Dose Escalation Trial of Tefinostat for Cancer Associated Inflamation in Hepatocellular Carcinoma (HCC) (CHR-2845)

This is an open label, dose escalating, phase I/II study of Tefinostat administered orally, once or twice daily in 28 day cycles of treatment in patients with advanced hepatocellular carcinoma.

The starting dose of the Phase I dose escalation stage of the study has been based on the results of a previous Phase I trial of Tefinostat in patients with haematological malignancies. The starting dose of Tefinostat will be 360mg OD. As Tefinostat has a median plasma half-life of 0.47h (range 0.19 to 1.18) and CHR-2847 a median half-life of 1.4 h (range 0.98 to 3.79) twice daily dosing will also be investigated, starting at 240mg BID.

Phase I Up to 5 cohorts of 3-6 patients will be treated for 28 days once or twice daily (360, 480mg once daily, then 240, 360, 480mg twice daily) to determine safety and tolerability of Tefinostat and to identify the recommended dose for Phase II (RP2D). Patients with stable disease or with a tumour response will be allowed to continue treatment until PD or unacceptable toxicity, at the discretion of the Investigator.

Patients with advanced HCC who have not received prior systemic therapy will be eligible for the study if they are Child-Pugh classification A and are not candidates for surgical treatment, with adequate bone marrow, hepatic and renal function. Patients should not have a history of organ allograft or any serious concurrent illness.

Doses will be increased in a stepwise fashion and the decision to do so will be made by the participating Investigators on the basis of DLT, PK and PD. The starting dose will be 360mg od. Should this dose not be safe the dose level may be reduced to 240mg od. Dosing will initially take place once a day, for 28 days, while later cohorts will investigate twice daily dosing. More than one DLT in a once daily dose cohort will not preclude investigation of twice daily dosing at a lower dose.

Decisions to escalate to the next dose level, will be made jointly by the participating Investigators based on review of all the available data from the first cycle of treatment for each patient of that cohort. The first subject must have completed 7 days of the course of treatment before the next two subjects are enrolled. All subjects treated in that cohort must have undergone repeated safety evaluations prior to enrolment of the next dose cohort.

If a subject withdraws or is withdrawn from the study prior to completion of the first treatment period, in the absence of a DLT, that subject must be replaced and the replacement patient dosed at the scheduled dose, not completed, before dose escalation can occur.

Upon completion of the first treatment period of 28 days (dose finding, Phase I), suitable patients may continue with further treatment as described under Duration of Treatment, at the discretion of the investigator.

The available clinical and safety information from this trial as well as the previous single agent study of Tefinostat will be reviewed by the participating investigators, who will agree the RP2D.

The Phase I data will be reviewed by the participating investigators prior to progressing to Phase II.

Patients will be treated at the recommended phase II dose (RP2D) selected in Phase I, over an 84 day course of treatment. Approximately 39 patients with advanced HCC will be treated. Patients who have stable disease or with a tumour response after the 84 day treatment period will be allowed to continue treatment until PD or unacceptable toxicity, at the discretion of the treating investigator. Patient recruitment will continue until approximately 40 patients treated at the RP2D, including those already treated at that dose in Phase 1, are evaluable for response following treatment with at least 84 days of study therapy.