This is an open-label, multi-center Phase 1/2 study of ARQ 531 in patients with selected
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.
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
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
- Cohort C: Richter's transformation subjects who have failed at least one prior
- 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
- 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 ×
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.
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
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,
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.