UAB 0143

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

1. 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.



2. To define the dose-limiting and non dose-limiting toxicities of DX-5951f in this patient population.



3. To determine the effects of renal dysfunction on the plasma pharmacokinetics and pharmacodynamics of DX-8951f.



4. To establish a model for dosing DX-8951f in patients with impaired renal function.



5. To validate the utility of Technetium Tc 99m Pentetate Injection (technetum-DTPA) as an indicator of DX-8951f renal elimination.



6. 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:

1. All patients must have histologically or cytologically confirmed advanced solid tumor malignancy.



2. Patients refractory to standard therapy or for which no standard therapy exists.



3. Men and women of any racial and ethnic group who are 18 years of age or older will be included.



4. ECOG performance status 0-2.



5. Expected survival of at least 12 weeks.



6. 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.



7. Fully recovered from any previous surgery (at least four weeks since major surgery).



8. 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)


9. Must have recovered from prior radiation therapy (at least four weeks since radiation).



10. Must provide written informed consent.



11. 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:

1. Prior cancer chemotherapy with DX-895f.



2. Concurrent cancer chemotherapy, radiotherapy or surgery.



3. 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.



4. 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.



5. 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.



6. 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.



7. Overty psychosis or mental disability or otherwise incompetent to give informed consent.



8. 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.