An Open-Label, Single Arm, Phase 1 Study of the Pharmacokinetics and Safety of Carfilzomib in Subjects with Relapsed Multiple Myeloma and End-stage Renal Disease

Summary

This study is a multi-center, non-randomized, comparative pharmacokinetci (PK) study of carfilzomib in subjects with relapsed multiple myeloma and end-stage renal disease (eSRD) versus those with relapsed multiple myeloma and normal renal function.

Systemic exposure (as measured by area under the curve [auC]), CL, and other PK parameters in subjects with eSRD treated with carfilzomib will be compared to PK parameters in subjects with normal renal function to assess the need for dose modification of carfilzomib in subjects with eSRD.

each of 2 cohorts will be composed of at least 8 PK-evaluable subjects for a total of approximately 16 PK-evaluable subjects.

Carfilzomib will be administered over 30 minutes ((+-) 5 minutes) as an intravenous (iV) infusion on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle.

Pharmacokinetic evaluable subjects are defined as subjects who complete all PK assessments, receive all protocol-specified carfilzomib doses through cycle 2 Day 1, and are not dose-reduced through Cycle 2 Day 1. Subjects who are not considered PK evaluable will be replaced. Based on the calculated creatinine clearance (CrCl) by Cockcroft-Gault at baseline (Day 1), subjects will be assigned to one of the following two groups:

Cohort 1: Subjects with CrCl [GreaterThanorequalTo] 75 mL/min (normal renal function; n[?]8)
Cohort 2: Subjects on hemodialysis (eSRD; n[?]8)


Subjects may continue study treatment until progressive disease (PD),unacceptable toxicity, withdrawal of consent, study closure, or death, whichever occurs earliest.

Blood samples will be collected to measure plasma concentration of carfilzomib and for measurement of the major metabolites (metabolites PR-389/M14, PR-413/M15, and PR-519/M16) on C1D16 and C2D1.

endpoints:
Primary endpoint:
The primary endpoints are the area under the curve, from time 0 to the last concentration measures (auC(0-last)) and area under the curve, from time 0 extrapolated to infinity (auC(0-inf)) of carfilzomib 56 mg/m2 at Cycle 2 Day1

Secondary endpoints:
* Pharmacokinetics of carfilzomib 56 mg/m2 at C2D1: maximum plasma concentration (Cmax), time to maximum concentration (tmax), clearance (CL), terminal half-life (t1/2), volume of distribution at steady state (Vss), and mean residence time (MRT)
* Pharmacokinetics of carfilzomib 27 mg/m2 at C1D16: auC(0-last), auC(0-inf), Cmax, tmax, CL, t1/2, Vss, and MRT
* Pharmacokinetics of major metabolites (metabolites PR-389/M14, PR-413/M15, and PR-519/M16) at C1D16 (27 mg/m2) and C2D1 (56 mg/m2): auC0-last, auC0-inf, Cmax, tmax, t1/2, and MRT
* Safety and tolerability of carfilzomib: incidence, severity and causal relationship for all adverse events (aes) (including serious adverse events [Saes]); incidence of laboratory shifts for key analytes to and from limits of normal range Common Terminology Criteria for adverse events (CTCae) Grade relative to baseline in key laboratory parameters

exploratory endpoints:
* overall response rate (oRR) (partial response (PR) or better)
* Clinical benefit response (CBR) (defined as oRR + minimal response (MR))
* Duration of response (DoR)
* Progression-free survival (PFS)

Participant Eligibility

1. Relapsed multiple myeloma at study entry (may be refractory to the last treatment
regimen prior to study entry)
2. Evaluable multiple myeloma with at least one of the following:
a. Serum M-protein >= 0.5 g/dL, or
b. Urine M-protein >= 200 mg/24 hour, or
c. In subjects without detectable serum or urine M-protein, serum free light chain
(SFLC) > 100 mg/L (involved light chain) and an abnormal kappa/lambda
ratio of < 0.26 for subjects with monoclonal lambda free light chain (monoclonal lambda FLC)
or > 1.65 for subjects with monoclonal kappa FLC, or
3. Received at least 1 prior treatment regimen or line of therapy for multiple myeloma. (Induction therapy followed by stem cell transplant and consolidation/maintenance therapy will be considered as one line of therapy)
4. Prior therapy with carfilzomib is allowed as long as the subject had at least a PR to prior
carfilzomib therapy, did not discontinue carfilzomib therapy due to toxicity, and had at
least a 6-month treatment-free interval from last dose of carfilzomib received until first
study treatment. (Subjects may receive maintenance therapy with drugs that are not in
the proteasome inhibitor class during this 6-month carfilzomib treatment-free interval).
The exception to this is for subjects enrolled in any other Onyx-sponsored trial who are
still in post treatment follow-up (these subjects are excluded from participation).
5. Prior therapy with a bortezomib-containing regimen is allowed as long as the subject had
at least 1 21-day bortezomib treatment-free interval from last dose received until first study treatment.
6. Renal Function criteria: Clinical diagnosis of ESRD requiring hemodialysis for at least 1 month prior to enrollment. Subjects should be stable (i.e., without acute complications). Subjects with
Normal Renal Function will have a calculated CrCl >= 75 mL/min at screening using the
Cockcroft-Gault equation.
7. Males and females >= 18 years of age
8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2
9. Adequate hepatic function within 21 days prior to C1D1, with bilirubin < 1.5 times the
upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) < 3 times the ULN
10. Left ventricular ejection fraction (LVEF) >= 40% withing the 21 days prior to C1D1. (2-D transthoracic echocardiogram (ECHO) is the preferred method of evaluation. Multi-gated acquisition scan (MUGA) is acceptable if ECHO is not available
11. Absolute neutrophil count (ANC) >= 1000/mm3 within 21 days prior to enrollment.
Screening ANC should be independent of growth factor support for >= 7 days
12. Hemoglobin >= 8.0 g/dL within 21 days prior to enrollment. Use of erythropoietic
stimulating factors and red blood cell (RBC) transfusions per institutional guidelines
is allowed, however most recent RBC transfusion may not have been given within 7 days
prior to obtaining screening hemoglobin
13. Platelet count >= 50,000/mm3 (>= 30,000/mm3 if myeloma involvement in the bone marrow
is > 50%) within 21 days prior to enrollment. Subjects should not have received platelet
transfusions for at least 7 days prior to obtaining the screening platelet count
14. Written informed consent in accordance with federal, local, and institutional guidelines
15. Female subjects of child-bearing potential (FCBP) must have a negative serum pregnancy
test within 21 days prior to enrollment and agree to use an effective method of
contraception during and for 3 months following last dose of drug (more frequent
pregnancy tests may be conducted if required per local regulations). This protocol
defines a FCBP as a sexually mature woman who: 1) has not undergone a hysterectomy
or bilateral oophorectomy, or 2) has not been naturally postmenopausal for at least
24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive
months).
16. Male subjects must use an effective barrier method of contraception during study and for
30 days following the last dose if sexually active with a female of child-bearing potential