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.

Eligibility Criteria:
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.