Cidofovir in Renal Transplant Recipients With BKVN

The primary objectives of this randomized, double-blind, placebo-controlled, dose-escalation
study are to evaluate the safety and tolerability of 3 dose levels of cidofovir when
administered to renal transplant recipients with BK virus nephropathy and to identify the
maximum tolerated doses (MTD) among the 3 dose levels of cidofovir in renal transplant
recipients with BK virus nephropathy. The secondary study objectives are to evaluate the
antiviral effect of cidofovir at each of 3 dose levels; to evaluate the pharmacokinetics (PK)
of cidofovir in renal transplant recipients with underlying renal impairment; to evaluate the
pharmacodynamics (PD) of cidofovir in this setting; to evaluate allograft function at the
completion of the study; and to assess allograft rejection at the completion of the study.
Patients with BKVN (virus nephropathy) diagnosed by positive plasma polymerase chain reaction
(PCR) or renal allograft biopsy will be randomized to receive study drug within 60 days of
the date of the renal biopsy or plasma PCR assay that established the diagnosis of BKVN. The
study consists of three dose cohorts (0.25 mg/kg, 0.5 mg/kg and 1.0 mg/kg); each cohort will
consist of approximately 12 subjects randomized 2:1 to receive either cidofovir or placebo
(0.9% normal saline) to define the MTD among the three specified doses of cidofovir. Once the
MTD is established, approximately 12 additional patients will be enrolled at that dose. The
MTD is defined as the dose in which no more than 2 of the 8 cidofovir treated subjects
experience a dose limiting toxicity (DLT). The target enrollment is 48 subjects if all dose
cohorts are fully enrolled. A 25% over-enrollment may be tolerated to allow for continued
enrollment of subjects in the lower dose cohort if data are under concomitant review by the
Data and Safety Monitoring Board (DSMB) or to replace non-evaluable study participants. Study
participants who have been randomized and have received cidofovir/placebo (in any cohort)
will be considered non-evaluable if they discontinue from the study or die for any reason
except toxicities definitely related to study treatment, including DLTs. These subjects may
be replaced. There will be a 5-week drug administration period (4 doses) followed by a 2 week
end-of-study observation and evaluation period for each cohort. At about 3 months after last
dose of study infusion, a member of the research staff will assess the study participant and
counsel on pregnancy status via a phone call. The study will be overseen by a DSMB who will
review the data after each dose cohort is completed. The primary endpoint of the study will
assess the safety and tolerability of cidofovir in kidney transplant recipients this will be
assessed by enumeration of adverse events (AEs) reported by the subjects and/or investigator,
and changes observed in the physical examination (including vital signs) and laboratory
evaluations during the drug administration and end-of-treatment observation and evaluation
periods. The severity and relationship of AEs to receipt of study drug will be determined
because the primary endpoint is focusing on the safety. The secondary endpoints are the
effect of cidofovir on BK virus as determined by: percentage of subjects who achieve an
undetectable BK virus urine and plasma PCR between baseline and end of treatment; rate of
reduction in urine and plasma BK virus load by quantitative PCR between baseline and end of
treatment; and time to reduction in BK virus urine and plasma PCR; the detailed PK of
cidofovir will be evaluated in subjects at the MTD; the PD of cidofovir will be assessed by
quantitating the change in BK virus deoxyribonucleic aci

Inclusion Criteria:

- Aged greater than or equal to 18 years.

- Kidney or kidney/pancreas transplant recipient.

- New onset BK Virus Nephropathy (BKVN) diagnosed by a positive plasma polymerase chain
reaction (PCR) assay for BK virus deoxyribonucleic acid (DNA) or by a renal biopsy
demonstrating BK virus (by immunohistochemistry, electron microscopy and/or in situ
hybridization) obtained as part of standard medical care within 60 days prior to
receipt of first dose of study drug.

- BK virus load in plasma greater than 10,000 copies/mL within prior 21 days.

- Glomerular filtration rate greater than 30 mL/min using Levey calculations.

- Absolute neutrophil count greater than 1000/microliter [with granulocyte colony
stimulating factor (GCSF) support as necessary].

- Women must be post-menopausal, surgically sterile or willing to use adequate
contraception (barrier method with spermicide, intrauterine device, oral
contraceptives, implant or other licensed hormone method) from time of study
enrollment through 1 month after the last dose of study treatment. Men must be
surgically sterile or willing to use contraception (barrier method with spermicide)
from time of study enrollment through 3 months after the last dose of study treatment.

Exclusion Criteria:

- Unable to provide valid informed consent.

- History of intolerance to cidofovir or related compounds (i.e. other nucleotide
derivatives [adefovir or tenofovir]).

- Pregnant or breast feeding women.

- Prior treatment with cidofovir within the last 2 weeks.

- Receipt of another investigational drug with proven nephrotoxic drug interaction with
cidofovir or known antipolyoma virus activity one month prior to study entry.

- Contraindication to renal biopsy (e.g., anticoagulant medication, unwilling to undergo
biopsy).

- Currently receiving or anticipated to receive any of the following within 2 weeks of
randomization:

- Amphotericin preparation (intravenous)

- Aminoglycosides (intravenous)

- Platinum - based chemotherapeutic agents

- NSAIDs - non steroidal anti-inflammatory drugs (aspirin given for cardioprotective
treatment is acceptable up to 650 mg per oral daily)

- Foscarnet

- Pentamidine (intravenous)

- Probenecid

- Leflunomide

- Hypotony or uveitis.