Clinical Trials /

A Study of ARQ 531 in Patients With Selected Hematologic Malignancies

NCT03162536

Description:

This is an open-label, multi-center Phase 1/2 study of ARQ 531 in patients with selected hematologic malignancies.

Related Conditions:
  • B-Cell Non-Hodgkin Lymphoma
  • Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
  • Diffuse Large B-Cell Lymphoma
  • Grade 1 Follicular Lymphoma
  • Grade 2 Follicular Lymphoma
  • Grade 3 Follicular Lymphoma
  • High Grade B-Cell Lymphoma with MYC and BCL2 and/or BCL6 Rearrangements
  • Mantle Cell Lymphoma
  • Marginal Zone Lymphoma
  • Richter Syndrome
  • Waldenstrom Macroglobulinemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of ARQ 531 in Patients With Selected Hematologic Malignancies
  • 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

Clinical Trial IDs

  • ORG STUDY ID: 1026-001
  • SECONDARY ID: ARQ 531-101
  • NCT ID: NCT03162536

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

Interventions

DrugSynonymsArms
ARQ 531Phase I : Dose Escalation and Determination of RP2D
ARQ 531Food Effect Cohort: B-cell NHL, CLL/SLL and WM Patients

Purpose

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 9 cohorts depending on tumor histology and prior treatment
      history. Cycle length will be 28 days.
    

Trial Arms

NameTypeDescriptionInterventions
Phase I : Dose Escalation and Determination of RP2DExperimentalPhase I : Dose Escalation and determination of RP2D, multiple dose levels of ARQ 531 to be evaluated
  • ARQ 531
Phase II : Relapsed/Refractory (R/R) CLL/SLL subjectsExperimentalPhase 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
  • ARQ 531
Phase II : R/R CLL/SLL SubjectsExperimentalPhase 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
  • ARQ 531
Phase II : Richter's Transformation SubjectsExperimentalPhase II : Richter's transformation subjects who have failed at least one prior therapy
  • ARQ 531
Phase II : Follicular Lymphoma (FL) SubjectsExperimentalPhase II : Follicular Lymphoma (FL) subjects who have failed at least 2 prior systemic therapies and are histology grade 1, 2, or 3A
  • ARQ 531
Phase II : Mantle Cell Lymphoma (MCL) SubjectsExperimentalPhase II : Mantle Cell Lymphoma (MCL) subjects who have failed at least 2 prior systemic therapies
  • ARQ 531
Phase II : Marginal Zone Lymphoma (MZL) SubjectsExperimentalPhase II : Marginal Zone Lymphoma (MZL) subjects who have failed at least 2 prior systemic therapies
  • ARQ 531
Phase II : High-grade B-cell Lymphoma SubjectsExperimentalPhase 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
  • ARQ 531
Phase II : Waldenström macroglobulinemia (WM) SubjectsExperimentalPhase II : Waldenström macroglobulinemia (WM) subjects who have failed at least 2 prior systemic therapies
  • ARQ 531
Food Effect Cohort: B-cell NHL, CLL/SLL and WM PatientsExperimentalFood Effect Cohort: B-cell NHL, CLL/SLL and WM patients
  • ARQ 531

Eligibility Criteria

        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 and 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
                  confirmed by FISH or overexpression by IHC.

               -  Cohort H: Waldenström macroglobulinemia (WM) subjects who have failed at least 2
                  prior systemic therapies.

               -  Cohort I (Food Effect): 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.

          5. Disease status requirement:

               1. For CLL subjects, symptomatic disease that mandates treatment (Hallek 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 ≥ 30 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. Subjects with platelet count ≥ 25,000/μL can be
                  enrolled in study as long as bone marrow biopsy demonstrates thrombocytopenia due
                  to marrow infiltration.

               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. For women of child-bearing potential and male subjects with a non-pregnant female
             partner of child-bearing potential, willing to use highly effective birth control for
             the duration of the study and for 90 days following the last dose of study drug.

         10. Female subjects of child-bearing potential must have a negative serum pregnancy test
             within 14 days of the first day of drug dosing.

         11. 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:

          1. Had immunotherapy, radiotherapy, radioimmunotherapy, biological therapy, chemotherapy,
             or treatment with an investigational product within 5 half-lives or ≤ four weeks (28
             days) (whichever is shorter) prior to treatment initiation, or oral therapy within 5
             half-lives or one week (whichever is shorter) prior to treatment initiation.

             a. For subjects at high risk for disease flare up on discontinuation of previous
             therapy (e.g. covalent BTK inhibitor), upon discussion with the medical monitor the
             washout period may be waived and ARQ 531 started 1 day following cessation of previous
             therapy.

          2. Subjects with FL who have transformed to a more aggressive subtype of lymphoma or
             grade 3b FL (For cohort D only).

          3. 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.

          4. Prior allogeneic bone marrow transplant.

          5. Active central nervous system (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), uncontrolled significant arrhythmia, or a history of unstable
             angina pectoris or cardiac infarction in the past six months, and psychiatric illness
             that would limit compliance with study requirements.

          9. QTcF prolongation (defined as a QTcF > 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 QTcF > 450 msecs, the ECG can be submitted for
             a centralized, cardiologic evaluation.

         10. Active 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 < 1 year, except for basal cell or squamous cell
             carcinoma of the skin, cervical cancer in situ or other in situ carcinomas.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended Phase 2 dose (RP2D) of ARQ 531.
Time Frame:Up to the first 28 days (1 cycle) of therapy.
Safety Issue:
Description:RP2D is defined as the dose level at which no more than one out of six subjects has an observable dose limiting toxicity (DLT).

Secondary Outcome Measures

Measure:Incidence of treatment emergent adverse events graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) guidelines.
Time Frame:From the moment when a subject takes the first dose of ARQ 531 to 30-days after the last dose of ARQ 531.
Safety Issue:
Description:
Measure:Assess the time of occurrence for maximum drug concentration (Tmax) of the pharmacokinetic (PK) profile of ARQ 531
Time Frame:Cycle 1 Day 1 (C1D1) (each cycle is 28 days), C1D2, C2D1, C2D2, C3D1
Safety Issue:
Description:
Measure:Assess the peak plasma concentration (Cmax) of the pharmacokinetic (PK) profile of ARQ 531
Time Frame:Cycle 1 Day 1 (C1D1) (each cycle is 28 days), C1D2, C2D1, C2D2, C3D1
Safety Issue:
Description:
Measure:Assess the area under the plasma concentration vs. time curve (AUC) of the pharmacokinetic (PK) profile of ARQ 531
Time Frame:Cycle 1 Day 1 (C1D1) (each cycle is 28 days), C1D2, C2D1, C2D2, C3D1
Safety Issue:
Description:
Measure:Assess the half-life of ARQ 531 of the pharmacokinetic (PK) profile of ARQ 531
Time Frame:Cycle 1 Day 1 (C1D1) (each cycle is 28 days), C1D2, C2D1, C2D2, C3D1
Safety Issue:
Description:
Measure:Overall response rate (ORR) in patients with lymphoma assessed by The Lugano Classification and patients with Waldenstrom's maacroglobulinemia assessed by Guidelines on the diagnosis and management of Waldenström macroglobulinaemia
Time Frame:Approximately 6 months (6 cycles, each cycle is 28 days).
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:ArQule

Trial Keywords

  • ARQ 531
  • Hematologic Malignancies
  • SLL
  • CLL
  • B-cell NHL
  • WM
  • BTK (Bruton's 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-Hodgkin's Lymphoma)
  • ONO-4059
  • Paraproteinemias
  • Small Lymphocytic Lymphoma
  • Tirabrutinib
  • Vascular Diseases
  • Waldenstrom Macroglobulinemia
  • Zanubrutinib

Last Updated

July 13, 2020