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

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.