A
Phase I Study of DX-8951f (Exatecan Mesylate for Injection)
in Patients with Renal Dysfunction (Sponsor Protocol 8951A-PRT026)
SPONSOR:
Daiichi Parmaceutical Corporation
PRINCIPAL
INVESTIGATOR: Wasif Saif, M.D.
OBJECTIVES
- To determine
the maximum tolerated dose of DX-8951f when given daily
for 5 consecutive days repeated every 3 weeks to patients
with renal dysfunction.
- To define
the dose-limiting and non dose-limiting toxicities of
DX-5951f in this patient population.
- To determine
the effects of renal dysfunction on the plasma pharmacokinetics
and pharmacodynamics of DX-8951f.
- To establish
a model for dosing DX-8951f in patients with impaired
renal function.
- To validate
the utility of Technetium Tc 99m Pentetate Injection (technetum-DTPA)
as an indicator of DX-8951f renal elimination.
- To correlate
the study and utility of the Erythromycin Breath Test
and the Caffeine Urinary Test as surrogate markers of
DX-8951f elimination.
PATIENT
SELECTION
Inclusion
Criteria
At the time of
screening, all patients must meet the following criteria
for inclusion into the study:
- All patients
must have histologically or cytologically confirmed advanced
solid tumor malignancy.
- Patients refractory
to standard therapy or for which no standard therapy exists.
- Men and women
of any racial and ethnic group who are 18 years of age
or older will be included.
- ECOG performance
status 0-2.
- Expected survival
of at least 12 weeks.
- Adequate liver
and bone marrow function, defined as: a total bilirubin
value within normal institutional limts: AST or ALT <
2x upper limit of normal; ANC > 1.5 x 103/mm3;
platelet count > 100 x 103/mm3;
hemoglobin > 9.0 gm/dL; albumin >
2.8 g/dL. All qualifying laboratory parameters must be
determined within two weeks prior to first treatment.
- Fully recovered
from any previous surgery (at least four weeks since major
surgery).
- Must qualify
based on renal function parameters as defined by :
- Normal
(CrCL > 80mL/min)
- Mild Dysfunction
(CrCL 50-80 mL/min)
- Moderate
Dysfunction (CrCL 30-50 mL/min)
- Severe
Dysfunction (CrCL < 30 mL/min)
- ESRD (requiring
dialysis)
- Must have
recovered from prior radiation therapy (at least four
weeks since radiation).
- Must provide
written informed consent.
- Patient must
be willing and able to undergo an assessment of renal
function by 24-hour urinary creatinine clearance (NOT
corrected for BSA) and a Technetium Tx99-DTPA glomerular
filtration rate test.
Exclusion
Criteria
At the time of
screening, patients will be excluded from the study if any
of the following apply:
- Prior cancer
chemotherapy with DX-895f.
- Concurrent
cancer chemotherapy, radiotherapy or surgery.
- Concurrent
serous infection or a life-threatening illness (unrelated
to tumor), e.g., active congestive heart failure, uncontrolled
angina, or myocardial infarction within 6 months prior
to study entry. Patients on chronic hemodialysis or ambulatory
peritoneal dialysis can be enrolled on the study; however,
the pharmacokinetic sampling scheme will be altered as
described in Appendix H.
- Because of
the teratogenic potential of DX-8951f, women with the
potential to become pregnant, unless utilizing birth control,
or who are pregnant are excluded from the study.
- A negative
pregnancy test must be documented durgin the screening
period for women of childbearing potetial. Breast feeding
women are excluded from this trial because of the potential
toxicity to the child. Men should avoid fathering children
during their participation in this study.
- Presence of
symptomatic/active brain metastasis (e.g., edema or progression
on a new scan). If patients have a history of brain metastasis,
a CT or MRI scan of the brain should be performed prior
to entry on study.
- Overty psychosis
or mental disability or otherwise incompetent to give
informed consent.
- Administration
of any investigational drug (including analgesics or anti-emetic)
within 28 days prior to receipt of DX-8951f.
ADDITIONAL
INFORMATION
For further information,
contact Linda Pleasant, RN, BSN, OCN at (205) 934-9236 or
page through the UAB Paging Operator at (205) 934-3411,
Pager #6659.
