A Phase I Open Label Study of the Farnesyltransferase Inhibitor CP-609,754 in Patients with Advanced Malignant Tumors

Abstract

Purpose: The purpose of this phase I clinical trial was to determine the maximum-tolerated dose and toxicity of CP-609,754 in patients with solid tumors refractory to standard therapies, to determine the cellular effects of CP-609,754 on its molecular target (farnesyltransferase), and to determine the recommended phase II dose (RP2D) of this agent.Experimental Design: Consenting patients with adequate bone marrow, liver, and renal function were enrolled with an accelerated dose strategy with single-patient parallel cohorts in whom the drug was given orally either once or twice daily. Once a dose-limiting toxicity was encountered or two patients developed Common Toxicity Criteria > grade 2 toxicities, a modified Fibonacci sequence was initiated. Blood samples were collected during cycle 1 for pharmacokinetic and pharmacodynamic analyses.Results: A total of 68 cycles of CP-609,754 was administered to 21 patients enrolled in this study. The dose escalation was from 20 mg once daily to 640 mg twice per day, and at the highest dose level, one of six patients developed a dose-limiting toxicity of grade 3 neuropathy. The drug was otherwise well tolerated, and the maximum-tolerated dose was not reached because of the large number of tablets that would have been required for additional dose escalation. Pharmacokinetic analyses showed a proportional increase in exposure with dose, rapid oral absorption, and a half-life of ϳ3 hours. Pharmacodynamic results predict a 95% maximal inhibition of peripheral blood mononuclear cell farnesyltransferase activity 2 hours postdose, on average, with a dose of 400 mg twice per day of CP-609,754.Conclusions: On the basis of the safety findings and the pharmacokinetic and pharmacodynamic analyses, the RP2D of CP-609,754 is >640 mg twice per day.

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“…The compound quarfloxin is also an anticancer compound (leukemia). The compound CP-609754 is under phase-I trial for treating advanced malignant tumours and exhibits its activity as farnesyltransferase inhibitor 54 . Among approved compounds, Tadalafil, Metocurine, Lorlatinib and Lumacaftor are respectively used for treating erectile dysfunction, muscular relaxant, ALK-positive metastatic non-small cell lung cancer and cystic fibrosis.…”

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“…We next determined if ykt6 could be targeted by small-molecule farnesyltransferase inhibitors (FTIs). We utilized a previously characterized FTI, LNK-754, that was developed for clinical use as potential cancer therapy and has shown selective in vivo target engagement of farnesyltransferase (Downward, 2003;Moulder et al, 2004). Upon culturing cells with the FTI, we found that it reduced the farnesyl-ykt6 signal by 40% ( Figure S6A).…”

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“…23 To avoid the use of subtherapeutic doses of romidepsin and bortezomib in patients with advanced MM, we used a novel accelerated dose escalation schedule in which cohorts of one new patient per dose level were enrolled during the initial accelerated stage of the trial. [24][25][26][27] Accelerated titration designs are more aggressive than standard approaches and therefore may be associated with a greater risk of unpredictable toxicity to individual patients. However, they have the capacity to significantly reduce the number of "undertreated" patients.…”