A Study With Tasquinimod Treating Patients With Hepatocellular, Ovarian, Renal Cell and Gastric Cancers
Condition: Advanced or Metastatic Hepatocellular Cancer; Advanced or Metastatic Ovarian Cancer; Metastatic Renal Cell Cancer; Advanced or Metastatic Gastric Carcinoma
MeSH terms: Carcinoma; Ovarian Neoplasms; Carcinoma, Renal Cell; Liver Neoplasms; Carcinoma, Hepatocellular; Stomach Neoplasms
Intervention: Tasquinimod; Tasquinimod; Tasquinimod; Tasquinimod
Intervention description: 1 capsule: initially at 0.5 mg/day, increasing to 1 mg/day, maintaining 0.5 mg/day or decreasing to 0.25 mg/day after at least 2 weeks.; 1 capsule: initially at 0.5 mg/day, increasing to 1 mg/day, maintaining 0.5 mg/day or decreasing to 0.25 mg/day after at least 2 weeks.; 1 capsule: initially at 0.5 mg/day, increasing to 1 mg/day, maintaining 0.5 mg/day or decreasing to 0.25 mg/day after at least 2 weeks.; 1 capsule: initially at 0.5 mg/day, increasing to 1 mg/day, maintaining 0.5 mg/day or decreasing to 0.25 mg/day after at least 2 weeks.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 201.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Advanced; Metastatic; Hepatocellular cancer; Ovarian cancer; Renal cell cancer; Gastric carcinoma

Summary:

      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.
    

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.