E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Phase I: To determine the safety, tolerability and dose-limiting toxicities (DLT) of tefinostat when administered orally to patients with advanced HCC
To determine the recommended Phase II dose (RP2D) of tefinostat in patients with advanced HCC
Phase II: To perform a preliminary assessment of the anti-disease activity of tefinostat as measured by mRECIST.
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E.2.2 | Secondary objectives of the trial |
Phase I: To perform a preliminary assessment of the anti-disease activity of tefinostat as measured by mRECIST.
Phase II: To determine the safety and tolerability of the recommended dose of tefinostat when administered orally to patients with advanced HCC
To determine the anti-disease activity of tefinostat as measured by mRECIST
Phase I and II: To determine pharmacokinetic parameters for tefinostat and CHR-2847 when administered orally at different dose levels and dose schedules
To confirm monocyte specific delivery, protein acetylation will be measured in lymphocytes, granulocytes and monocytes
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. Recovered from all acute adverse effects of prior therapies
5. Hepatitis is controlled by antiviral therapy (PEG-IFN, ribavirin, telaprevir, etc). Prophylactic Lamivudine for HBV carriers.
6. Child-Pugh classification A or B7.
7. Adequate bone marrow, hepatic and renal function including the following a.Hb ≥ 9.0 g/dL, absolute neutrophil count ≥ 1.5 x 109/L, platelets ≥75 x 109/L b.Total bilirubin ≤ 1.5 x upper normal limit, excluding cases where elevated bilirubin can be attributed to Gilberts Syndrome c.AST (SGOT), ALT (SGPT) ≤ baseline + 4 x upper normal limit d.Creatinine ≤ 1.5 x upper normal limit e.Serum albumin > 28 g/L f.INR < 1.5 or a Pt/PTT within normal limits
6. Age ≥ 18 years
7. Performance status (PS) 0-2 (ECOG scale)
8. Estimated life expectancy greater than 3 months
9. 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)
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E.4 | Principal 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 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 a.history of congestive heart failure requiring therapy b.history of unstable angina pectoris or myocardial infarction up to 6 months prior to trial entry c.presence of severe valvular heart disease d.presence of a ventricular arrhythmia requiring treatment e.LVEF < 50% (or less than institutional norm– some places have 45%) f.QTc interval ≥450 ms for men and ≥470 ms 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 v4.0 grade I)
12. Pregnant or breast-feeding women
13. Patients who have received an investigational drug within the last 4 weeks
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase I: a) Causality of each AE to tefinostat and grading severity according to CTCAE 4.03. MTD at either once or twice daily dosing.
b) To determine the recommended Phase II dose (RP2D) of tefinostat in patients with advanced HCC
Phase II: Radiological progression free survival (RPFS) rate at 3-months
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase I: a) End of phase 1 part of study b) End of phase 1 part of study
Phase II: 3 months |
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E.5.2 | Secondary end point(s) |
Phase I: To perform a preliminary assessment of the anti-disease activity of tefinostat as measured by mRECIST.
Phase II: a) To determine the safety and tolerability of the recommended dose of tefinostat when administered orally to patients with advanced HCC
b) To determine the anti-disease activity of tefinostat as measured by mRECIST
Phase I and II: a) To determine pharmacokinetic parameters for tefinostat and CHR-2847 when administered orally at different dose levels and dose schedules
b) To confirm monocyte specific delivery, protein acetylation will be measured in lymphocytes, granulocytes and monocytes
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase I: End of phase 1 part of study
Phase II: a) End of study b) End of study
Phase I and II: a) Last patient Cycle 2 Day 1 b) End of study |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The ‘end of trial’ is defined as the date when all patients have been followed-up for survival up to 12 months following Cycle 1, Day 1, of the final patient recruited or when all patients have died. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |