Study of the Pharmacokinetics and Safety of Carfilzomib in Subjects With Advanced Malignancies and Hepatic Impairment

The primary objective of this study is to assess the influence of hepatic impairment on area
under the curve (both area under the curve, from time 0 to the last concentration measured
[AUC0-last] and area under the curve, from time 0 extrapolated to infinity [AUC0-inf]) of
carfilzomib at Cycle 1 Day 16 (C1D16) in subjects with relapsed or progressive advanced
malignancies.

Key Inclusion Criteria:

1. Relapsed or progressive advanced malignancies (solid tumors or hematologic
malignancies)

2. At least ≥ 2 prior treatment regimens for the underlying malignancy

3. Confirmed advanced solid tumor or hematologic malignancy

4. Measurable or evaluable disease

5. Clinical diagnosis of chronic hepatic impairment that is stable with no acute
worsening of liver failure within one month prior to enrollment. Hepatic impairment
will be assessed as per NCI-ODWG schema and will fall into one of the following three
categories:

- Cohort 2 (mild): Bilirubin > 1-1.5 × upper limit of the normal range (ULN) or
aspartate aminotransferase (AST) > ULN, but bilirubin ≤ ULN

- Cohort 3 (moderate): ≥ 1.6-3 × ULN; any AST

- Cohort 4 (severe): Bilirubin > 3 × ULN; any AST

Exception to Inclusion Criterion #5 for Subjects with Normal Hepatic Function:

All subjects enrolled with normal hepatic function (N=10) must meet all inclusion
criteria as outlined with the exception of Inclusion Criterion

#5, which should be substituted with the following criterion to be enrolled into the
study:

- Cohort 1 (normal hepatic function): Bilirubin ≤ ULN; AST ≤ ULN

6. ECOG Performance Status 0-2

7. Left ventricular ejection fraction (LVEF) ≥ 40%

8. Adequate renal function (calculated creatinine clearance ≥ 30mL/min)

9. Active congestive heart failure (New York Heart Association [NYHA] Class III to IV),
symptomatic ischemia, conduction abnormalities uncontrolled by conventional
intervention or myocardial infarction within the protocol-specified period prior to
enrollment

Key Exclusion Criteria:

1. Subjects with symptomatic brain metastasis or central nervous system [CNS] disease

2. Significant neurotoxicity (Grade 2 with pain or higher) at the time of enrolment

3. Known HIV, Hepatitis B virus and Hepatitis C virus infection (Exception: Subjects
with chronic or cleared HBV and HCV infection and stable liver function tests
[bilirubin, AST] will be allowed)