Phase I and pharmacokinetic study of ABI-007, a Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel.
OBJECTIVE
ABI-007 is a novel Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel. The absence of Cremophor EL may permit ABI-007 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. This Phase I study examines the toxicity profile, maximum tolerated dose (MTD), and pharmacokinetics of ABI-007.


METHODS
ABI-007 was administered in the outpatient setting, as a 30-min infusion without premedications. Doses of ABI-007 ranged from 135 (level 0) to 375 mg/m2 (level 3). Sixteen patients participated in pharmacokinetic studies.


RESULTS
Nineteen patients were treated. No acute hypersensitivity reactions were observed during the infusion period. Hematological toxicity was mild and not cumulative. Dose-limiting toxicity, which occurred in 3 of 6 patients treated at level 3 (375 mg/m2), consisted of sensory neuropathy (3 patients), stomatitis (2 patients), and superficial keratopathy (2 patients). The MTD was thus determined to be 300 mg/m2 (level 2). Pharmacokinetic analyses revealed paclitaxel C(max) and area under the curve(inf) values to increase linearly over the ABI-007 dose range of 135-300 mg/m2. C(max) and area under the curve(inf) values for individual patients correlated well with toxicity.


CONCLUSIONS
ABI-007 offers several features of clinical interest, including rapid infusion rate, absence of requirement for premedication, and a high paclitaxel MTD. Our results provide support for Phase II trials to determine the antitumor activity of this drug.
Ibrahim
Nuhad K
NK
Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Desai
Neil
N
Legha
Sewa
S
Soon-Shiong
Patrick
P
Theriault
Richard L
RL
Rivera
Edgardo
E
Esmaeli
Bita
B
Ring
Sigrid E
SE
Bedikian
Agop
A
Hortobagyi
Gabriel N
GN
Ellerhorst
Julie A
JA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000068196:Albumin-Bound Paclitaxel; D000418:Albumins / Q000737:chemistry; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D002368:Castor Oil / Q000031:analogs & derivatives* / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009422:Nervous System Diseases / Q000139:chemically induced; D017239:Paclitaxel / Q000009:adverse effects / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010316:Particle Size; D013280:Stomatitis / Q000139:chemically induced; D043823:Taxoids; D016896:Treatment Outcome
D000068196:Albumin-Bound Paclitaxel; D000418:Albumins; D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; C023040:polyethoxylated castor oil; D002368:Castor Oil; D017239:Paclitaxel