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

A Phase I/II Dose Escalation Trial of HDAC Inhibitor Tefinostat for Cancer Associated Inflamation in Hepatocellular Carcinoma

This study is being carried out to assess the best dose of a new drug, called tefinostat, in treating liver cancer.

Tefinostat is a new drug that blocks enzymes called histone deacetylases (pronounced dee-as-et-isle-azes). Cells need these enzymes to grow and divide. Blocking them may stop cancer growing. Drugs that block these enzymes are called histone deacetylase inhibitors or 'HDAC inhibitors'.

Tefinostat has never been given to patients with liver cancer before so it isn't known which dose is best at treating liver cancer. To find this out the study will be testing one dose and if that is safe, then test a higher dose and so on.

The aim of this study is to find the best dose of tefinostat without causing side effects. The study will be looking closely at any side effects patients might experience from this treatment.

Study Overview

• Status: Unknown
• Conditions: Hepatocellular Carcinoma
• Intervention / Treatment: Drug: Tefinostat

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 69
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Glasgow, United Kingdom
    • Beatson Cancer Centre
  • Liverpool, United Kingdom
    • Clatterbridge Cancer Centre
  • London, United Kingdom
    • University College London Hospital
  • Greater London
    • London, Greater London, United Kingdom, EC1M 7BE
      • Barts Health NHS Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Signed, informed consent.

2. Histologically or cytologically confirmed malignant HCC refractory to standard therapy or for which no standard therapy exists.

   a. Patients with alcoholic cirrhosis may be included dependent on clinical judgement as to their ability to conform to the protocol.

3. Patient is not a transplant candidate.
4. Hepatitis is controlled by antiviral therapy (PEG-IFN, ribavirin, telaprevir, etc). Prophylactic Lamivudine for HBV carriers.
5. Child-Pugh classification A or B7.

6. Adequate bone marrow, hepatic and renal function including the following:

   • Hb ≥ 9.0g/dL, absolute neutrophil count ≥ 1.5 x 109/L, platelets ≥75 x 109/L.
   • Total bilirubin ≤ 1.5 x upper normal limit, excluding cases where elevated bilirubin can be attributed to Gilberts Syndrome.
   • AST (SGOT), ALT (SGPT) ≤ baseline + 4 x upper normal limit .
   • Creatinine ≤ 1.5 x upper normal limit.
   • Serum albumin > 28g/L.
   • INR < 1.5 or a Pt/PTT within normal limits.
7. Age ≥ 18 years.
8. Performance status (PS) 0-2 (ECOG scale).
9. Estimated life expectancy greater than 3 months.
10. Female patients with reproductive potential must have a negative serum pregnancy test within 7 days prior to start of trial. Both women and men must agree to use a medically acceptable method of contraception throughout the treatment period and for 3 months after discontinuation of treatment. Acceptable methods of contraception include IUD, oral contraceptive, subdermal implant and double barrier (condom with a contraceptive sponge or contraceptive pessary).

Exclusion Criteria:

1. Anti-cancer therapy including chemotherapy, radiotherapy, TACE, endocrine therapy, immunotherapy or use of other investigational agents within the 4 weeks prior to trial.
2. Use of medicines known to prolong QTc within 14 days prior to the first dose of study drug (see Appendix III).
3. Candidate for surgical resection, orthotopic liver transplantation, or loco-regional therapy such as radio-frequency ablation or chemoembolization.
4. History of organ allograft.
5. Co-existing active infection or serious concurrent illness.

6. Significant cardiovascular disease as defined by:

   • History of congestive heart failure requiring therapy.
   • History of unstable angina pectoris or myocardial infarction up to 6 months prior to trial entry.
   • Presence of severe valvular heart disease.
   • Presence of a ventricular arrhythmia requiring treatment.
   • LVEF < 50% (or less than institutional norm- some places have 45%).
   • QTc interval ≥ 450ms for men and ≥ 470ms for women (using Bazett's formula).
7. Any co-existing medical condition that in the Investigator's judgement will substantially increase the risk associated with the patient's participation in the study.
8. Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary studies.
9. Gastrointestinal disorders that may interfere with absorption of the study drug.
10. Patients requiring palliative radiotherapy within the last 4 weeks of study entry.
11. Uncontrolled hypercalcaemia (>CTCAE v4.03 grade I).
12. Pregnant or breast-feeding women.
13. Patients who have received an investigational drug within the last 4 weeks.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: Tefinostat; 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. Up to 5 cohorts of 3-6 patients (number is dependent on DLT occurrence) 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.

Drug: Tefinostat; Tefinostat is a novel type of HDACi used in cancer targeted specifically to cell of monocyte - macrophase lineage

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine Maximum Tolerated Dose	Determining the maximal dose at either once or twice daily dosing at which no more than one patient (out of 3) at that dose level experiences a DLT.	For 28 days following commencing IMP treatment. (Phase I)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response Assessment	Response assessment (stable disease (SD), partial response (PR) or complete response (CR)) determined according to modified Response Evaluation Criteria in Solid Tumours (mRECIST v1.1) in all patients receiving at least one cycle of treatment. Response assessment should take place at 1 month and then again after every 2 months of further treatment.	From registration to disease progression.
Phase I & II: To determine pharmacokinetic parameters for tefinostat and CHR-2847 when administered orally at different dose levels and dose schedules.	Measurement of PK parameter values for tefinostat and CHR-2847 on day 1 and day 28 of the 1st cycle, using PK profiles generated from samples taken at the protocol specified time points.	Phase I: End of 28 day treatment period; Phase II: End of 84 days period

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase I & II: To assess responses to target inhibition by tefinostat.	Inhibition of target genes and microarray target gene responses in tumour biopsies and peripheral blood monocytes.	Phase I: End of 28 day treatment period; Phase II: End of 84 days period
Phase I & II: The impact of HDACi on circulating cytokine profiles.	Ex vivo analysis of plasma using the Meso Scale Discovery (MSD) platform, correlation to disease status and response.	Phase I: End of 28 day treatment period; Phase II: End of 84 days period
Phase I & II: To explore the feasibility of measuring tefinostat levels in tumour tissue.	Measurement of tissue concentrations of tefinostat.	Phase I: End of 28 day treatment period; Phase II: End of 84 days period
Phase I & II: To establish relationships between measures of tumour expression of hCE-1 and objective tumour response.	hCE-1 expression in liver biopsies will be quantified by IHC. Correlation between presence/absence of hCE-1 versus objective tumour response will be analysed.	Phase I: End of 28 day treatment period; Phase II: End of 84 days period
Phase I & II: To explore Enhanced Liver Function (ELF) test to monitor liver toxicity under tefinostat.	The combination of HA, P3NP and TIMP-1 measured by ELISA be used to determine the severity of liver fibrosis with good accuracy (Rosenberg et al, 2004).	Phase I: End of 28 day treatment period; Phase II: End of 84 days period
Phase I & II: To determine the impact of HDACi on anti-tumour immune responses.	Serial assessment of TAA-specific CTLs in peripheral blood using EliSPOT, gamma capture and multimer assays (and, where feasible, on T cells from serial tumour biopsies).	Phase I: End of 28 day treatment period; Phase II: End of 84 days period

Collaborators and Investigators

• Sponsor: Queen Mary University of London
• Collaborators: Chroma Therapeutics
• Investigators: Principal Investigator: David Propper, Barts NHS Trust

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2013
• Primary Completion (Anticipated): December 1, 2018
• Study Completion (Anticipated): December 1, 2018

Study Registration Dates

• First Submitted: October 23, 2014
• First Submitted That Met QC Criteria: April 28, 2016
• First Posted (Estimate): May 3, 2016

Study Record Updates

• Last Update Posted (Actual): December 20, 2018
• Last Update Submitted That Met QC Criteria: December 19, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Keywords: Inflammation; Hepatocellular Carcinoma; HDAC Inhibitor; Tefinostat; Cancer associated Inflammation in Hepatocellular Carcinoma
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular
• Other Study ID Numbers: 008260QM; 2012-000326-22 (EudraCT Number)