Phase I trial of daily imatinib mesylate and weekly paclitaxel in patients with advanced refractory solid tumors

Abstract

3087 Background: Inhibition of PDGF receptors by a selective PDGF receptor kinase inhibitor (such as Gleevec) decreases the interstitial pressure of tumor and increases capillary-to-interstitial transport of low molecular mass compounds such as EDTA. Combination of Gleevec(G) and paclitaxel(P) has resulted in enhancement of P activity against s.c.KAT-4 tumors in SCID mice. Myelosupression of G has prevented successful combination therapy with cytotoxic agents such as gemcitabine and doxorubicine. Methods: This phase I clinical trial studies the pharmacokinetics (PK) and toxicities of the combination of G and P in patients (pts) with advanced solid tumors. At dose level (DL) 1, pts received G daily in combination with P on days 1, 8, and 15, given every 28 days. Results: 6 pts were enrolled at DL 1 (G 400mg, P 60 mg/m2). 5 pts developed grade III neutropenia. The neutropenia caused significant delay in treatment and dose escalation was not possible. 5 pts were enrolled to DL -1 (G 300 mg, P 60 mg/m2), one pt developed G III neutropenia. No DLT's have been observed. Other toxicities observed include: gr1 fatigue (all pts), gr1 nausea (9 pts), gr 2 alopecia (2 pts), gr 2 rash ( 1 pt), gr 2 diarrhea ( 2 pts), gr 1 neuropathy (2 pts).Two patients had a PR (both on cycle 6, one has NSCL cancer and the other esophageal cancer ) and one has had stable disease (on cycle 4, colon carcinoma).Preliminary PK analysis has not shown any clear effect of G on P. In order to dose escalate but maintain PDGF inhibition, we amended the protocol to G 400 mg on D1–4 and P on D 3,10 and 17. Three pts have been evaluated on this DL (DL 1A, G 400 mg D1–4 and P 60 mg/m2 D3, D10, D17). None has developed grade II or higher neutropenia and accrual to the next dose level is now ongoing. Conclusions: Neutropenia appears to be the main obstacle in combining daily G with chemotherapy agents such as P, even at low doses. Administration of G on intermittent schedule with chemotherapy may avoid significant neutropenia, allowing combination of G with desired doses of cytotoxic agents. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis; Roche Novartis; Roche Novartis