E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Unresectable, advanced or metastatic hepatocellular carcinoma |
|
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019828 |
E.1.2 | Term | Hepatocellular carcinoma non-resectable |
|
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 estimate the 6-month progression free survival rate in patients with unresectable locally advanced or metastatic hepatocellular carcinoma (HCC) with no prior chemotherapy for HCC, treated with 800 mg QD of BMS-582664 orally or with doxorubicin intravenously at a dose of 60 mg/m2 Q 3 weeks. |
|
E.2.2 | Secondary objectives of the trial |
• To estimate the difference in 6 month PFS rate in patients treated with BMS-582664 at 800 mg QD with patients treated with 60 mg/m2 of doxorubicin Q3-Weeks • To estimate tumor response rate, time to response, duration of response, progression free survival, overall survival, and disease control rate in each arm • To assess the safety and tolerability of BMS-582664 versus doxorubicin in this patient population. • To obtain samples for population PK of BMS-540215 (the active moiety) in patients with hepatocellular carcinoma treated with BMS-582664. • To assess the effects of the BMS-582664 and doxorubicin on pharmacodynamic markers in patients with hepatocellular carcinoma. • To obtain blood, paraffin embedded biopsy (if available) and (optional) fresh tumor samples to identify potential predictive markers of biological response
See protocol section 2.2 for more objectives
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Signed written informed consent
Target population 2) Patient with diagnosis of hepatocellular carcinoma meeting the criteria below: a) Biopsy-proven HCC (Histology or cytology) OR b) Radiological evidence of HCC by contrast-enhanced CT scan or contrastenhanced MRI AND i) Serology positive for Hepatitis B or C AND ii) Alpha fetoprotein > 400 µg/L 3) Not appropriate for curative surgical resection. 4) Subjects who have received local therapy such as surgery, chemoembolization, radiation therapy, hepatic arterial embolization, radiofrequency ablation, percutaneous ethanol injection or cryoablation are eligible, provided that they either have a index lesion which has not been subjected to local therapy and/or the index lesion(s) within the field of the local therapy has shown an increase of ≥ 25% in size. Local therapy must be completed at least 4 weeks prior to the baseline scan. 5) Measurable disease All patients must have at least one previously un-irradiated, bi-dimensionally measurable lesion by CT or magnetic resonance imaging (MRI) scan of ≥ 20 mm. Triphasic spiral CT or MRI scans are preferred when such equipment is available. All CT scans should employ a “hepatoma protocol” image capture technique. The following are not considered measurable lesions: a) Lesions seen on colonoscopy examination or barium studies b) Ascites 6) More than 4 weeks since surgery (with the exception of venous port access) 7) “Cancer for the Liver Italian Program” Score (CLIP) ≤ 3 a) No evidence of encephalopathy 8) ECOG performance status of 0, 1, 2 9) Adequate bone marrow function: a) Absolute neutrophil count ≥ 1500/mm3 b) Platelet count ≥ 80,000/mm3 c) Hemoglobin ≥ 9 g/dL 10) Adequate hepatic function: a) Total bilirubin ≤ 2.5 mg/dL b) AST/ALT ≤ 5 times the upper limit of normal (ULN) c) Serum albumin > 2.8 g/dL d) PT or INR ≤ 1.8 times ULN 11) Adequate renal function: a) Creatinine ≤ 2.0 mg/dL, OR b) Creatinine clearance ≥ 45 mL/min based on Cockcroft formula 12) Screening blood pressure of < 150/100 mmHg 13) Left ventricular ejection fraction (LVEF) ≥ 50%
Age and Sex 14) Men and women, ages 18 and older. Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 12 weeks after the study in such a manner that the risk of pregnancy is minimized. |
|
E.4 | Principal exclusion criteria |
Sex and Reproductive Status 1) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 12 weeks after the study. 2) WOCBP not using an acceptable method of contraception sufficient to prevent pregnancy according to the instructions of the Principal Investigator. 3) Women who are pregnant or breastfeeding 4) Women with a positive blood serum pregnancy test on enrollment or prior to study drug administration.
Target Disease Exceptions 5) Exclude patients with CLIP score >3.
Medical History and Concurrent Diseases 6) Active bacterial infections, HIV/AIDS or other severe disease that would preclude study participation. 7) Gastrointestinal tract disease or prior surgery, resulting in an inability to take or absorb oral medication. 8) Other primary malignancy except carcinoma in situ of the cervix or urinary bladder or non-melanoma skin cancer. 9) Mental incapacitation or psychiatric illness that would preclude study participation 10) Uncontrolled or significant cardiovascular disease including: myocardial infarction within 12 months, uncontrolled angina within 6 months, Class III-IV New York Heart Association (NYHA) congestive heart failure, grade 3 cardiac valve dysfunction
Physical and Laboratory Test Findings 11) Clinically significant ascites refractory to diuretic therapy 12) Presence of portal-systemic encephalopathy 13) Evidence of portal hypertension with bleeding esophageal or gastric varices within the past 2 months a) Prior variceal bleed permitted if patient has undergone banding and there has been no evidence of bleeding for 2 months 14) Hyponatremia with sodium < 125 mEq/L
Allergies and Adverse Drug Reactions 15) History of allergy to BMS-582664 or related compounds.
Prohibited Therapies and/or Medications 16) Prior systemic therapy for HCC, including systemic chemotherapy, biological therapy, or hormone therapy. 17) Patients with previous thalidomide or anti-angiogenesis therapy
Other Exclusion Criteria 18) Prisoners or patients who are compulsorily detained 19) Subjects with a history of bleeding disorders and thrombosis, including portal vein thrombosis coagulopathy, and are on chronic anti-platelet therapy (aspirin > 300 mg/day, clopidrogel; patients entering trial on warfarin should have frequent monitoring of INR for at least the first month on study and may require longer monitoring to insure that degree of anticoagulation does not go outside the therapeutic range.) 20) Subjects with fibrolamellar disease 21) Subjects with portal-caval shunts 22) Subjects who are on a liver transplant list 23) Subjects who have any known history of known brain metastases. Should patient have any signs and symptoms of possible brain metastases, a CT/MRI of the brain should be conducted prior to enrollment as clinically indicated. 24) Subjects with hepatitis B DNA levels ≥ 1,650 IU/ml using the Roche Taqman assay. 25) Subjects with centrally located cavitating lung lesions. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy Measures: The primary efficacy endpoint for this study is the 6 month progression free survival (PFS) rate.
Secondary efficacy endpoints include: Tumor response rate, time to response, duration of response, progression free survival, disease control rate, patient reported symptoms, and survival.
Response will be assessed according to the modified WHO criteria for tumor response. These assessments will be made every 6 weeks or more frequently if indicated. Serum levels of AFP will be monitored. Disease progression and tumor assessment will be confirmed by an Independent Response Review Committee (IRRC).
Primary Safety Outcome Measures: Safety will be assessed on the treated population and based on medical review of adverse event reports and the results of vital sign measurements, electrocardiograms, echocardiograms, physical examinations, and clinical laboratory tests. The incidence of adverse events will be tabulated and reviewed for potential significance and clinical importance. Laboratory values, adverse events and other symptoms will be graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.
Pharmacokinetics: BMS-582664 plasma concentration data will be used in conjunction with samples from other studies as part of the population PK assessment.
Pharmacodynamic Measures: Pharmacodynamic markers will be measured in plasma samples collected at specified intervals. |
|
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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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 | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
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 | Yes |
E.8.1.1 | Randomised | Yes |
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 | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Cross-over possibility for subjects randomized to the doxo arm, for unequivocal disease progression |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
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 | Information not present in EudraCT |
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 |
|
E.8.7 | Trial has a data monitoring committee | Yes |
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |