Clinical trial NCT03162536: A Study of Nemtabrutinib (MK-1026) in Participants With Relapsed or Refractory Hematologic Malignancies (ARQ 531-101/MK-1026-001)
Official title: A Phase 1/2 Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of ARQ 531 in Selected Subjects With Relapsed or Refractory Hematologic Malignancies
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Lymphoma, B-Cell
Small Lymphocytic Lymphoma
Chronic Lymphocytic Leukemia
Waldenstrom Macroglobulinemia
Mantle Cell Lymphoma
Diffuse Large B Cell Lymphoma
Richter's Transformation
Follicular Lymphoma
Marginal Zone Lymphoma
Keywords: nemtabrutinib
Hematologic Malignancies
SLL
CLL
B-cell NHL
WM
BTK (Brutons tyrosine kinase)
cancer
refractory
relapsed
Acalabrutinib
ArQule
BGB-3111
Blood Protein Disorders
Follicular Lymphoma
BTK Intolerant
C481
C481S
C481S Mutation
Cardiovascular Diseases
Chronic Lymphocytic Leukemia
DLBCL (Diffuse Large B-cell lymphoma)
GS-4059
Hemorrhagic Disorders
Hemostatic Disorders
Ibrutinib
Immune System Diseases
Immunoproliferative Disorders
Leukemia
Leukemia, B-Cell
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Lymphatic Diseases
Lymphoma
Lymphoma, B-Cell
Lymphoma, B-Cell, Marginal Zone
Lymphoma, Mantle-Cell
Lymphoma, Non-Hodgkin
Lymphoproliferative Disorders
Mantle Cell Lymphoma
Marginal zone lymphoma
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Plasma Cell
NHL (Non-Hodgkins Lymphoma)
ONO-4059
Paraproteinemias
Small Lymphocytic Lymphoma
Tirabrutinib
Vascular Diseases
Waldenstrom Macroglobulinemia
Zanubrutinib
Lead sponsor: ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA)
Sponsor class: INDUSTRY
First posted: 2017-05-22
Enrollment: 190
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Intervention model description: Single group assignment (definition : A type of intervention model describing a clinical trial in which all participants receive the same intervention/treatment.)
Primary purpose: TREATMENT

Brief summary: This study aims to evaluate the safety, tolerability, pharmacodynamic, and pharmacokinetic (PK) of nemtabrutinib (formerly ARQ 531) tablets in selected participants with relapsed or refractory hematologic malignancies. No formal hypothesis testing will be performed for this study.

Detailed description: This study includes 2 parts: Phase 1 (dose escalation) and Phase 2 (dose expansion). In Phase 1, participants will enroll using 3+3 dose escalation design. The starting dose of nemtabrutinib in oral tablet form was 5mg/day continuously. Dose escalation will continue until the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) and dosing schedule is reached based on protocol-defined dose limiting toxicity (DLT). After the determination of the RP2D, 9 expansion cohorts will be initiated to evaluate the safety, tolerability, and efficacy of nemtabrutinib at RP2D in participants with specifically defined disease.

Eligibility criteria: Inclusion Criteria

Each prospective participant must meet ALL of the following inclusion criteria in order to be eligible for this study:

* Signed written informed consent granted prior to initiation of any study-specific procedures
* For the dose escalation cohorts, relapsed or refractory (R/R) participants with a diagnosis of B-cell Non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL) and Waldenstrom macroglobulinemia (WM) who have received at least two prior systemic therapies . Participants must have failed or are intolerant to standard therapies and cannot be a candidate for standard salvage regimens. Participants with low grade lymphoma must be progressing and requiring treatment
* For the expansion cohorts, the following criteria must be met:

  * Cohort A: R/R CLL/SLL participants with at least 2 prior systemic therapies and previously treated with a covalent Bruton's tyrosine kinase inhibitor (BTKi) who must have a documented Bruton's tyrosine kinase (BTK) mutation on C481 residue
  * Cohort B: R/R CLL/SLL participants who have failed or were intolerant to a BTKi with documentation of the absence of BTK mutation on C481 residue. In this study, intolerance to standard therapy is defined as having experienced a grade 3 or higher adverse event that was caused by the standard therapy and resulted in treatment discontinuation
  * Cohort C: Richter's transformation (RT) participants who have failed at least one prior therapy
  * Cohort D: Follicular Lymphoma (FL) participants who have failed at least 2 prior systemic therapies and are histology grade 1, 2, or 3A
  * Cohort E: Mantle Cell Lymphoma (MCL) participants who have failed at least 2 prior systemic therapies
  * Cohort F: Marginal Zone Lymphoma (MZL) participants who have failed at least 2 prior systemic therapies
  * Cohort G: High-grade B-cell lymphoma participants who have failed at least 2 prior systemic therapies and have known MYC and BCL2 and/or BCL6 translocations
  * Cohort H: WM participants who have failed at least 2 prior systemic therapies
  * Cohort I (Food Effect): relapsed or refractory participants with a diagnosis of B-cell NHL, CLL/SLL or WM who have received at least 2 prior systemic therapies, or 1 prior therapy for RT participants. Participants must have failed or are intolerant to standard therapies and cannot be a candidate for standard salvage regimens. Participants with low grade lymphoma must be progressing and requiring treatment.
* Disease status requirement:

  * For CLL participanst symptomatic disease that mandates treatment (Hallek et al. 2018)
  * For B-cell NHL participants, measurable disease by imaging scan
  * For WM, serum immunoglobulin M (IgM) with a minimum IgM level of ≥ 2 times the upper limit of normal (ULN)
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
* Good organ function
* Creatinine clearance of ≥ 60 mL/min as estimated by the Cockcroft-Gault equation or by 24-hour urine collection
* Total bilirubin ≤ 1.5 x institutional ULN (total bilirubin of ≤ 3 x institutional ULN in participants with documented Gilbert's syndrome)
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × institutional ULN
* Platelet count ≥ 50,000/µL
* Absolute neutrophil count (ANC) ≥ 1000/µL
* Hemoglobin (Hgb) ≥ 8.0 g/dL, stable for ≥ 1 week.
* For men and women of child-bearing potential, willing to use adequate contraception (e.g., latex condom, cervical cap, diaphragm, abstinence, etc.) for the entire duration of the study
* Female participants of child-bearing potential must have a negative serum pregnancy test within 14 days of the first day of drug dosing
* Ability to swallow oral medications without difficulty

Exclusion Criteria

Potential participants who meet ANY of the following exclusion criteria are not eligible for enrollment into this study:

* Had immunotherapy, radiotherapy, radioimmunotherapy, biological therapy, chemotherapy, or treatment with an investigational product within 5 half-lives or four weeks (whichever is shorter) prior to treatment initiation, or oral therapy within 5 half-lives or one week (whichever is shorter) prior to treatment initiation
* Transformation of follicular lymphoma (FL) to a more aggressive subtype of lymphoma or grade 3b FL
* Participants currently being treated with the following drugs:

  * CYP2C8 substrates with a narrow therapeutic index (such as paclitaxel)
  * P-gp substrates with a narrow therapeutic index (such as digoxin)
  * CYP3A strong inducers (such as rifampin) Note: A washout period of at least 5 times the half-life after the last dose of any of the above treatments is required for a participant to be eligible for study enrollment
* Active central nervous system (CNS) involvement
* Pregnant or breast-feeding women
* Has significant, ongoing co-morbid conditions which would preclude safe delivery of the study drug
* Uncontrolled illness including but not limited to ongoing or active infection, symptomatic congestive heart failure (New York Heart Association \[NYHA\] Class III or IV heart failure), unstable angina pectoris, cardiac arrhythmia, cardiac infarction in the past six months, and psychiatric illness that would limit compliance with study requirements
* QT corrected (QTc) prolongation (defined as a QTc \> 450 msecs) or other significant electrocardiogram (ECG) abnormalities including 2nd degree atrioventricular (AV) block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50 beats/min).
* Active Hepatitis B or Hepatitis C infection.
* Other medical or psychiatric illness or organ dysfunction which, in the opinion of the Investigator, would either compromise the participant's safety or interfere with the evaluation of the safety of the study agent
* History of prior cancer within \< 1 year, except for basal cell or squamous cell carcinoma of the skin, cervical cancer in situ or other in situ carcinomas

Primary outcomes:
measure: Phase 1: Number of Participants Experiencing Dose Limiting Toxicity (DLT)
timeFrame: Cycle 1 (up to 28 days)
measure: Phase 1: Number of Participants Who Experienced an Adverse Event (AE)
timeFrame: Up to approximately 86 months
measure: Phase 1: Number of Participants Who Discontinued Study Treatment Due to an AE
timeFrame: Up to approximately 86 months
measure: Phase 2: Expansion Cohorts A, B & C: Objective Response Rate (ORR) per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Criteria as Assessed by the Investigator
timeFrame: Up to approximately 64 months
measure: Phase 2: Expansion Cohorts A, B, C: ORR per Lugano Classification as Assessed by the Investigator
timeFrame: Up to approximately 64 months
Secondary outcomes:
measure: Phase 2: Number of Participants Who Experienced an AE
timeFrame: Up to approximately 64 months
measure: Phase 2: Number of Participants Who Discontinued Study Treatment Due to an AE
timeFrame: Up to approximately 64 months
measure: Time to Maximum Concentration (Tmax) of Nemtabrutinib
timeFrame: Cycles 1-92: Days 1, 2: Predose and up to 16 hours postdose (each cycle length = 28 days, up to approximately 86 months)
measure: Maximum Concentration (Cmax) of Nemtabrutinib
timeFrame: Cycles 1-92: Days 1, 2: Predose and up to 16 hours postdose (each cycle length = 28 days, up to approximately 86 months)
measure: Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC 0-24hrs)of Nemtabrutinib
timeFrame: Cycles 1-92: Days 1, 2: Predose and up to 24 hours postdose (each cycle length = 28 days, up to approximately 86 months)
measure: Terminal Elimination Half-Life (t1/2) of Nemtabrutinib
timeFrame: Cycles 1-92: Days 1, 2: Predose and up to 16 hours postdose (each cycle length = 28 days, up to approximately 86 months)
measure: Phase 2: Expansion Cohorts D-H: ORR per iwCLL Criteria as Assessed by the Investigator
timeFrame: Up to approximately 64 months
measure: Phase 2: Expansion Cohorts D-H: ORR per Lugano classification as Assessed by the Investigator
timeFrame: Up to approximately 64 months
measure: Phase 2: Expansion Cohorts A, B, H: Duration of Response (DOR) per iwCLL Criteria as Assessed by the Investigator
timeFrame: Up to approximately 64 months
measure: Phase 2: Expansion Cohorts C-G: DOR per Laguna Classification As Assessed by Investiigator
timeFrame: Up to approximately 64 months
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic Hospital ( Site 0140)
state: Arizona
city: Los Angeles
country: United States
facility: UCLA Hematology & Oncology ( Site 0017)
state: California
city: Denver
country: United States
facility: Colorado Blood Cancer Institute ( Site 0225)
state: Colorado
city: Ann Arbor
country: United States
facility: University of Michigan ( Site 0018)
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic - Rochester ( Site 0138)
state: Minnesota
city: Durham
country: United States
facility: Duke Cancer Center ( Site 0067)
state: North Carolina
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center ( Site 0056)
state: Ohio
city: Nashville
country: United States
facility: Tennessee Oncology, PLLC ( Site 0020)
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern Medical Center ( Site 0116)
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah, Huntsman Cancer Institute ( Site 0122)
state: Utah
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Woyach JA, Stephens DM, Flinn IW, Bhat SA, Savage RE, Chai F, Eathiraj S, Reiff SD, Muhowski EM, Granlund L, Szuszkiewicz L, Wang W, Schwartz B, Ghori R, Farooqui MZH, Byrd JC. First-in-Human Study of the Reversible BTK Inhibitor Nemtabrutinib in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia and B-Cell Non-Hodgkin Lymphoma. Cancer Discov. 2024 Jan 12;14(1):66-75. doi: 10.1158/2159-8290.CD-23-0670.
citation: Kipps TJ. Mining the Microenvironment for Therapeutic Targets in Chronic Lymphocytic Leukemia. Cancer J. 2021 Jul-Aug 01;27(4):306-313. doi: 10.1097/PPO.0000000000000536.