Title: UAB 0708 - A Pharmacokinetic Study of BMS-582664 in Subjects with Advanced Solid Malignancies and Normal Hepatic Function, and/or Hepatocellular Carcinoma with Impaired Hepatic Function
Sponsor: Bristol Myers Squibb
Investigator: James A. Posey, III, MD
OBJECTIVES
- To compare the pharmacokinetics of BMS-582664 in subjects with (HCC) and defined levels of hepatic impairment (as assessed using Child-Pugh classification) with the pharmacokinetics of BMS-582664 in subjects with other advanced solid malignancies and normal hepatic function.
- To assess safety and tolerability of BMS-582664 in subjects with HCC with mild, moderate, and severe hepatic impairment and in subjects with advanced malignancies with normal hepatic function.
- To assess the relationship between exposure to BMS-540215 and other measures of hepatic impairment or function including Cancer of the Liver Italian Program (CLIP) score and monoethylglycinexylidide (MEGX) elimination test.
- To assess efficacy of BMS-582664 in subjects with advanced solid tumor malignancies and subjects with HCC.
STUDY DESIGN
This is a Phase I, multi-institutional, open label multi dose study of BMS-582664 in subjects with advanced solid tumor malignancies and normal hepatic function or HCC and varying levels of hepatic impairment. Subjects will be assigned to one of four treatment groups based on tumor type and level of hepatic impairment as assessed by the Child-Pugh Classification (CPC).
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Group Assignments
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Group A = Hepatocellular Carcinoma + Child Pugh "A"
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Group B = Hepatocellular Carcinoma + Child Pugh "B"
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Group C = Hepatocellular Carcinoma + Child Pugh "C"
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Group D = Advanced Solid Malignancy (non-HCC) and normal hepatic function
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Based on PK results from Group B and Group C, adjusted dosing for new groups (Group E and/o F) may be added
Group E* = Hepatocellular Carcinoma + Child Pugh "B"
Group F* = Hepatocellular Carcinoma + Child Pugh "C"
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Subjects will undergo screening evaluations to determine eligibility within 28 days prior to the first dose of BMS-582664.
Subjects from Group A and D will be enrolled to the study first. On Day 1, subjects will be administered a single dose of 400mg of BMS-582664. Blood samples for pharmacokinetics will be collected over a 72 hour period. Serial plasma PK analyses of BMS-540215 concentration will be performed on Days 1 (pre-dose, 0.5, 1, 2, 4, 6, 8, 24, 48, 72 hrs) and Day 28 (pre-dose, 0.5, 1, 2, 4, 6, 8, 24 hrs). Subjects must be fasting for Day 1 and Day 28 pre-dose PK sample collections.
Day 1 dosing for subjects enrolled to Groups B and C will be calculated from the ratio of the point estimates for the AUC from Groups A and D. The first dose of BMS-582664 initiates the start of the on treatment period. A treatment period will consist of continuous daily dosing with study medications. The initial dosing period is defined as the first 3 weeks of study participation.
INCLUSION CRITERIA
Eligibility criteria for this study have been carefully considered to ensure the safety of the study subjects and to ensure that the results of the study can be used. No exceptions to eligibility criteria will be allowed. For entry into the study, the following criteria must be met:
1. A signed informed consent must be obtained prior to initiation of study specific activities or evaluations.
2. Subjects with a biopsy proven advanced solid tumor for Group D. Samples of archived tissue will be collected, OR
3. Subjects with a biopsy proven diagnosis of hepatocellular carcinoma for Groups, A, B, C, E, and F (HCC). Samples of archived tissue will be collected.
4. Subjects without a biopsy proven HCC must meet the criteria below:
a. Bi-dimensionally measurable disease with lesion 2cm, as seen on enhanced spiral CT or MIR, AND
b. Serology positive for Hepatitis B or C, AND
c. Alpha fetoprotein > 400mg/L
5. Fibrolamellar histology allowed if considered not appropriate for surgical resection based on tumor size, extra hepatic involvement, or multiple lobe involvement.
a. Subjects should not be appropriate for curative surgical resection.
b. Concurrent assignment to a transplantation list is allowed.
6. Prior chemotherapy treatment and liver-directed therapies (e.g., Radio Frequency Ablation, chemo-embolization, etc.) are allowed provided there is evidence the tumor has progressed since treatment and the following criteria are met:
a. Toxicity related to prior therapy must either have resolved, returned to baseline or been deemed irreversible and documented in the patient's medical record.
b. At least 4 weeks must have elapsed since the last chemotherapy, immuno-therapy, radiotherapy, anti-cancer hormonal therapy, or targeted therapy (e.g., sorafenib) and the beginning of protocol therapy (at least 6 weeks for Avastin and nitrosoureas).
7. Subjects with biliary obstruction for which a stent has been placed are eligible provided the stent has been in place for at least 10 days prior to the first dose of study drug and hepatic function has stabilized (two measurements at least two days apart that put the subject in the same hepatic dysfunction stratum will be accepted as evidence of stable hepatic function).
8. Physical and Laboratory Test Findings
9. More than 4 weeks since any prior major surgery.
10. ECOG performance status of 0-3.
11. Adequate bone marrow function:
a. Absolute neutrophil count 1500/mm3
b. Platelet count 80,000/mm3
c. Hemoglobin 9g/dL
12. Adequate hepatic function for Group D
a. Total bilirubin ≤ IULN (except for known Gilbert's syndrome)
b. AST and/or ALT ≤ 1.5 x IULN
c. Serum albumin > 3.5g/dL
d. INR ≤ 1.8 x IULN
13. Adequate renal function:
a. Creatinine ≤ 2.0mg/dL OR creatinine clearance 45mL/min based on Cockcroft-Gault formula
b. Screening blood pressure of < 150/100mm/Hg
14. Left ventricular ejection fraction (LVEF) 45% on baseline Echocardiogram.
Age and Sex
Men and women, ages 18 and older.
- WOCBP must have a negative serum pregnancy test (minimum sensitivity 25IU/L or equivalent units of HCG) within 72 hours prior to the start of study medication and before the start of each continuous cycle of therapy.
- 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.
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 using a prohibited contraceptive method such as only spermicidal/barrier method.
3. Women who are pregnant or breastfeeding.
4. Women with a positive pregnancy test on enrollment or prior to study drug administration.
Target Disease Exceptions
5. For sites also participating in primary HCC Clinical Protocol CA182006, subjects must be deemed ineligible for that study to participate in this clinical trial.
6. Portal-systemic encephalopathy with a clinical Grade 2.
7. Evidence of portal hypertension.
8. Prior variceal bleed permitted if subject has undergone banding and there has been no evidence of bleeding in last 2 months.
Medical History and Concurrent Disease
9. HIV/AIDS or other severe disease that would preclude study participation.
10. Gastrointestinal tract disease or prior abdominal surgery, resulting in an inability to take or absorb oral medication.
11. Evidence of biliary sepsis.
12. Other primary malignancy except carcinoma in situ of the cervix or urinary bladder or non-melanoma skin cancer diagnosed within the last 5 years.
13. Subjects with known brain metastasis. Subjects with signs or symptoms suggestive of brain metastasis are not eligible unless brain metastases are ruled out by CT or MRI.
14. Mental incapacitation or psychiatric illness that would preclude study participation.
15. History of thrombo-embolic disease requiring full anti-coagulation within the last six (6) months.
16. Uncontrolled or significant cardiovascular disease including:
a. Myocardial infarction within 12 months
b. Uncontrolled angina within 6 months
c. Class III-IV New York Heart Association (NYHA) congestive heart failure.
d. LVEF < 45%
e. Uncontrolled hypertension (Systolic BP > 150 and diastolic BP > 100mmHg for 24 hours). BP must be below 150/100mmHg at screening. Subjects with a history of hypertension on medication with calcium channel blockers that are CYP3A4 substrates should be changed to an alternative antihypertensive medication before study entry.
f. History of stroke, TIA or other ischemic event within the last 12 months.
g. Severe Cardiac Valve dysfunction.
h. Subjects with a history of bleeding disorders and thrombosis, including portal vein thrombosis coagulopathy, and are on chronic anti-platelet therapy (aspirin > 300mg/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.)
ADDITONAL INFORMATION
Contact: Robyn Wilson, RN
Telephone: 205-975-6347
Email: robyn.wilson@ccc.uab.edu