BTK Inhibitor in B Cell Malignancies

Overview

M7583 is an investigational drug that is being evaluated for the treatment of participants 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 participants 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).

Full Title of Study: “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”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Sequential Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: September 1, 2021

Interventions

  • Drug: M7583
    • All participants who received M7583 80/160 mg or 300 mg or 600 mg or 900 mg PiC orally OD or 300 mg BID in fasted state for 28 days in each 28 day cycle until disease progression, withdrawal of consent, or discontinuation from the study.

Arms, Groups and Cohorts

  • Experimental: M7583 80/160 mg QD
    • Participants received M7583 80 mg powder in capsule (PiC) orally once daily (OD) for 3 days followed by M7583 160 mg OD in fasted state for 28 days in each 28 day cycle until disease progression, withdrawal of consent, or discontinuation from the study.
  • Experimental: M7583 300 mg QD
    • Participants received M7583 300 mg PiC orally OD in fasted state for 28 days in each 28 day cycle until disease progression, withdrawal of consent, or discontinuation from the study.
  • Experimental: M7583 600 mg QD
    • Participants received M7583 600 mg PiC orally OD in fasted state for 28 days in each 28 day cycle until disease progression, withdrawal of consent, or discontinuation from the study.
  • Experimental: M7583 300 mg BID
    • Participants received M7583 300 mg PiC orally twice daily (BID) in fasted state for 28 days in each 28 day cycle until disease progression, withdrawal of consent, or discontinuation from the study.
  • Experimental: M7583 900 mg QD
    • Participants received M7583 900 mg PiC orally OD in fasted state for 28 days in each 28 day cycle until disease progression, withdrawal of consent, or discontinuation from the study.

Clinical Trial Outcome Measures

Primary Measures

  • 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)
    • 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.
  • Part 2 (dose expansion): Best Overall Response (BOR)
    • Time Frame: Baseline up to 6 months
    • 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 and Owen criteria for Waldenstrӧm macroglobulinaemia (WM).

Secondary Measures

  • Part 1 and 2: Best Overall Response
    • Time Frame: Months 3 and 6
    • 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.
  • Part 1 and 2: Duration of Response
    • Time Frame: Months 3 and 6
    • 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
  • Part 1 and 2: Progression-free Survival Time
    • Time Frame: Months 3 and 6
    • 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.
  • Part 1 and 2: 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
    • 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.
  • Part 1 and 2: 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
  • Part 1 and 2: 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
  • Part 1 and 2: Area Under the Plasma Concentration-time Curve From Time Zero to 8 Hours After Administration (AUC 0-8h)
    • 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
  • Part 1 and 2: 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
  • Part 1 and 2: 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
  • Part 1 and 2: Dose Normalized Area Under the Curve From Time 0 to 8 hours (AUC 0-8h/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
    • Dose normalized AUC 0-8 hours is calculated as the AUC0-8 divided by dose of the drug.
  • Part 1 and 2: 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
  • Part 1 and 2: 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
    • Accumulation ratio for AUC is calculated as AUC0-8h on cycle1 Day 15 divided by AUC0-8h, on cycle 1 Day 1.
  • Part 1 and 2: 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
    • Accumulation ratio for Cmax is calculated as Cmax on cycle1 Day 15 divided by Cmax on cycle 1 Day 1.

Participating in This Clinical Trial

Inclusion Criteria

  • Participants population In the dose escalation cohorts: Participants with pathologically confirmed B cell malignancy (i.e. DLBCL, CLL, small lymphocytic lymphoma [SLL], follicular lymphoma [FL], mantle cell lymphoma (MCL), Morbus Waldenström [MW], Marginal zone lymphoma [MZL], with at least 1, but not more than 3 prior lines of therapy
  • In the dose expansion cohort: Participants 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 2007
  • 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 criteria 2007 for NHL, except MW, Hallek criteria for CLL, and Owen criteria for Morbus Waldenstrӧm [MW]) and Halleck criteria) after the most recent treatment regimen
  • The participant 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 participants 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 study 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, or any prior allogenic stem cell transplant
  • 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, and anti-patelet agents (e.g. aspirin) Participants 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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • EMD Serono Research & Development Institute, Inc.
  • Collaborator
    • Merck KGaA, Darmstadt, Germany
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Medical Responsible, Study Director, Merck KGaA, Darmstadt, Germany

Citations Reporting on Results

Eugenio Gaudio, Chiara Tarantelli, Emanuele Zucca, Davide Rossi, Anastasios Stathis, Francesco Bertoni. The two novel BTK-inhibitors M2951 and M7583 show in vivo anti-tumor activity in pre-clinical models of B cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4182. doi:10.1158/1538-7445.AM2017-4182

Samantha M. Goodstal, Jianguo Ma, Jing Lin, Timothy Crandall, Lindsey Crowley, Andrew Bender, Riham Iadevaia and Anderson Clark. M7583 Is a Highly Selective and Potent Second Generation BTK Inhibitor for Treatment of B-Cell Malignancies. Blood 2017 130:3845.

Wojciech Jurczak, Simon Rule, William Townsend, David Tucker, Martin Dyroff, Barbara Sarholz, Jürgen Scheele, John G. Gribben and Pier Luigi Zinzani. First in Human, Phase I/II Trial of the Bruton's Tyrosine Kinase Inhibitor (BTKi) M7583 in Patients with B Cell Malignancies: Study Design and Initial Outcomes. Blood 2017 130:2778.

Simon Rule, David Tucker, Anup Kalapur, Barbara Sarholz, Jürgen Scheele, Pier Luigi Zinzani. Phase I/II, first in human trial of the Bruton's tyrosine kinase inhibitor (BTKi) M7583 in patients with B cell malignancies. J Clin Oncol 35, 2017 (suppl; abstr e14101).

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