cell (WBC) count greater than equal to (>=) 3 x 109/liter (L) with absolute neutrophil count (ANC) >= 1.0 x 109/L, platelet count >= 50 x 109/L, and haemoglobin >=9 gram per decilitre (g/dL).

- Adequate hepatic function defined by a total bilirubin level <= 1.5 x upper limit of normal (ULN), aspartate aminotransferase (AST) <= 2.5 x ULN, and alanine aminotransferase (ALT) <= 2.5 x ULN.

- Adequate renal function defined by an estimated glomerular filtration rate (GFR) greater than (>) 45 milliliter per minute (mL/min) according to the 4-component Modification of Diet in Renal Disease (MDRD) equation. (GFR [mL/min/1.73 m2] = 175 x serum creatinine (Scr)-1.154 x age-0.203 x 1.212 [if African American] x 0.742 [if female]).

- Documented disease progression (based on Cheson and Halleck criteria) after the most recent treatment regimen.

- The patient must also agree to pretreatment and on-treatment tumor biopsies of an affected lymph node or bone marrow aspirates if bone marrow is involved.

- Adult male and female patients aged ≥ 18 years.

Exclusion Criteria:

Previous exposure to any BTK inhibitor.

- Known central nervous system lymphoma or leukemia.

- History of Richter's transformation or prolymphocytic leukemia.

- Prior therapy with:

Anticancer treatment with chemotherapy, immunotherapy, hormonal therapy, biologic therapy, or with any other anticancer therapy within 28 days prior to Cycle 1 Day 1 (C1D1) of trial drug treatment; (6 weeks for nitrosurea or mitomycin C).

Any investigational agent within 28 days prior to C1D1 of trial drug treatment.

- Not recovered from toxicity due to prior therapy, to pretherapy status or Grade 1 or less (except alopecia).

- Received surgical intervention within 21 days prior to C1D1 of M7583 treatment or received prior allogeneic stem cell transplant or autologous bone marrow transplantation within 6 months prior to first dose of M7583.

- Current significant cardiac conduction abnormalities, including corrected QT duration (QTc) prolongation of > 480 msec or a history of past or paroxysmal atrial fibrillation or significant cardiac arrhythmia.

- A history of cardiovascular/cerebrovascular disease as follows: not fully recovered cerebral vascular accident/stroke (< 6 months prior to enrolment), myocardial infarction (less than (<) 6 months prior to enrolment), unstable angina or congestive heart failure (New York Heart Association Classification Class >= II).

- Current hypertension uncontrolled by medication.

- Concomitant treatment with non-permitted drugs, including but not limited, to warfarin or other Vitamin K antagonists.

Patients receiving medications, herbal supplements, or food known to be moderate or strong inhibitors of CYP3A within 7 days prior to the first dose of M7583, or moderate or strong inducers of CYP3A within 21 days prior to the first dose of M7583, or drugs mainly metabolized by CYP3A with a narrow therapeutic index that cannot be stopped before the first dose of trial treatment.

Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Both
Healthy Volunteers:No

Primary Outcome Measures

Measure:Part 1 (does escalation): Number of subjects with at least one dose limiting toxicity (DLT) during Cycle 1
Time Frame:Baseline up to 28 Days (Cycle 1)
Safety Issue:No
Description:DLT is defined as any of the adverse event (AEs) related to drug .Any drug related Grade 4 liver enzyme elevation; Any Grade >= 3 non-hematological AE related to drug excluding. Diarrhea of < 3 days duration following adequate & optimal therapy; Any asymptomatic Grade 3 increase in liver function tests resolving to base level in 7 days. Grade 3 skin toxicity resolving to Grade 2/ less in 7 days; Nausea & vomiting of < 3 days duration with therapy; Grade 3 hyperglycemia in patients with diabetes mellitus/decreased glucose tolerance which resolves in < 5 days with treatment; Fatigue /headache of < 7 days duration following initiation of supportive care; laboratory values out of the normal range with no clinical correlate & resolve to <=Grade 2 in 5 days with medical management; Any Grade 4 neutropenia of > 5 days duration, Grade >= 3 febrile neutropenia/Grade 4 hemoglobin decrease; Any Grade 4 thrombocytopenia/ Grade 3 thrombocytopenia with bleeding related to drug.

Secondary Outcome Measures

Measure:Part 1: Best overall response
Time Frame:Months 3 and 6
Safety Issue:No
Description:Best overall response would be assessed according to the revised International Working Group Criteria for non-Hodgkin's lymphoma and International workshop on CLL as assessed by Investigators.
Measure:Duration of response
Time Frame:Months 3 and 6
Safety Issue:No
Description:Duration of response defined as time from first response (complete response (CR) or partial response (PR) whichever is first recorded) to progressive disease based on the Investigator assessment or death from any cause within 30 days of last tumor assessment. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions
Measure:Progression- free survival time
Time Frame:Months 3 and 6
Safety Issue:No
Description:Progression free survival time defined as time from the first dose of trial treatment to progressive disease based on the Investigator assessment or death from any cause within 30 days of last tumor assessment.
Measure:Number of subjects With Adverse Events (AEs), Serious AEs, AEs Leading to Death and AEs Leading to Discontinuation
Time Frame:Screening (Day -21 to -1) up to 3 years
Safety Issue:No
Description:An adverse event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect.
Measure:Number of subjects with abnormalities in laboratory measurements, electrocardiogram (ECG)s, vital signs, and ECOG performance status
Time Frame:Screening (Day -21 to -1) up to 3 years
Safety Issue:No
Description:
Measure:Bruton's tyrosine kinase (BTK)occupancy in Peripheral blood mononuclear cell (PBMCs )
Time Frame:Screening (Day -21 to -1), Pre-dose , 2 hours post dose on Day 1, 15 ; post dose on Day 22
Safety Issue:No
Description:
Measure:Area under the plasma concentration-time curve from time zero to 8 hours after administration (AUC0 8h)
Time Frame:Predose, Hour 0.5, 1, 2, 3,4, 6, 8 post dose on Day 1 , 15 ; Hour 2 post dose on Day 22
Safety Issue:No
Description:
Measure:Maximum observed plasma concentration (Cmax)
Time Frame:Predose, Hour 0.5, 1, 2, 3,4, 6, 8 post dose on Day 1 , 15 ; Hour 2 post dose on Day 22
Safety Issue:No
Description:
Measure:Time to reach maximum plasma concentration (tmax),
Time Frame:Predose, Hour 0.5, 1, 2, 3,4, 6, 8 post dose on Day 1 , 15 ; Hour 2 post dose on Day 22
Safety Issue:No
Description:
Measure:Dose normalized Area under the Curve from time 0 to 8 hours(AUC0-8h)
Time Frame:Pre-dose, Hour 0.5, 1, 2, 3,4, 6, 8 post dose on Day 1 , 15 ; Hour 2 post dose on Day 22
Safety Issue:No
Description:Dose normalized AUC 0-8 hours is calculated as the AUC0-8 divided by dose of the drug.
Measure:Dose normalized Cmax (Cmax/dose)
Time Frame:Pre-dose, Hour 0.5, 1, 2, 3,4, 6, 8 post dose on Day 1 , 15 ; Hour 2 post dose on Day 22
Safety Issue:No
Description:
Measure:Accumulation ratio for Area under the curve AUC0-8h [Racc(AUC0-8h)]
Time Frame:Pre-dose, Hour 0.5, 1, 2, 3,4, 6, 8 post dose on Day 1 , 15 ; Hour 2 post dose on Day 22
Safety Issue:No
Description:Accumulation ratio for AUC is calculated as AUC0-8h on cycle1 Day 15 divided by AUC0-8h, on cycle 1 Day 1.
Measure:Accumulation ratio for maximum plasma concentration Cmax [Racc(Cmax)]
Time Frame:Pre-dose, Hour 0.5, 1, 2, 3,4, 6, 8 post dose on Day 1 , 15 ; Hour 2 post dose on Day 22
Safety Issue:No
Description:Accumulation ratio for Cmax is calculated as Cmax on cycle1 Day 15 divided by Cmax on cycle 1 Day 1.

Trial Keywords

  • M7583
  • Bruton's Tyrosine Kinase Inhibitor
  • Lymphoma
  • Open
  • Phase I