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Enzyme Inhibitors

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

Given PO Starting dose of ABC294640 250 mg once on day on Days 1-28 of each 28-day cycle. Subsequent cohort doses (if reached) are as follows: 250 BID, 500 BID, 750 BID, 1,000 BID, 1,500 BID, 2,000 BID, 2,500 BID

sphingosine kinase-2 inhibitor ABC294640

Carolyn Britten, MD

This phase I trial studies the side effects and best dose of ABC294640 in treating patients with advanced solid tumors. ABC294640 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Please note that the FDA OOPD is participating as a funding source.

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.

ABC294640 in Treating Patients With Advanced Solid Tumors

A Phase I, Open-label, Dose-Escalation, Safety, Pharmacokinetic and Pharmacodynamic Study of ABC294640 in Patients With Advanced Solid Tumors

MTD defined as the highest dose at which 0 or 1 patient of 6 experiences a DLT. The DLT rate will be estimated with its 95% confidence interval.

Assessed using the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) version 4.0. Adverse events (AEs) will be coded by body system and summary tables with incidence rates of adverse events will be generated. Descriptive statistics of AEs will be reported by doses and for subsets of patients with serious adverse events (SAEs), patients who discontinue due to AEs, and patients with related AEs.

Area under the drug concentration over time curve (AUC), maximum concentration, minimum concentration, and time to maximum concentration will be calculated for each subject.

Pharmacodynamic parameters for ABC294640 action will include measurement of plasma levels of S1P, including absolute concentration at each sampling time and chance from baseline concentration at each sampling time after drug administration.

All patients who have measureable disease according to RECIST 1.1, received at least one cycle of treatment, and have had disease re-evaluated will be included.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
ABC294640 in Treating Patients With Advanced Solid Tumors	NCT01488513	Pancreatic Canc... Unspecified Adu...	sphingosine kin...	18 Years -	RedHill Biopharma Limited
ABC294640 in Treating Patients With Advanced Solid Tumors	NCT01488513	Pancreatic Canc... Unspecified Adu...	sphingosine kin...	18 Years -	RedHill Biopharma Limited

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