A Study With Tasquinimod Treating Patients With Hepatocellular, Ovarian, Renal Cell and Gastric Cancers
A Study With Tasquinimod Treating Patients With Hepatocellular, Ovarian, Renal Cell and Gastric Cancers
This was an exploratory proof of concept study to determine the clinical activity of
 tasquinimod in patients with advanced or metastatic hepatocellular carcinoma, ovarian
 carcinoma, renal cell carcinoma and gastric carcinoma who had progressed after standard
 therapies.
This was an early stopping design, Phase II, open label, exploratory proof of concept study
 to evaluate the activity of tasquinimod in four independent cohorts of patients with
 different tumour types (patients with hepatocellular, ovarian, renal cell or gastric
 carcinoma, each with progressive disease after standard therapies). Patients initially
 received 0.5 mg/day tasquinimod dose, increasing to 1 mg/day after at least 2 weeks, unless
 there were any individual patient safety and tolerability concerns. The treatment period
 continued until patient disease progression, lost to follow-up, withdrawal or death. During
 the treatment period, initial study visits were at Week 2, 4 and 8 (± 2 days) for the
 hepatocellular carcinoma, the ovarian carcinoma and the renal cell carcinoma cohorts and at
 Week 2, 4 and 6 (± 2 days) for the gastric carcinoma cohort, to allow careful safety
 monitoring and to facilitate the identification of the individually tolerated dose. After
 Week 8, when most patients should have reached their tolerable dose, visit frequency was
 decreased as follows: at Week 16 and 24 (± 2 days) for the hepatocellular carcinoma, the
 ovarian carcinoma and the renal cell carcinoma cohorts; and at Week 12, 18 and 24 (± 2 days)
 for the gastric carcinoma cohort. Thereafter visits were once every 8 weeks (± 2 days) for
 all cohorts. An end of study treatment/withdrawal (EoST/WD) Visit was to be performed at
 least 14 days after the last dose of study treatment, and/or before treatment with any
 alternative antitumour therapy was started. Patients who stopped study treatment before
 disease progression were to be followed up with tumour imaging every 8 weeks until disease
 progression. Each patient was subsequently followed up for survival (by visit or telephone
 call) every 3 months after the EoST/WD Visit until death, lost to follow-up, or withdrawal of
 consent, or until all surviving patients had been followed-up for at least 9 months after
 their last administration of study treatment.

 The clinical activity of tasquinimod was evaluated independently in each cohort of patients
 of the four different tumour types. Data were presented as of the following study cut-off
 dates:

 -  Hepatocellular carcinoma cohort: 03 December 2014 (efficacy data); 11 April 2016 (safety
 data).

 -  Ovarian carcinoma cohort: 27 November 2013 (efficacy data); 05 October 2015 (safety
 data).

 -  Renal cell carcinoma cohort: 04 December 2013.

 -  Gastric carcinoma cohort: 27 September 2013.
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. Eastern Cooperative Oncology Group (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 Response Evaluation Criteria in Solid Tumours (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 included any tyrosine-kinase inhibitor.

 -  At least 4 weeks since the last dose of systemic anti-cancer therapy other than
 targeted therapy, which included 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 CrCl ≥60
 mL/min.

 11. Adequate hepatic function:

 - Serum bilirubin ≤1.5 mg/dL (≤25 μmol/L) for ovarian carcinoma, renal cell carcinoma
 and gastric carcinoma, serum bilirubin ≤3 mg/dL (≤50 μmol/L) for hepatocellular
 carcinoma cohorts.

 -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x ULN
 (≤5 x ULN if liver lesions were present i.e. liver metastasis or primary tumour
 of the liver for hepatocellular carcinoma cohort).

 12. Adequate bone marrow function:

 -  Absolute neutrophil count (ANC) ≥1.5 x 10^9/L.

 -  Platelets ≥50 x 10^9/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 have been
 documented prior to first administration of study treatment.

 16. For women who were 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.

 Inclusion Criteria - Hepatocellular Carcinoma Cohort:

 18. Histologically confirmed and documented hepatocellular carcinoma (excluding
 fibrolamellar carcinoma).

 19. Barcelona Clinic Liver Cancer (BCLC) stage C or BCLC stage B not amenable to
 locoregional therapy or refractory to locoregional therapy.

 20. 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.

 21. At least one measurable or evaluable lesion that was viable (i.e. vascularised), and
 had not been previously treated with locoregional therapy. A lesion that had been
 previously treated qualified as a measurable or evaluable lesion if there was
 demonstrable progression following locoregional therapy.

 22. Child-Pugh A Class only.

 23. Previously treated with sorafenib. Patients may have experienced radiographically
 documented disease progression during sorafenib therapy or after discontinuation of
 sorafenib therapy.

 24. The patient had received sorafenib as the most recent systemic therapeutic
 intervention (any hepatic locoregional therapy that had been administered prior to
 sorafenib was allowed, but not following sorafenib; radiation to metastatic sites
 [e.g. bone] following sorafenib therapy was permitted).

 Inclusion Criteria - Ovarian Carcinoma Cohort:

 18. Histologically confirmed and documented ovarian epithelial, fallopian tube, or primary
 peritoneal cavity cancer.

 19. Progression within 6 months of a platinum containing chemotherapy regimen (i.e.
 platinum resistant).

 20. Progression after up to three lines of chemotherapy.

 21. Maximum one line treatment with antiangiogenic therapy.

 Inclusion Criteria - Renal Cell Carcinoma Cohort:

 18. Metastatic renal cell carcinoma.

 19. Histologically or cytologically confirmed and documented renal cell carcinoma with a
 clear cell component.

 20. Previous treatment with at least one vascular endothelial growth factor inhibitor.

 21. Disease progression within 6 months prior to first study treatment.

 22. Patient had at most two prior targeted therapies for unresectable advanced or
 metastatic disease.

 Inclusion Criteria - Gastric Carcinoma Cohort:

 18. Histologically or cytologically confirmed and documented adenocarcinoma of the stomach
 or gastroesophageal junction.

 19. Unresectable advanced or initially metastatic or recurrent after curative resection.

 20. Progression after one prior regimen of chemotherapy including fluoropyrimidine and
 platinum (with or without trastuzumab, if human epidermal growth factor receptor 2 positive
 [HER2+]).

 21. Maximum one line treatment with antiangiogenic therapy.

 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 was symptomatic and/or required
 treatment.

 3. Malabsorption (other than in patients with gastric carcinoma and partial or complete
 gastrectomy) or intestinal obstruction.

 4. History of pancreatitis.

 5. Essential medications that are known potent inhibitors or inducers of CYP3A4.

 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) was 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 had 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 have compromised patient safety or interfered with the evaluation of
 the safety of the drug.

 12. Had known positive serology for human immunodeficiency virus.

 13. Investigational drug within 28 days or within five times the elimination half-life
 (whichever was longest) prior to first dose of study treatment.

 14. Known allergy to treatment medication or its excipients.

 15. Breastfeeding.

 Exclusion Criteria - Hepatocellular Carcinoma Cohort:

 16. Fibrolamellar carcinoma.

 Exclusion Criteria - Ovarian Carcinoma Cohort:

 16. Non-epithelial cancer and borderline tumours (e.g. tumours of low malignant potential).

 Exclusion Criteria - Gastric Carcinoma Cohort:

 16. Other histologic type than adenocarcinoma.