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Safety, PK, PD, and Antitumor Activity of ARQ 531 in Hematologic Malignancies

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03162536
Recruitment Status : Recruiting
First Posted : May 22, 2017
Last Update Posted : October 12, 2017
Information provided by (Responsible Party):

Brief Summary:
This Phase 1 dose escalation study will evaluate the safety, pharmacology, and activity of ARQ 531 in subjects with relapsed or refractory hematologic malignancies dosed orally once per day beginning at 5 mg/dose for 4 weeks with the following cohorts treating at escalating doses until a dose limiting toxicity or a recommended Phase 2 dose (RP2D) is reached. Expanded cohorts studying specific malignancies (e.g., B-cell NHL, WM, CLL) at the RP2D will be opened to further explore the safety, pharmacology, and activity of ARQ 531 as monotherapy.

Condition or disease Intervention/treatment Phase
Lymphoma, B-Cell Small Lymphocytic Lymphoma Chronic Lymphocytic Leukemia Waldenstrom Macroglobulinemia Mantle Cell Lymphoma Diffuse Large B Cell Lymphoma Drug: ARQ 531 Phase 1

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Intervention Model: Sequential Assignment
Intervention Model Description: The dose escalation phase of the study follows the 3+3 dose escalation design. Dose escalation will continue until the MTD and/or RP2D is reached based on protocol-defined DLT. Once MTD/RP2D is reached, expanded cohorts will be opened for specified malignancies (e.g., B-cell NHL, WM, and CLL).
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of ARQ 531 in Selected Subjects With Relapsed or Refractory Hematologic Malignancies
Actual Study Start Date : July 10, 2017
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : April 2019

Arm Intervention/treatment
Experimental: ARQ 531 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.

Primary Outcome Measures :
  1. 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

  2. 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.

Secondary Outcome Measures :
  1. 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

  2. Preliminary evidence of anti-tumor activity depending on specific cancer type [ Time Frame: Up to approximately 24 weeks ]
    Response rate (RR) will be assessed

  3. Characterization of Pharmacokinetics (Tmax) [ Time Frame: Up to approximately 24 weeks ]
    Time of occurrence for maximum drug concentration (Tmax)

  4. Characterization of Pharmacokinetics (Cmax) [ Time Frame: Up to approximately 24 weeks ]
    Maximum drug concentration (Cmax)

  5. Characterization of Pharmacokinetics (AUC) [ Time Frame: Up to approximately 24 weeks ]
    Area under the curve (AUC)

  6. Characterization of Pharmacokinetics (t1/2) [ Time Frame: Up to approximately 24 weeks ]
    Elimination half-life (t1/2)

  7. 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.

  8. 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

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Signed written informed consent granted prior to initiation of any study-specific procedures.
  2. 18 years of age and older.
  3. Relapsed or refractory SLL/CLL, WM, B-cell NHL who have received at least 2 prior lines of systemic therapy.
  4. Prior therapy must include a BTK inhibitor in diseases for which approved therapy includes a BTK inhibitor (i.e., SLL/CLL, WM, and mantle cell lymphoma). Subjects with DLBCL must have failed, refused, or be ineligible for autologous stem cell transplant. Subjects with low grade lymphoma must be progressing and requiring treatment.
  5. Disease status requirement:

    1. For CLL subjects, symptomatic disease that mandates treatment (Halleck et al. 2008).
    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 ≤ 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 × 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. 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:

  1. Had immunotherapy, radiotherapy, radioimmunotherapy, biological therapy, chemotherapy, or treatment with an investigational product within 4 weeks prior to treatment initiation (or oral therapy within 1 week prior to treatment initiation).
  2. Subjects who were intolerant to a BTK inhibitor
  3. Subjects currently being treated with a CYP 2C9, CYP 2C8, CYP 2C19, CYP 2D6, and P-gp substrate with a narrow therapeutic index.
  4. Prior allogeneic bone marrow transplant.
  5. Active CNS involvement
  6. Pregnant or breast-feeding women.
  7. Has significant, ongoing, co-morbid conditions which would preclude safe delivery of the study drug.
  8. 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 6 months, and psychiatric illness that would limit compliance with study requirements.
  9. QTc prolongation (defined as a QTc > 450 msecs) or other significant ECG abnormalities including 2nd degree atrioventricular (AV) block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50 beats per minute [bpm]). If the screening ECG has a QTc > 450 msecs, the ECG can be submitted for a centralized, cardiologic evaluation.
  10. Active human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C infection.
  11. 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.
  12. History of prior cancer within < 2 years, except for basal cell or squamous cell carcinoma of the skin, cervical cancer in situ or other in situ carcinomas.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03162536

Contact: ArQule, Inc. 781-994-0300

United States, Ohio
Wexner Medical Center at The Ohio State University Recruiting
Columbus, Ohio, United States, 43210
Contact    781-994-0300   
United States, Tennessee
Sarah Cannon Research Institute Recruiting
Nashville, Tennessee, United States, 37203
Contact    781-994-0300   
United States, Utah
University of Utah, Huntsman Cancer Institute Recruiting
Salt Lake City, Utah, United States, 84112
Contact    781-994-0300   
Sponsors and Collaborators

Responsible Party: ArQule Identifier: NCT03162536     History of Changes
Other Study ID Numbers: ARQ 531-101
First Posted: May 22, 2017    Key Record Dates
Last Update Posted: October 12, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by ArQule:
ARQ 531
Hematologic Malignancies
B-cell NHL

Additional relevant MeSH terms:
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, B-Cell
Lymphoma, Mantle-Cell
Lymphoma, Large B-Cell, Diffuse
Waldenstrom Macroglobulinemia
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Lymphoma, Non-Hodgkin
Neoplasms, Plasma Cell
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders