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A Study of ARQ 531 in Patients With Selected Hematologic Malignancies

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ClinicalTrials.gov Identifier: NCT03162536
Recruitment Status : Recruiting
First Posted : May 22, 2017
Last Update Posted : May 3, 2021
Sponsor:
Information provided by (Responsible Party):
ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)

Tracking Information
First Submitted Date  ICMJE May 15, 2017
First Posted Date  ICMJE May 22, 2017
Last Update Posted Date May 3, 2021
Actual Study Start Date  ICMJE June 26, 2017
Estimated Primary Completion Date September 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 4, 2020)
  • Phase 1/2 : To determine the recommended Phase 2 dose (RP2D) and schedule of ARQ 531 for treatment of selected subjects with relapsed or refractory hematologic malignancies [ Time Frame: Up to approximately 28 weeks ]
  • Phase 1/2 : To assess the safety and tolerability of ARQ 531 in selected subjects with relapsed or refractory hematologic malignancies [ Time Frame: Up to approximately 24 weeks ]
    dose. If 2 or more treated subjects at a dose level experience a DLT before Day 29, dose escalation will stop and the prior dose level will be considered the MTD for that schedule.
Original Primary Outcome Measures  ICMJE
 (submitted: May 19, 2017)
  • Safety and tolerability of ARQ 531 as assessed by adverse events [ Time Frame: Up to approximately 28 weeks ]
    Adverse events will be graded using NCI CTCAE guidelines, version 4.03
  • RP2D and dosing schedule of ARQ 531 [ Time Frame: Up to approximately 24 weeks ]
    The RP2D may be the maximum tolerated dose (MTD) or may be a lower dose. If 2 or more treated subjects at a dose level experience a DLT before Day 29, dose escalation will stop and the prior dose level will be considered the MTD for that schedule.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 4, 2020)
  • Phase 1: Characterization of Pharmacokinetics (Tmax) [ Time Frame: Up to approximately 24 weeks ]
    Time of occurrence for maximum drug concentration (Tmax)
  • Phase 1: Characterization of Pharmacokinetics (Cmax) [ Time Frame: Up to approximately 24 weeks ]
    Maximum drug concentration (Cmax)
  • Phase 1: Characterization of Pharmacokinetics (AUC) [ Time Frame: Up to approximately 24 weeks ]
    Area Under the Curve (AUC)
  • Phase 1: Characterization of Pharmacokinetics (t1/2) [ Time Frame: Up to approximately 24 weeks ]
    Elimination half-life (t1/2)
  • Phase 2: Preliminary evidence of anti-tumor activity, in terms of Objective Response Rate (ORR) [ Time Frame: Up to approximately 24 weeks ]
  • Phase 2 : Preliminary evidence of anti-tumor activity, in terms of Duration of Response (DOR) [ Time Frame: Up to approximately 24 weeks ]
Original Secondary Outcome Measures  ICMJE
 (submitted: May 19, 2017)
  • Preliminary evidence of anti-tumor activity depending on specific cancer type [ Time Frame: Up to approximately 24 weeks ]
    Progression free survival (PFS) will be assessed
  • Preliminary evidence of anti-tumor activity depending on specific cancer type [ Time Frame: Up to approximately 24 weeks ]
    Response rate (RR) will be assessed
  • Characterization of Pharmacokinetics (Tmax) [ Time Frame: Up to approximately 24 weeks ]
    Time of occurrence for maximum drug concentration (Tmax)
  • Characterization of Pharmacokinetics (Cmax) [ Time Frame: Up to approximately 24 weeks ]
    Maximum drug concentration (Cmax)
  • Characterization of Pharmacokinetics (AUC) [ Time Frame: Up to approximately 24 weeks ]
    Area Under the Curve (AUC)
  • Characterization of Pharmacokinetics (t1/2) [ Time Frame: Up to approximately 24 weeks ]
    Elimination half-life (t1/2)
  • Pharmacodynamic activity in blood samples [ Time Frame: Up to approximately 24 weeks ]
    Paired blood samples will be used to assess changes in phosphorylated-BTK (p-BTK) and BTK in peripheral blood mononuclear cells (PBMC) in blood.
  • Pharmacodynamic activity in tissue samples [ Time Frame: Up to approximately 24 weeks ]
    Paired tissue samples may be used to assess changes in p-BTK and BTK in tumor cells
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of ARQ 531 in Patients With Selected Hematologic Malignancies
Official Title  ICMJE 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
Brief Summary This is an open-label, multi-center Phase 1/2 study of ARQ 531 in patients with selected hematologic malignancies.
Detailed Description This study includes 2 parts: phase 1 (dose escalation) and phase 2 (dose expansion). In phase 1, patients were enrolled using 3+3 dose escalation design. The starting dose of ARQ 531 in oral tablet form was 5mg/day continuously. The RP2D has been determined at 65mg/day, patients will be enrolled to one of 8 cohorts depending on tumor histology and prior treatment history. Cycle length will be 28 days.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
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.)
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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
Intervention  ICMJE
  • Drug: ARQ 531
    ARQ 531 will be orally administered once per day under fasted conditions (1 hour prior to or 2 hours after a meal) and is available in tablets in strengths of 5 mg or 20 mg.
  • Drug: ARQ 531
    ARQ 531 will be orally administered once per day under fasted conditions (1 hour prior to or 2 hours after a meal), or non-fasted conditions and is available in tablets in strengths of 5 mg or 20 mg.
Study Arms  ICMJE
  • Experimental: Phase I : Dose Escalation and Determination of RP2D
    Phase I : Dose Escalation and determination of RP2D, multiple dose levels of ARQ 531 to be evaluated
    Intervention: Drug: ARQ 531
  • Experimental: Phase II : Relapsed/Refractory (R/R) CLL/SLL subjects
    Phase II : Relapsed/Refractory (R/R) CLL/SLL subjects with at least 2 prior systemic therapies and previously treated with a covalent Bruton's tyrosine kinase inhibitor (BTKi) who must have a documented BTK mutation on C481 residue
    Intervention: Drug: ARQ 531
  • Experimental: Phase II : R/R CLL/SLL Subjects
    Phase II : R/R CLL/SLL subjects who have failed or were intolerant to a BTKi with documentation of the absence of BTK mutation on C481 residue
    Intervention: Drug: ARQ 531
  • Experimental: Phase II : Richter's Transformation Subjects
    Phase II : Richter's transformation subjects who have failed at least one prior therapy
    Intervention: Drug: ARQ 531
  • Experimental: Phase II : Follicular Lymphoma (FL) Subjects
    Phase II : Follicular Lymphoma (FL) subjects who have failed at least 2 prior systemic therapies and are histology grade 1, 2, or 3A
    Intervention: Drug: ARQ 531
  • Experimental: Phase II : Mantle Cell Lymphoma (MCL) Subjects
    Phase II : Mantle Cell Lymphoma (MCL) subjects who have failed at least 2 prior systemic therapies
    Intervention: Drug: ARQ 531
  • Experimental: Phase II : Marginal Zone Lymphoma (MZL) Subjects
    Phase II : Marginal Zone Lymphoma (MZL) subjects who have failed at least 2 prior systemic therapies
    Intervention: Drug: ARQ 531
  • Experimental: Phase II : High-grade B-cell Lymphoma Subjects
    Phase II : High-grade B-cell lymphoma subjects who have failed at least 2 prior systemic therapies and have known MYC and BCL2 and/or BCL6 translocations
    Intervention: Drug: ARQ 531
  • Experimental: Phase II : Waldenström macroglobulinemia (WM) Subjects
    Phase II : Waldenström macroglobulinemia (WM) subjects who have failed at least 2 prior systemic therapies
    Intervention: Drug: ARQ 531
  • Experimental: Food Effect Cohort: B-cell NHL, CLL/SLL and WM Patients
    Food Effect Cohort: B-cell NHL, CLL/SLL and WM patients
    Intervention: Drug: ARQ 531
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 4, 2020)
146
Original Estimated Enrollment  ICMJE
 (submitted: May 19, 2017)
120
Estimated Study Completion Date  ICMJE September 1, 2022
Estimated Primary Completion Date September 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria

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

  1. Signed written informed consent granted prior to initiation of any study-specific procedures.
  2. 18 years of age and older.
  3. For the dose escalation cohorts, relapsed or refractory subjects with a diagnosis of B-cell NHL, CLL/SLL and WM who have received at least two prior systemic therapies . Subjects must have failed or are intolerant to standard therapies and cannot be a candidate for standard salvage regimens. Subjects with low grade lymphoma must be progressing and requiring treatment..
  4. For the expansion cohorts, the following criteria must be met:

    • Cohort A: Relapsed/Refractory (R/R) CLL/SLL subjects with at least 2 prior systemic therapies and previously treated with a covalent BTKi who must have a documented BTK mutation on C481 residue
    • Cohort B: R/R CLL/SLL subjects 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 subjects who have failed at least one prior therapy
    • Cohort D: Follicular Lymphoma (FL) subjects who have failed at least 2 prior systemic therapies and are histology grade 1, 2, or 3A
    • Cohort E: Mantle Cell Lymphoma (MCL) subjects who have failed at least 2 prior systemic therapies
    • Cohort F: Marginal Zone Lymphoma (MZL) subjects who have failed at least 2 prior systemic therapies
    • Cohort G: High-grade B-cell lymphoma subjects who have failed at least 2 prior systemic therapies and have known MYC and BCL2 and/or BCL6 translocations
    • Cohort H: Waldenström macroglobulinemia (WM) subjects who have failed at least 2 prior systemic therapies
  5. Disease status requirement:

    1. For CLL subjects, symptomatic disease that mandates treatment (Hallek et al. 2018).
    2. For B-cell NHL subjects, measurable disease by imaging scan.
    3. For WM, serum immunoglobulin M (IgM) with a minimum IgM level of ≥ 2 times the upper limit of normal (ULN).
  6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
  7. Good organ function

    1. Creatinine clearance of ≥ 60 mL/min as estimated by the Cockcroft-Gault equation or by 24-hour urine collection.
    2. Total bilirubin ≤ 1.5 x institutional ULN (total bilirubin of ≤ 3 x institutional ULN in subjects with documented Gilbert's syndrome).
    3. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × institutional ULN.
    4. Platelet count ≥ 50,000/µL
    5. Absolute neutrophil count (ANC) ≥ 1000/µL.
    6. Hemoglobin (Hgb) ≥ 8.0 g/dL, stable for ≥ 1 week.
  8. 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.
  9. Female subjects of child-bearing potential must have a negative serum pregnancy test within 14 days of the first day of drug dosing.
  10. Ability to swallow oral medications without difficulty.

    Exclusion Criteria

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

  11. 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.
  12. Transformation of FL to a more aggressive subtype of lymphoma or grade 3b FL
  13. Subjects currently being treated with the following drugs:

    1. CYP 2C9 substrates with a narrow therapeutic index (such as warfarin, phenytoin)
    2. CYP 2C8 substrates with a narrow therapeutic index (such as paclitaxel)
    3. CYP 2C19 substrates with a narrow therapeutic index (such as S-mephenytoin)
    4. CYP 2D6 substrates with a narrow therapeutic index (such as thioridazine, pimozide)
    5. P-gp substrates with a narrow therapeutic index (such as digoxin) 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 subject to be eligible for study enrollment.
  14. Prior allogeneic bone marrow transplant.
  15. Active central nervous system (CNS) involvement.
  16. Pregnant or breast-feeding women.
  17. Has significant, ongoing co-morbid conditions which would preclude safe delivery of the study drug.
  18. 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.
  19. 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). If the screening ECG has a QTc > 450 msecs, the ECG can be submitted for a centralized, cardiologic evaluation.
  20. Active human immunodeficiency virus (HIV) infection, Hepatitis B, or Hepatitis C infection.
  21. Other medical or psychiatric illness or organ dysfunction which, in the opinion of the Investigator, would either compromise the subject's safety or interfere with the evaluation of the safety of the study agent.
  22. 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Toll Free Number 1-888-577-8839 Trialsites@merck.com
Listed Location Countries  ICMJE United States
Removed Location Countries Israel,   Italy
 
Administrative Information
NCT Number  ICMJE NCT03162536
Other Study ID Numbers  ICMJE 1026-001
ARQ 531-101 ( Other Identifier: ArQule Protocol Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php
Responsible Party ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
Study Sponsor  ICMJE ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Merck Sharp & Dohme Corp.
PRS Account ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP