Clinical trial NCT01335074 (phase 1/phase 2, status: withdrawn)
Conditions: hepatocellular carcinoma
ICD codes: C22.0, C4A.9, C7B.1, C4A.0, C4A.31, C4A.51, C4A.8
Drugs: temsirolimus + sorafenib
SMILES: CNC(=O)C1=NC=CC(OC2=CC=C(NC(=O)NC3=CC(=C(Cl)C=C3)C(F)(F)F)C=C2)=C1
Eligibility criteria:

        Inclusion Criteria:

          -  Male or female patients ≥ 18 years of age

          -  Patients who have a live expectancy of at least 12 weeks

          -  Patients with histologically or radiologically and serologically confirmed advanced
             HCC; documentation of original biopsy for diagnosis is acceptable if tumor tissue is
             unavailable

          -  At least one tumor lesion that can be accurately measured in at least one dimension
             according to RECIST and which has not been treated with local therapy (TACE, PEI,
             radiofrequency ablation); CT or MRI scans should be not more than 2 weeks old to be
             used as baseline scan

          -  Patients who received sorafenib at 400 mg bid with consecutive dose reduction to 200
             mg bid due to intolerance, toxicity or adverse events or patients who are not eligible
             for full-dose first-line therapy with sorafenib, e.g. due to myocardial ischemia.

          -  At least a period of 4 weeks prior to baseline scan after completion of a local
             therapy such as surgery, radiation therapy, hepatic arterial embolization, TACE, PEI,
             radiofrequency ablation, cryoablation or others

          -  Patients who have an ECOG PS of 0, 1 or 2 or a Karnofsky Performance Status > 70 %

          -  Cirrhotic status of Child-Pugh class A or B; Child-Pugh status should be calculated
             based on clinical findings and laboratory results during the sorafenib pretreatment
             period

          -  No signs of decompensated liver cirrhosis

          -  White blood cells ≥ 3,000/mm³

          -  Neutrophils ≥ 1,500/mm³

          -  Platelets ≥ 100,000/mm³

          -  Bilirubin ≤ 3x ULN

          -  AST and ALT ≤ 3x ULN

          -  Creatinine normal

          -  PTT ≤ 1.5 ULN

          -  INT 2.0 to 3.0

          -  Fasting serum cholesterol ≤ 350 mg/dL

          -  Triglycerides ≤ 300 mg/dL

          -  Proteinuria ≤ 1 g in 24 h

          -  No history of allergic reactions to compounds similar to temsirolimus or sorafenib

          -  No prior thromboembolic disease

          -  No history of hematemesis or hemoptysis

          -  No other uncontrolled illness

          -  Women of childbearing potential must have had a negative serum or urine pregnancy test
             48 h prior to the administration of the first study treatment

          -  Patients who give a written informed consent obtained according to local guidelines

          -  No other concurrent investigational drugs or anticancer agents

          -  No concurrent traditional Chinese or herbal medicine (e.g. sho-saiko-to, silymarine)

        Exclusion Criteria:

          -  Patients currently receiving chemotherapy, immunotherapy or radiotherapy or who have
             received these with 4 weeks of study entry except for standard sorafenib therapy

          -  Prior use of systemic investigational agents for HCC

          -  Previous concurrent cancer that is distinct in primary site or histology from HCC,
             except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder
             tumors and any cancer curatively treated > 3 years prior to entry is permitted

          -  Chronic treatment with steroids or another immunosuppressive agents

          -  A known history of HIV seropositivity

          -  Renal failure requiring hemo- or peritoneal dialysis

          -  History of cardiac disease: congestive heart failure (NYHA > 2), active coronary
             artery disease, cardiac arrhythmias requiring anti-arrhythmic therapy other than
             b-blockers or digoxin, uncontrolled hypertension; myocardial infarction more than 6
             months prior to study entry is permitted

          -  Comedication with known strong Cyp3A4 inhibitors or Cyp3A4/5 inducers

          -  Active clinically serious infections (> grade 2 CTCAE v.3.0)

          -  Known carcinomatous meningitis or uncontrolled brain disease

          -  Patients with clinically significant gastrointestinal bleeding with 30 days prior to
             study entry or on oral anti-vitamin K medication (except low dose coumarin, i.e. INR
             outside the therapeutic range of 2.0 to 3.0)

          -  History of organ allograft

          -  Uncontrolled diabetes

          -  Impairment of gastrointestinal function of gastrointestinal disease that may
             significantly alter the absorption of sorafenib (e.g. ulcerative colitis, uncontrolled
             nausea, vomiting, diarrhea, malabsorption syndrome)

          -  Patients who have not recovered from surgery

          -  Female patients who are pregnant or breast feeding, or adults of reproductive
             potential who are not using effective birth control methods; if barrier contraceptives
             are being used, these must be continued throughout the trial by both sexes

          -  Patients who are using other investigational agents or who had received
             investigational drugs < 4 weeks prior to study entry

          -  Patients with contraindications to sorafenib or temsirolimus treatment.

          -  History of noncompliance to medical regimens

          -  Patients unwilling or unable to comply with the protocol

          -  Substance abuse, medical, psychological or social conditions that may interfere with
             the patients participation in the study or evaluation of the study results