ABC294640 in Refractory / Relapsed Multiple Myeloma

Objectives for Phase 1b:

Primary Objectives • To assess safety and determine the maximum tolerated dose (MTD) of
single agent ABC294640 in patients with refractory or relapsed multiple myeloma (MM) who have
been previously treated with proteasome inhibitors and immunomodulatory agents.

Secondary Objectives

- To assess the antitumor activity of single agent ABC294640 in patients with refractory
or relapsed MM after 3 cycles of treatment.

- To determine the pharmacokinetics of ABC294640 following administration of the drug.

- To describe the effects of ABC294640 on plasma levels of sphingosine 1-phosphate and
IL-6 in patients with refractory or relapsed MM.

- To assess pharmacodynamic markers (SK2 mRNA level or activity, sphingolipid metabolites,
c-Myc, Mcl-1 and pS6) in bone marrow CD138+ myeloma cells.

Objectives for Phase 2:

Primary Objectives

• Assess overall treatment response rate and overall survival in patients with relapsed or
refractory MM treated with single-agent ABC294640.

Secondary Objectives

- To assess the treatment response of ABC294640 in patients with refractory or relapsed MM
after 3 cycles of treatment.

- To determine if pharmacodynamic markers (SK2 mRNA or activity, sphingolipid metabolites,
c-Myc, Mcl-1 and pS6) in bone marrow CD138+ myeloma cells predict tumor response to the
treatment with ABC294640.

The projected ABC294640 doses for the escalation phase are: 250, 500, and 750 mg BID orally
continuously as determined in the single agent trial for ABC294640. The dose will be given
under fasting conditions (at least 1 hour before or 2 hours after eating). Each cycle of
treatment is 28 days.

Patients will be monitored for safety and pharmacodynamics effects weekly in Cycle 1,
biweekly for Cycles 2-4, and monthly for subsequent cycles.

Myeloma treatment response will be assessed as follows:

- Serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP) and serum
free light chains before each cycle.

- Skeletal survey at screening, then every year or at the end of study if the study ends
before the anniversary.

- Bone marrow biopsy and aspirates at the last day of cycle #3 and cycle #6 (± 7 days).

For the phase II portion of the study, patients will be treated with single agent ABC294640
at the MTD determined from the phase Ib study (or highest dose used, if MTD is not reached)
until disease progression or intolerable toxicity occurs.

Inclusion Criteria:

1. Patient must have a diagnosis of symptomatic multiple myeloma, relapsed or refractory
after previous treatment with a proteasome inhibitor (bortezomib or carfilzomib) and
an immunomodulatory agent (thalidomide, lenalidomide or pomalidomide).

2. Have measurable disease as defined by at least one of the following:

- Serum monoclonal (M) protein ≥1.0 g/dl by protein electrophoresis

- >200 mg of M protein in the urine on 24 hour electrophoresis

- Serum immunoglobulin free light chain ≥10 mg/dL AND abnormal serum immunoglobulin
kappa to lambda free light chain ratio

- Monoclonal bone marrow plasmacytosis ≥30%

3. Voluntary signed and dated institutional review board (IRB) approved informed consent
form in accordance with regulatory and institutional guidelines.

4. Time interval from last systemic chemotherapy (not including low dose dexamethasone)
more than 2 weeks prior to initiation of ABC294640. Patients receiving high dose
dexamethasone defined as 40mg dexamethasone a day for 4 days will need 2 weeks washout
prior to initiation of ABC294640

5. 18 years of age or older.

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

7. Acceptable liver function:

- Bilirubin ≤ 1.5 times upper limit of normal (CTCAE Grade 1 baseline)

- AST (SGOT), ALT (SGPT) ≤ 5 x ULN (CTCAE Grade 2 baseline)

- Serum creatinine ≤1.5 XULN (CTCAE Grade 1 baseline)

8. Acceptable hematologic status (with or without transfusion support):

- Absolute neutrophil count ≥1000 cells/mm3,

- Platelet count ≥50,000 (plt/mm3),

- Hemoglobin ≥9 g/dL.

9. Urinalysis: No clinically significant abnormalities.

10. PT and PTT ≤ 1.5 X ULN after correction of nutritional deficiencies that may
contribute to prolonged PT/PTT.

11. As determined by the treating investigator, the patient must have well-controlled
blood pressure, defined as systolic blood pressure <150mmHg and/or diastolic blood
pressure <100 mmHg for the majority of measurements.

12. A negative pregnancy test (if female of child bearing potential).

13. For men and women of child-producing potential, willingness to use effective
contraceptive methods during the study.

Exclusion Criteria:

1. Pregnant or nursing women.

2. Patients who are currently participating in any other clinical trial of an
investigational product.

3. Major surgery within 30 days prior to start of treatment

4. Acute active infection requiring treatment (systemic antibiotics, antivirals, or
antifungals) within 14 days prior to start of treatment

5. Known human immunodeficiency virus infection

6. Active hepatitis B or C infection with abnormal liver functions (i.e., LFTs > 2 x
upper normal limits)

7. Unstable angina or myocardial infarction within 4 months prior to start of treatment,
New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina,
history of severe coronary artery disease, severe uncontrolled ventricular
arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia
or Grade 3 conduction system abnormalities unless subject has a pacemaker

8. Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to start of
treatment

9. Nonhematologic malignancy within the past 3 years with the exception of a) adequately
treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b)
carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or
less with stable prostate-specific antigen levels; or d) cancer considered cured by
surgical resection or unlikely to impact survival during the duration of the study,
such as localized transitional cell carcinoma of the bladder

10. Subjects with pleural effusions requiring thoracentesis or ascites requiring
paracentesis within 14 days prior to initiation of ABC294640

11. Any other clinically significant medical or psychiatric disease or condition, or
social situation that, in the Investigator's opinion, may interfere with protocol
adherence or a subject's ability to give informed consent