E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
advanced or metastatic hepatocellular, ovarian, renal cell and gastric carcinomas in patients who have progressed after standard therapies |
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E.1.1.1 | Medical condition in easily understood language |
hepatocellular, ovarian, renal cell and gastric cancer in patients who have progressed after standard therapies |
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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 |
To determine the clinical activity of tasquinimod in advanced or metastatic hepatocellular, ovarian, renal cell and gastric carcinomas in patients who progressed after standard therapies Clinical activity will be measured by the proportion of patients who have neither progressed nor died at a prespecified timepoint (progression free survival [PFS] rate): • In advanced or metastatic hepatocellular carcinoma (HCC) after one line of sorafenib • In advanced or metastatic ovarian carcinoma (OC) resistant to platinum containing therapy • In metastatic renal cell carcinoma (mRCC) previously treated with vascular endothelial growth factor (VEGF) inhibitor • In advanced or metastatic gastric carcinoma (GC) after one line of platinum containing therapy. |
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E.2.2 | Secondary objectives of the trial |
In each tumour cohort: • To determine the activity and other clinical endpoints such as PFS, response rate, time to progression (TTP), and overall survival • To evaluate the safety and tolerability of tasquinimod • To assess the tolerability of a starting dose of 0.5 mg/day of tasquinimod • To characterise the pharmacokinetics (PK) of tasquinimod in each tumour cohort, particularly female patients, patients with gastrectomy and patients with cirrhosis Child-Pugh A. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
All Patients: 1. Able and willing to provide written informed consent and to comply with the study protocol and procedures 2. Age ≥18 years 3. ECOG performance status 0 or 1 4. Life expectancy greater than 3 months in the Investigator’s opinion 5. Disease progression during or after previous cancer treatment 6. Measurable disease as per RECIST Criteria (v1.1) 7. The following time must have elapsed between previous therapy for cancer and first administration of tasquinimod: - At least 2 weeks since previous systemic targeted therapy with small molecule inhibitors, which includes any tyrosine-kinase inhibitor - At least 4 weeks since the last dose of systemic anti-cancer therapy other than targeted therapy, which includes cytotoxic agents, monoclonal antibody therapy, immunotherapy and prior radiotherapy - At least 1 week since prior hormonal therapy - At least 3 months since prior interferon therapy 8. Recovery to Grade 1 from the effects (excluding alopecia) of any prior therapy for their malignancies 9. At least 4 weeks since any major surgery or open biopsy and 7 days since a core biopsy before first study treatment 10. Adequate renal function: - Creatinine ≤1.5 times upper limit of normal (ULN) or calculated creatinine clearance (CrCl) using the Cockcroft Gault formula ≥60 mL/min or measured CrCl ≥60 mL/min 11. Adequate hepatic function: - Serum bilirubin ≤1.5 mg/dL (≤25 μmol/L) for OC, RCC and GC, serum bilirubin ≤3 mg/dL (≤50 μmol/L) for HCC - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x ULN (≤5 x ULN if liver lesions present i.e. liver metastasis or primary tumour of the liver for HCC) 12. Adequate bone marrow function: - Absolute neutrophil count ≥1.5 x 10E9/L - Platelets ≥50 x 10E9/L - Haemoglobin ≥90 g/L 13. Adequate coagulation tests: international normalised ratio (INR) ≤1.5 x ULN 14. Able to swallow capsules 15. For women of childbearing potential, a negative pregnancy test must be documented prior to first administration of study treatment 16. For women who are not postmenopausal (12 months of amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to use adequate methods of contraception (e.g., hormonal implants, combined oral contraceptives, vasectomised partner), during the treatment period and for at least 3 months after the last dose of study treatment 17. For men: agreement to use a barrier method of contraception during the treatment period and for at least 3 months after the last dose of study treatment HCC H18. Histologically confirmed and documented HCC (excluding fibrolamellar carcinoma) H19. Barcelona Clinic Liver Cancer (BCLC) stage C or BCLC stage B not amenable to locoregional therapy or refractory to locoregional therapy H20. Liver mass measuring at least 2 cm with characteristic vascularisation seen on either triphasic computed tomography (CT) scan or magnetic resonance imaging (MRI) with gadolinium H21. At least one measurable or evaluable lesion that is viable (i.e. vascularised), and has not been previously treated with locoregional therapy. A lesion that has been previously treated will qualify as a measurable or evaluable lesion if there was demonstrable progression following locoregional therapy H22. Child-Pugh A Class only H23. Previously treated with sorafenib. Patients may have experienced radiographically documented disease progression during sorafenib therapy or after discontinuation of sorafenib therapy H24. The patient has received sorafenib as the most recent systemic therapeutic intervention (any hepatic locoregional therapy that has been administered prior to sorafenib is allowed, but not following sorafenib; radiation to metastatic sites following sorafenib therapy is permitted) OC O18. Histologically confirmed and documented ovarian epithelial, fallopian tube, or primary peritoneal cavity cancer O19. Progression within 6 months of a platinum containing chemotherapy regimen (i.e. platinum resistant) O20. Progression after up to three lines of chemotherapy O21. Maximum one line treatment with antiangiogenic therapy RCC R18. Metastatic RCC R19. Histologically or cytologically confirmed and documented RCC with a clear cell component R20. Previous treatment with at least one VEGF inhibitor R21. Disease progression within 6 months prior to first study treatment R22. Patient had at most two prior targeted therapies for unresectable advanced or metastatic disease GC G18. Histologically or cytologically confirmed and documented adenocarcinoma of the stomach or gastroesophageal junction G19. Unresectable advanced or initially metastatic or recurrent after curative resection G20. Progression after one prior regimen of chemotherapy including fluoropyrimidine and platinum (with or without trastuzumab, if HER2+) G21. Maximum one line treatment with antiangiogenic therapy |
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E.4 | Principal exclusion criteria |
All Patients: 1. Other primary malignancy within the past 3 years (except for fully-resected non-melanoma skin cancer, localised prostate cancer with normal prostate specific antigen level, or cervical cancer in situ) 2. Known central nervous system metastasis that is symptomatic and/or requires treatment 3. Malabsorption (other than in patients with GC and partial or complete gastrectomy) or intestinal obstruction 4. History of pancreatitis 5. Essential medications that are known potent inhibitors or inducers of cytochrome P450 (CYP) 3A4 6. Ongoing treatment with CYP1A2 (including warfarin) or CYP3A4 metabolised drug substance with narrow therapeutic range at the start of study. Treatment with low molecular weight heparin (LMWH) is permitted 7. History of myocardial infarction, unstable angina, congestive heart failure New York Heart Association class III/IV, cerebrovascular accident, transient ischaemic attack, limb claudication at rest in the previous 6 months, or ongoing symptomatic dysrhythmias, or uncontrolled atrial, or ventricular arrhythmias, or uncontrolled hypertension defined as systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥90 mmHg 8. Evidence of bleeding diathesis or known coagulopathy 9. History of venous thromboembolic disease within 3 months prior to first administration of study treatment 10. The patient has current, severe and uncontrolled medical condition such as infection, diabetes mellitus or other systemic disease 11. Any condition or illness that, in the opinion of the Investigator or the medical monitor, would compromise patient safety or interfere with the evaluation of the safety of the drug 12. Has known positive serology for human immunodeficiency virus 13. Investigational drug within 28 days or within five times the elimination half-life (whichever is longest) prior to first dose of study treatment 14. Known allergy to treatment medication or its excipients. 15. Breastfeeding Hepatocellular Carcinoma (Cohort H) H15. Fibrolamellar carcinoma. Ovarian Carcinoma (Cohort O) O15. Non-epithelial cancer and borderline tumours (e.g., tumours of low malignant potential). Gastric Carcinoma (Cohort G) G15. Other histologic type than adenocarcinoma. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the proportion of patients who have neither progressed nor died (PFS rate) as measured by RECIST v1.1 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
PFS rate at: • Cohort H (HCC) - 16 weeks • Cohort O (OC) - 24 weeks • Cohort R (RCC) - 16 weeks • Cohort G (GC) - 12 weeks
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E.5.2 | Secondary end point(s) |
Efficacy Endpoints 1. Proportion of patients who have neither progressed nor died (PFS rate) at 16 weeks measured by Choi criteria in Cohort H. 2. Response rate defined by RECIST v1.1 for all cohorts (also Choi criteria for Cohort H) at futility and final analysis timepoints 3. Clinical benefit per cohort: complete response + partial response + stable disease lasting ≥12 weeks 4. PFS defined as the time from first study treatment to progression or death due to any cause 5. Time to progression 6. Overall survival defined as the time from first study treatment to death due to any cause.
Safety Endpoints 1. Complete physical examination including the evaluation of performance status using ECOG, body weight and vital signs 2. AEs and laboratory abnormalities as characterised using the NCI CTCAE v4.03 and SAEs 3. Clinical laboratory assessments 4. Dose reductions and discontinuations for toxicity and tolerability 5 ECG.
Pharmacokinetic Endpoints 1. A limited and targeted PK sampling strategy and a population PK analysis of concentration/time data using the Nonlinear Mixed Effects Modelling Tool (NONMEM) software (version 6.0 or above) 2. An estimate of exposure at steady state (AUCss) and summarised by cohort, where appropriate.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy: 1 & 2. Tumour assessments at each visit 3, 4 & 5. PFS & TTP and OS assessed throughout study
Safety: 1 - 4. Assessed at each study visit 5. ECG at screening or baseline, weeks 2 and 4, end-of-study treatment, and as clinically indicated.
PK 1 & 2. PK samples at baseline, weeks 2, 4, 6 and 12 |
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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 | No |
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) | No |
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 | Yes |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Canada |
France |
Spain |
United Kingdom |
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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 study will be considered to have finished (end of study) when all of the patients have died or when all patients have been followed up for 9 months after their last dose of study treatment. |
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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 |