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Phase I And Pharmacokinetics (PK) Of DJ-927, An Oral Taxane, In Patients (Pts) With Advanced Cancers.

S. Syed, M. Beeram, C. Takimoto, J. Jakubowitz, M. Kimura, M. Ducharme, S. Gadgeel, R. D. De Jager, E. Rowinsky, P. LoRusso
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], 3 mg/m2 [3], 6 mg/m2 [3], 12 mg/m2 [3], 18 mg/m2 [4], 27 mg/m2 [8], 35 mg/m2 [8] and 40 mg/m2 [8]. Demographics: 23 male / 17 female; median [range] age- 57 [31-81]; PS 0 [7], PS 1 [31], and PS 2 [2]. Primary tumors are colorectal [15], breast [4], pancreas [5], renal cell [3], soft tissue sarcoma [3] and others [10]. Minimal drug-related toxicities were observed at doses 5 days duration [7] and grade 3 thrombocytopenia [4] 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 [1] at 27 mg/m2, grade 3 diarrhea and grade 3 mucositis [1] at 40mg/m2. Minor responses were seen in taxane-refractory breast carcinoma [1] and transitional cell carcinoma of the bladder [1]. 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].

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