Phase I/II study of sequential-intermittent docetaxel (D) and imatinib (Im) in hormone refractory prostate cancer (HRPC) (NYU 04–47)

Abstract

15613 Background: Platelet-derived growth factor (PDGF) is frequently expressed in advanced prostate cancer (PC) lesions where it supports PC cell growth and neo-angiogenesis. Im. is a PDGF inhibitor that blocks cell cycle progression in G1-S through inhibition of erk1–2 kinase. D. blocks cell cycle progression in G2-M. Anti-tumor responses can increase when the block to cell cycle progression in G2M precede the blocks in G1-S. This study was designed to determine tolerablity and activity of sequential D followed by Im in HRPC patients (pts). Methods: Eligibility: 2 prior hormone manipulations, any prior chemotherapy, PSA= 5 ng/ml, ECOG PS 0–2. Treatment schema: D IV day 1 followed in 24–36 hours by Im PO daily x 14 days, every 21 days until toxicity or progression. Cohorts (C) planned were: #1, D. 60 mg/m2, Im. 400 mg; #2, D 70mg/m2, Im 400 mg; #3, D 70mg/m2, Im 600 mg. Results: 12 pts enrolled: 6 in C#1, 3 each in C#2,3. Median age,73 (range: 61 to 85). Median number cycles (Cy) 3 (range: 2 to 10). Toxicity grade (TG)1–2 observed in 9 (75%) pts (6, 2, 1 in C#1, 2,3 respectively): anemia 9, neutropenia 1, lymphopenia 6, thrombocytopenia 3, hyperglycemia 8, hyponatremia 2, abnormal bicarbonate 7, hypoalbuminemia 3, fatigue 5, neuropathy 3, nausea/vomiting 3, constipation 2, pain 2, fever 2, increased creatinine 2. TG3: afebrile neutropenia, 4 pts. Cy1. TG 4: febrile neutropenia,1 pt C#1,Cy1; GI bleed/intestinal perforation, 1 pt C#3, Cy7. PSA decline =50%: 1 pt C#2; 2 pts C#3. Conclusions: sequential and intermittent dosing of D and Im was well tolerated with high doses of both drugs. The most common toxicity was neutropenia which was prevented with growth factors. The MTD was not reached. PSA responses occurred at the higher doses. An ongoing phase II study of sequential D. 70mg/m2 and Im. 600 mg x 14 days will define activity. No significant financial relationships to disclose.