ABC294640 in Treating Patients With Advanced Solid Tumors

PRIMARY OBJECTIVES:

I. To assess safety and determine the maximum tolerated dose (MTD) and the dose limiting
toxicities (DLT) of ABC294640 (sphingosine kinase-2 inhibitor ABC294640) in patients with
solid organ tumors. (Part I) II. To assess the safety and tolerability of ABC294640 at the
MTD in an expanded cohort of hepatocellular carcinoma (HCC) patients. (Part II)

SECONDARY OBJECTIVES:

I. To establish the dose of ABC294640 recommended for future phase II protocols. (Part I)
II. To describe the pharmacokinetics of ABC294640 in patients with solid organ tumors. (Part
I) III. To describe the effects of ABC294640 on plasma levels of sphingosine 1-phosphate in
patients with solid organ tumors. (Part I) IV. To assess antitumor activity of ABC294640 in
patients with solid organ tumors by objective radiographic assessment using Response
Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. (Part I) V. To describe the
pharmacokinetics of ABC294640 in HCC patients. (Part II) VI. To describe the effects of
ABC294640 on plasma levels of sphingosine 1-phosphate in HCC patients. (Part II) VII. To
assess antitumor activity of ABC294640 in HCC patients by objective radiographic assessment
using RECIST 1.1 criteria. (Part II)

OUTLINE: This is a dose-escalation study.

Patients receive sphingosine kinase-2 inhibitor ABC294640 orally (PO) twice daily (BID) on
days 1-28. Courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up monthly for 1 year.

Inclusion Criteria:

- PART I:

- Patients with histologically confirmed solid organ carcinomas

- Tumor progression after receiving standard/approved chemotherapy or as first-line
therapy for malignancies where there is no standard therapy

- One or more tumors measurable on computed tomography (CT) scan per RECIST 1.1

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Life expectancy of at least 3 months

- Age > 18 years

- Signed, written Institutional Review Board (IRB)-approved informed consent

- A negative pregnancy test (if female)

- Acceptable liver function:

- Bilirubin =< 3 times upper limit of normal (ULN) (Common Terminology Criteria for
Adverse Events [CTCAE] Grade 2 baseline)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]),
alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) =< 3 x
ULN (CTCAE Grade 1 baseline)

- Serum creatinine =< 1.5 X ULN (CTCAE Grade 1 baseline)

- Absolute neutrophil count >= 1000 cells/mm^3

- Acceptable hematologic status:

- Absolute neutrophil coun > 1000 cells/mm3

- Platelet count >= 75,000 (plt/mm^3) (CTCAE Grade 1 baseline)

- Hemoglobin >= 9 g/dL

- Acceptable blood sugar control:

- Fasting glucose value < 160 mg/dL (CTCAE Grade 1 baseline)

- Urinalysis: No clinically significant abnormalities

- Prothrombin time (PT) and partial thromboplastin time (PTT) =< 1.5 X ULN after
correction of nutritional deficiencies that may contribute to prolonged PT/PTT

- For men and women of child-producing potential, willingness to use of effective
contraceptive methods during the study; if female (or female partner of male
subject), is either not of childbearing potential (defined as postmenopausal for >= 1
year or surgically sterile [bilateral tubal ligation, bilateral oophorectomy or
hysterectomy]) or practicing 1 of the following medically acceptable methods of birth
control and agrees to continue with the regimen throughout the duration of the study:

- Oral, implantable or injectable contraceptives for 3 consecutive months before the
baseline/randomization visit

- Total abstinence from sexual intercourse (>= 1 complete menstrual cycle before the
baseline/randomization visit)

- Intrauterine device (IUD)

- Double barrier method (condoms, sponge, diaphragm or vaginal ring with spermicidal
jellies or cream)

- PART II:

- To be eligible for inclusion in Part II, patients must meet the eligibility for Part
1 as well as the following:

- Patients with histologically confirmed HCC for whom there is no standard/approved
chemotherapy

Exclusion Criteria:

- New York Heart Association Class III or IV, cardiac disease, myocardial infarction
within the past 6 months, unstable arrhythmia, or evidence of ischemia on
electrocardiogram (ECG)

- Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic
therapy

- Pregnant or nursing women; NOTE: Women of child-bearing potential and men must agree
to use adequate contraception (hormonal or barrier method of birth control; or
abstinence) prior to study entry and for the duration of study participation; should
a woman become pregnant or suspect she is pregnant while participating in this study,
she should inform her treating physician immediately

- Treatment with radiation therapy, surgery, chemotherapy, or investigational therapy
within one month prior to study entry

- Unwillingness or inability to comply with procedures required in this protocol

- Known infection with human immunodeficiency virus (HIV)

- Serious nonmalignant disease (e.g., hydronephrosis, liver failure, or other
conditions) that could compromise protocol objectives in the opinion of the
Investigator and/or the Sponsor

- Patients who are currently receiving any other investigational agent

- Patients who are receiving drugs that are sensitive substrates of CYP450 1A2, 3A4,
2C9, 2C19 or 2D6, or strong inhibitors or inducers of all major CYP450 isozymes that
cannot be stopped at least 7 days or 5 half-lives (whichever is longer) before
starting treatment with ABC294640 and either replaced with another appropriate
medication or not given for the duration of the clinical study

- Patients who are currently taking Coumadin or Coumadin derivatives

- Patients who have received any antineoplastic therapy within 1 month of starting
treatment with ABC294640 or who have not adequately recovered from side effects and
toxicities of previous antineoplastic therapy