A Study of ARQ 531 in Patients With Selected Hematologic Malignancies
A Study of ARQ 531 in Patients With Selected Hematologic Malignancies
This is an open-label, multi-center Phase 1/2 study of ARQ 531 in patients with selected
 hematologic malignancies.
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.
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.