Protocol Number: 04-C-0280

Title:

Randomized, Crossover, Pharmacokinetic Study of Paclitaxel (Taxol) and ABI-007 (a Cremophor EL-Free, Protein Stabilized, Nanoparticle Paclitaxel) in Patients with Advanced Solid Tumors

Number:

04-C-0280

Summary:

Paclitaxel is registered for advanced breast cancer, ovarian cancer and non-small cell lung cancer and is usually administered at a dose of 135-225 mg/m2 in a 3-hour infusion every 3 weeks. Currently, paclitaxel is commercially available in a formulation containing Cremophor EL (CrEL) and dehydrated ethanol USP (1:1, vol/vol; Taxol). In recent years, substantial evidence has been generated suggesting that CrEL is a biologically and pharmacologically active compound; its use has been associated with acute hypersensitivity reactions as well as with pharmacokinetic alterations of paclitaxel itself or with other agents administered concomitantly. ABI-007 is a novel CrEL-free, protein-stabilized, nanoparticle formulation of paclitaxel. The absence of CrEL permits paclitaxel to be administered without the premedications used routinely for the prevention of hypersensitivity reactions. Furthermore, this novel formulation permits a higher paclitaxel concentration in solution and, thus, a decreased infusion volume and time. To assess the clinical pharmacological implications of the altered drug formulation, a group of 14 patients with advanced solid tumors will be treated in a randomized crossover design with paclitaxel formulated in the absence (ABI-007) and presence (Taxol) of CrEL. Patients will be treated with at least 3 cycles of chemotherapy until evidence of disease progression is noted. The objectives of the study will be to determine whether a change in the formulation alters the pharmacokinetic profile of paclitaxel in plasma, to attempt to correlate pharmacokinetic data with a change in the percent decrease in neutrophil counts at nadir, to evaluate intra- and inter-individual pharmacokinetic variability of ABI-007, and to evaluate protein binding of paclitaxel via measurement of -1-acid glycoprotein and serum albumin levels in patients receiving ABI-007 and patients receiving Taxol.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

INCLUSION CRITERIA:

1. Patients must have histologically confirmed malignant solid tumor.

2. Patients must have incurable, locally advanced or metastatic tumors that are likely to be responsive to taxanes.

3. Patients must be equal to or greater than 18 years of age.

4. Patients must have an ECOG performance status of 0, 1, or 2.

5. Patients must have a life expectancy of 3 months or longer.

6. Patients of childbearing potential must be willing to use an effective means of contraception during their participation on trial.

7. Patients must have adequate bone marrow and organ function defined by the following:

-Granulocyte count greater than or equal to 1500/microL

-Platelet count greater than or equal to 100,000/microL

-Total bilirubin within normal institutional limits

-ALT/SGPT and AST/SGOT less than or equal to 1.5 x institutional upper limit of normal (ULN)

-Creatinine within normal institutional limits or if above institutional ULN, measured creatinine clearance greater than or equal to 60 ml/min

8. Patients must be willing to comply with on-study and follow-up procedures, e.g. blood sampling for the purpose of pharmacokinetic analysis.

9. Patients must be able to sign a written informed consent.

10. Patients must have a left ventricular ejection fraction of greater than or equal to 40% without clinical signs or symptoms of heart failure.

EXCLUSION CRITERIA

1. Patients who have had chemotherapy or radiotherapy less than 3 weeks (less than 6 weeks for nitrosoureas or mitomycin) or hormonal therapy less than 2 weeks prior to entering the study, and patients who are refractory to paclitaxel and patients with previously untreated locally advanced breast cancer. Prostate cancer patients may continue LHRH.

2. Patients with symptomatic or untreated brain metastases or carcinomatous meningitis. Also patients who are unable to remain free of corticosteroid therapy for more than 4 weeks due to CNS disease.

3. Patients who are on concurrent investigational agent(s).

4. Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to paclitaxel, such as docetaxel, CrEL, polysorbate 80 (Tween 80), or CrEL-containing medication, such as cyclosporine.

5. Patients with uncontrolled intercurrent illness including active serious infection, symptomatic congestive heart failure, unstable angina pectoris, psychiatric illness or social situations that would limit compliance with study requirements.

6. Patients who are pregnant or lactating.

7. Patients with hematological malignancies.

8. Concurrent other chemotherapy, immunotherapy or radiotherapy.

9. Concurrent use of other substances known or likely to interfere with the pharmacokinetics of paclitaxel (e.g., verapamil, cyclosporine).

10. Use of drugs, herbal preparations and dietary supplements known to influence the expression and function of CYP3A (e.g., phenytoin, rifampin, St. John's wort, garlic supplements, grapefruit juice) and/or CYP2C8 within 2 weeks preceding study entry.

11. Patients with a history of seizure disorder who require anticonvulsant therapy.

Special Instructions: Currently Not Provided

Keywords:

Carcinoma

Pharmacology

Disposition

Formulation

Plasma

Recruitment Keywords:

None

Conditions:

Investigational Drug(s):

ABI-007

Investigational Device(s):

None

Contacts:

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citations:

Wani MC, Taylor HL, Wall ME, Coggon P, McPhail AT. Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia.

J Am Chem Soc. 1971 May 5;93(9):2325-7.

Gelderblom H, Verweij J, Nooter K, Sparreboom A. Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation. Eur J Cancer. 2001 Sep;37(13):1590-8.

Adams JD, Flora KP, Goldspiel BR, Wilson JW, Arbuck SG, Finley R. Taxol: a history of pharmaceutical development and current pharmaceutical concerns. J Natl Cancer Inst Monogr. 1993;(15):141-7.

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