A Phase 2 Study of SGI-110 in the Treatment of Advanced Hepatocellular Carcinoma (HCC) Subjects Who Failed Prior Treatment With Sorafenib

Summary

This is an open-label, single-arm, non-randomized Phase 2 study using Simon's 2-stage design. in Stage 1, a minimum of 15 subjects will be enrolled and at least 6 subjects need to demonstrate disease control at 16 weeks to proceed to Stage 2. at Stage 2, enrollment will proceed to a total of 46 subjects and at least 19 subjects should have disease control at 16 weeks to declare that SGi-110 is of interest in the treatment of advanced HCC after failure of prior sorafenib. This design uses the following assumptions: p0[?]30%, p1[?]50%, [RegisteredTM][?]0.05, and [MiCRo-SYMBoL][?]0.20, where p0 is the minimum DCR at or below which SGi-110 is judged to be of no interest in this indication, while p1 is the qualifying DCR at or above which, SGi-110 would be of interest in this clinical indication.

This is a standard Simon's two-stage design of single agent treatment of SGi-110 in HCC subjects. The estimates of the acceptable or desired level of activity in terms of DCR were derived from other published studies with targeted agents (sunitnib, brivanib, and everolimus) used in second-line treatment [19-21]. in those studies, DCR was reported as 40-46%, however there was no standard minimum duration of stable disease to qualify inclusion in the DCR. We have therefore estimated that the minimum DCR at 16 weeks in Stage 1 would be lower than 40% (setting the p0 rate at 30%) and that the desired DCR at 16 weeks should be higher than 40% (setting the p1 rate at 50%). The 16 weeks duration is chosen to provide clinically meaningful duration of stabilization of disease and it also coincides with
the second scheduled assessment of response as response is evaluated every 8 weeks in most studies.

in addition, study of methylation patterns in Line-1 and in selected genes before and after treatment will allow the investigation of potential predictive biomarkers for response to SGi-110 treatment. Mutation status of selected genes at baseline will also be explored as predictive biomarkers for response. if results of those predictive markers (methylation status, and/or gene mutations) in Stage 1 suggest that subjects with certain predictive markers have the highest potential for disease control, the Stage 1 may be expanded to allow for evaluation of only those subjects with the predictive marker instead of the overall population.

Primary endpoint:
* DCR at 16 weeks defined as percentage of subjects who achieve a best clinical response of CR or PR
plus subjects who are SD at 16 weeks using ReCiST v1.1

Secondary endpoints:
* The incidence and severity of adverse events (aes)
* DCR as defined above using modified ReCiST (mReCiST) assessment for HCC
* Percentage of subjects with aFP level reduction by 50% or more
* Duration of response (DoR)
* Progression-free survival (PFS)
* overall survival (oS)
* Global Dna methylation (Line-1 assay) in blood and in tumor tissue after SGi-110 treatment
compared to baseline levels.
* Methylation status of selected genes (e.g. RaSSF1a, SFRP, MZB1, P16, and others) in tumor tissue
before and after SGi-110 treatment
* evaluation of methylation of circulating cell free Dna and analysis of mutation status of selected
genes such as p53 in both tumor tissue and circulating tumor Dna.

Participant Eligibility

Subjects must fulfill all of the following inclusion criteria. See Section 5.0 for the details of the study eligibility.
1. Subjects who are 18 years of age or older
2. Subjects who have histological or cytological confirmed HCC, with advanced stage disease
3. Subject with life expectancy of at least 16 weeks
4. Subjects who have received prior sorafenib treatment, and showed evidence of disease progression, which is defined as Investigator verified radiologic progression, or intolerance of prior systemic therapy, which is defined as having had clinically significant adverse events that persisted despite one or more dose reductions or interruptions. Subjects may have received prior systemic therapy other than sorafenib, or other treatment for HCC such as embolization, chemoembolization, intra-arterial chemotherapy, ethanol injection, ablative therapy, cryosurgery, or other locoregional
or targeted therapy.
5. Subjects with ECOG performance status of 0-1
6. Subjects with acceptable organ function, as evidenced by laboratory data:
A. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 5.0 X upper limit of normal (ULN)
B. Total serum bilirubin <= 2 mg/dL
C. Absolute neutrophil count (ANC) >= 1000 cells/mm^3
D. Platelets >= 75,000/mm^3
E. Serum creatinine levels <= 1.25 X ULN OR calculated (by Cockcroft-Gault formula)/measured creatinine clearance (CrCL) >= 50 mL/min
F. Prothrombin time (PT) <= 6 sec above ULN, or international normalized ratio (INR) <= 2.3
7. Subjects and their partners with reproductive potential must agree to use effective contraceptive measures during the study and for 3 months following the last dose of study drug. Effective contraception includes methods such as oral contraceptives, double-barrier method (condom plus spermicide or diaphragm), or abstaining from sexual intercourse.
8. Subjects who sign an approved informed consent form for the study
9. Subjects who are willing and able to comply with the protocol and study procedures, in particular willingness to undergo tumor biopsy before (at baseline pretreatment), and after treatment with SGI-110 (Day 8 of Cycles 1 or 2)