Dose Escalation Trial of Tefinostat for Cancer Associated Inflamation in Hepatocellular Carcinoma (HCC) (CHR-2845)
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ClinicalTrials.gov Identifier: NCT02759601 |
Recruitment Status : Unknown
Verified December 2018 by Queen Mary University of London.
Recruitment status was: Active, not recruiting
First Posted : May 3, 2016
Last Update Posted : December 20, 2018
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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.
Condition or disease | Intervention/treatment | Phase |
---|---|---|
Hepatocellular Carcinoma | Drug: Tefinostat | Phase 1 Phase 2 |
Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 69 participants |
Allocation: | N/A |
Intervention Model: | Single Group Assignment |
Masking: | None (Open Label) |
Masking Description: | Open label |
Primary Purpose: | Treatment |
Official Title: | A Phase I/II Dose Escalation Trial of HDAC Inhibitor Tefinostat for Cancer Associated Inflamation in Hepatocellular Carcinoma |
Actual Study Start Date : | January 2013 |
Estimated Primary Completion Date : | December 2018 |
Estimated Study Completion Date : | December 2018 |
Arm | Intervention/treatment |
---|---|
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 |
- Determine Maximum Tolerated Dose [ Time Frame: For 28 days following commencing IMP treatment. (Phase I) ]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.
- Response Assessment [ Time Frame: From registration to disease progression. ]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.
- Phase I & II: To determine pharmacokinetic parameters for tefinostat and CHR-2847 when administered orally at different dose levels and dose schedules. [ Time Frame: Phase I: End of 28 day treatment period; Phase II: End of 84 days period ]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 & II: To assess responses to target inhibition by tefinostat. [ Time Frame: Phase I: End of 28 day treatment period; Phase II: End of 84 days period ]Inhibition of target genes and microarray target gene responses in tumour biopsies and peripheral blood monocytes.
- Phase I & II: The impact of HDACi on circulating cytokine profiles. [ Time Frame: Phase I: End of 28 day treatment period; Phase II: End of 84 days period ]Ex vivo analysis of plasma using the Meso Scale Discovery (MSD) platform, correlation to disease status and response.
- Phase I & II: To explore the feasibility of measuring tefinostat levels in tumour tissue. [ Time Frame: Phase I: End of 28 day treatment period; Phase II: End of 84 days period ]Measurement of tissue concentrations of tefinostat.
- Phase I & II: To establish relationships between measures of tumour expression of hCE-1 and objective tumour response. [ Time Frame: Phase I: End of 28 day treatment period; Phase II: End of 84 days period ]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 & II: To explore Enhanced Liver Function (ELF) test to monitor liver toxicity under tefinostat. [ Time Frame: Phase I: End of 28 day treatment period; Phase II: End of 84 days period ]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 & II: To determine the impact of HDACi on anti-tumour immune responses. [ Time Frame: Phase I: End of 28 day treatment period; Phase II: End of 84 days period ]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).
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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Signed, informed consent.
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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.
- Patient is not a transplant candidate.
- Hepatitis is controlled by antiviral therapy (PEG-IFN, ribavirin, telaprevir, etc). Prophylactic Lamivudine for HBV carriers.
- Child-Pugh classification A or B7.
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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.
- Age ≥ 18 years.
- Performance status (PS) 0-2 (ECOG scale).
- Estimated life expectancy greater than 3 months.
- 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:
- Anti-cancer therapy including chemotherapy, radiotherapy, TACE, endocrine therapy, immunotherapy or use of other investigational agents within the 4 weeks prior to trial.
- Use of medicines known to prolong QTc within 14 days prior to the first dose of study drug (see Appendix III).
- Candidate for surgical resection, orthotopic liver transplantation, or loco-regional therapy such as radio-frequency ablation or chemoembolization.
- History of organ allograft.
- Co-existing active infection or serious concurrent illness.
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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).
- 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.
- Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary studies.
- Gastrointestinal disorders that may interfere with absorption of the study drug.
- Patients requiring palliative radiotherapy within the last 4 weeks of study entry.
- Uncontrolled hypercalcaemia (>CTCAE v4.03 grade I).
- Pregnant or breast-feeding women.
- Patients who have received an investigational drug within the last 4 weeks.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02759601
United Kingdom | |
Barts Health NHS Trust | |
London, Greater London, United Kingdom, EC1M 7BE | |
Beatson Cancer Centre | |
Glasgow, United Kingdom | |
Clatterbridge Cancer Centre | |
Liverpool, United Kingdom | |
University College London Hospital | |
London, United Kingdom |
Principal Investigator: | David Propper | Barts NHS Trust |
Responsible Party: | Queen Mary University of London |
ClinicalTrials.gov Identifier: | NCT02759601 |
Other Study ID Numbers: |
008260QM 2012-000326-22 ( EudraCT Number ) |
First Posted: | May 3, 2016 Key Record Dates |
Last Update Posted: | December 20, 2018 |
Last Verified: | December 2018 |
HDAC Inhibitor Tefinostat Inflammation Hepatocellular Carcinoma Cancer associated Inflammation in Hepatocellular Carcinoma |
Carcinoma Carcinoma, Hepatocellular Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Neoplasms Adenocarcinoma |
Liver Neoplasms Digestive System Neoplasms Neoplasms by Site Digestive System Diseases Liver Diseases |