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Phase I And Pharmacokinetics (PK) Of DJ-927, An Oral Taxane, In Patients (Pts) With Advanced Cancers.
Published 2004 · Medicine
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2028 Background: DJ-927, a novel semi-synthetic taxane and a poor substrate of P-glycoprotein (Pgp), is orally bioavailable and possesses potent anti-tumor activity against Pgp expressing human cancers. Preclinically, DJ-927 is more potent than both paclitaxel and docetaxel. METHODS This first-in-human study assessed the maximum tolerated dose [MTD], dose limiting toxicities [DLT] and PK of DJ-927 administered as a single oral 3-weekly dose. Pts were stratified based on prior therapy into minimally (MP) and heavily (HP) pretreated cohorts. The starting dose of DJ-927, 1.5 mg/m2, was increased in 100% increments until grade 2 toxicities occurred during course 1 and by 50% thereafter, until consistent DLT were observed. RESULTS To date, 40 pts have received 109 courses [median-2; range 1-8] at the following doses: 1.5 mg/m2 , 3 mg/m2 , 6 mg/m2 , 12 mg/m2 , 18 mg/m2 , 27 mg/m2 , 35 mg/m2  and 40 mg/m2 . Demographics: 23 male / 17 female; median [range] age- 57 [31-81]; PS 0 , PS 1 , and PS 2 . Primary tumors are colorectal , breast , pancreas , renal cell , soft tissue sarcoma  and others . Minimal drug-related toxicities were observed at doses 5 days duration  and grade 3 thrombocytopenia  were the predominant hematological toxicities observed at 40 and 35 mg/m2 doses. Non-hematological toxicities included: transient grade 3 peripheral sensory neuropathy after 3 cycles  at 27 mg/m2, grade 3 diarrhea and grade 3 mucositis  at 40mg/m2. Minor responses were seen in taxane-refractory breast carcinoma  and transitional cell carcinoma of the bladder . Disease stabilization for >3 months was noted in 8 pts. Plasma PK of DJ- 927 were dose proportional over the dose range explored. The Cmax, mean (CV%) 58.83 (70.2) μg/L, AUC (inf) 1792.7 (36.4) h*μg/L), clearance/F 45.93 (48.6) L/h, and terminal half-life 175.5 (38.2) h were seen at 40 mg/m2 dose (8). CONCLUSIONS DJ-927 generates predictable systemic drug exposures and has been well tolerated when orally administered. Dose escalation ceased due to DLT in 2/3 MP + 2/5 HP at 40 mg/m2 and 2/6 MP + 2/2 HP at 35 mg/m2. MTD has been defined as 27 mg/m2 for MP and HP patients. [Table: see text].