Comparison of Pharmacokinetics and Pharmacodynamics of Subcutaneous Versus Intravenous Administration of Bortezomib in Patients With Multiple Myeloma

Nantes University Hospital (NUH)

Status and phase

Completed

Phase 1

Conditions

Multiple Myeloma

Treatments

Drug: bortezomib

Study type

Interventional

Funder types

Other

Identifiers

NCT00291538

BRD/05/9-B

Details and patient eligibility

About

In this open-label randomised phase I trial, bortezomib will be administrated to 2 groups of 10 patients with MM who have inclusion criteria use the extended 2nd line indication, either intravenously (group 1 = 10 patients) or subcutaneously (group 2 = 10 patients). The schedule of administration of bortezomib will be the following : 1.3 mg per square meter of body-surface area twice weekly for 2 weeks, followed by 1 week without treatment, for up to eight cycles, either IV (group 1) or SC (group 2).

The primary objective is to characterize the pharmacokinetics of the 2 routes of administration.

The secondary objectives are to characterize the pharmacodynamics (20S proteasome inhibition in whole blood), toxicity, including cardiac safety, and efficacy of the 2 routes of administration.

Enrollment

20 estimated patients

Sex

All

Ages

Under 75 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

diagnosis of MM according to the SWOG criteria (annex I)
symptomatic MM stage II or III according to Durie-Salmon staging system (annex II) or stage I with one symptomatic osteolytic lesion
with progressive disease after at least one prior therapy and who have already undergone or are unsuitable for bone marrow transplantation
with measurable levels of paraprotein in the serum (> 1g/dl) or in the urine (> 0.2g/24h)
age < 75 years
able to understand and to given an informed consent
male, female without childbearing potential or negative urine pregnancy test within 72 hours prior to beginning the treatment. Women of childbearing potential must be following adequate contraceptive measures. Men must agree to use an acceptable method of contraception (for themselves or female partners) for the duration of the study
no active systemic infection. In the presence of any active systemic infection, adequate broad-spectrum or organism-specific antibiotic coverage must be administered. Patients must be afebrile with stable vital signs while receiving antibiotics for at least 48 hours prior to beginning the treatment with Bortezomib.
Each subject will weigh ³50 kg and have a body mass index (BMI) of £30 kg/m2 (see annex V for BMI formula).

Exclusion criteria

life expectancy < 2 months
ECOG performance status > 2 (annex III)
proven amyloidosis
positive HIV serology
antecedents of severe psychiatric disease
> NCI grade 2 peripheral neuropathy (Annex IV)
History of clinically relevant cardiac disease, including prior myocardial infarction, prior or existing heart failure, existing uncontrolled angina or clinically significant pericardial disease Evidence of arrhythmia, 2nd degree or greater AV block or prolonged QTc interval (>0.45 seconds in males, >0.47 seconds in females) on screening ECG
serum biochemical values as follow
creatinine level > 200mmol/l
bilirubin, transaminases or gGT > 3 the upper normal limit
potassium, calcium or magnesium outside of upper or lower normal limits
haematology values as follow
platelet < 70x 109 /L within 14 days of enrollment
absolute neutrophil count <1.0 x 109/L within 14 days of enrolment
concomitant use of drugs able to modify QTc interval within 1 week prior to the first dose of bortezomib and during Cycle 1 (Annex VI)
concomitant use of potent inhibitors or inducers of the cytochrome P450 (CYP) enzymes 3A and 2C19 within 1 week prior to the first dose of bortezomib and during Cycle 1 (see annex VII list of representative drugs).
use of any experimental drugs within 30 days of baseline
hypersensitivity to bortezomib, boron, or mannitol