Phase I study of the safety, tolerability and pharmacokinetics of PHA-848125AC, a dual tropomyosin receptor kinase A and cyclin-dependent kinase inhibitor, in patients with advanced solid malignancies

Abstract

Summary Purpose This phase I trial assessed the safety, maximally tolerated dose (MTD) and pharmacokinetics of TRKA/CDK inhibitor PHA-848125AC in adult patients with advanced/metastatic solid tumors. Patients and methods Patients with relapsed or refractory solid tumors, for which no standard therapy existed, were eligible. PHA-848125AC was administered orally in two schedules: daily for 7 consecutive days in 2-week cycles (i.e. 7 days on/7 days off q2wks; S1) or daily for 4 consecutive days a week for 3 weeks in 4-week cycles (i.e. 4 days on/3 days off × 3wks q4wks; S2). Result Thirty-seven patients were treated in this study, 22 in S1 and 15 in S2. The recommended phase II dose (RP2D) was 150 mg/day for either schedule. The dose-limiting toxicities (DLTs) in S1 included ataxia (Grade 2–4) and tremors (Grade 2–3). In S2, DLTs included tremors (Grade 2–3), elevated lipase (Grade 3), increased creatinine (Grade 2), and nausea and vomiting (Grade 3). These events were all reversible. In S2, out of 14 patients evaluable for efficacy, 2 patients with thymic carcinoma, showed partial response and stable disease was observed in 3 patients. Stable disease was observed in 6 out 14 patients evaluable for efficacy on S1. Drug pharmacokinetics demonstrated a half-life of approximately 33 h, and dose-proportionality with accumulation by a factor of 3 after repeated administrations. Conclusion The RP2D of PHA-848125AC was 150 mg/day on both schedules. Based on the responses noted in thymic carcinoma, a phase II study for patients with that disease is currently enrolling.

TRKing Down an Old Oncogene in a New Era of Targeted Therapy

“…Currently, little data exists on the toxicities of the more selective Trk inhibitors. A phase I study of PHA-848125AC with significant blood-brain penetration produced dose-limiting (grade 3) ataxia and tremors, but as this drug inhibits cyclin-dependent kinases in addition to TrkA, it is unclear which drug target was responsible for these side effects (88). One of the largest reported studies of a drug with TrkA inhibition was a randomized study of lestaurtinib in FLT3 mutant AML (89).…”

Antitumor activity in advanced cancer patients with thymic malignancies enrolled in early clinical drug development programs (Phase I trials) at Gustave Roussy

“…In our cohort, 1 patient harboring a TC and who received sunitinib showed stable disease. The variety of drugs assessed in this study showed that other groups of agents such as cyclin-dependent kinase inhibitors, tropomyosin receptor kinase inhibitors, antimitotic agents or drugs triggering apoptosis should be of interest, showing a rather good safety profile and yielded promising preliminary results, supported by several studies [40]. For instance, one patient (#12) treated with a recombinant human Apo2Ligand/Tumor necrosis factor related apoptosis inducing ligand (rhApo2L/TRAIL) in combination with paclitaxel, carboplatin and bevacizumab showed a PR of 45%.…”

Pharmacological cyclin dependent kinase inhibitors: Implications for colorectal cancer

“…Nerviano Medical Sciences, Nerviano, Italy Metastatic solid tumors [27,28] Cyclin E and CDK-2 Cyclin A and CDK-2 LY2835219 Cyclin D and CDK-4/6 Eli Lilly, Indianapolis, IN, United States Lung cancers [29] LEE011 Cyclin D and CDK-4/6 Novartis, Basel, Switzerland Gastrointestinal cancers [30] Breast Cancer [31] AZD5438 Cyclin D and CDK-4/6 Astra Zeneca, London, England Solid malignancies [32] Cyclin E and CDK-2 Cyclin A and CDK-2 Cyclin A and CDK-1 BAY 1000394 Cyclin D and CDK-4/6…”

“…Lastly, CDK4 overexpression is linked to a poor prognosis in colorectal cancer [26] . From the list of inhibitors currently in clinical trials, found in Table 1 [23, [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] , there have been a few that have been studied more specifically in colorectal cancer. One that has shown particular promise is PD-0332991, from Pfizer, New York, NY.…”