| General information |
| Database: | DB00311 |
| Objective: | Thisphase I trial assessed the safety, maximally tolerated dose (MTD) and pharmacokinetics of TRKA/CDK inhibitor PHA848125AC in adult patients with advanced/metastatic solid tumors. |
| Authors: | theyiss GJ, et al |
| Title: | Phase I study of the safety, tolerability and pharmacokinetics of PHA848125AC, a dual tropomyosin receptor kinase A and cyclindependent kinase inhibitor, in patients with advanced solid malignancies. |
| Journal: | Invest New Drugs. |
| Year: | 2012 |
| PMID: | 22160853 |
| Trial Design |
| Clinical Trial Id: | NA |
| Agent: | PHA848125AC
|
| Target: | dual tropomyosin receptor kinase A and cyclindependent kinase
|
| Cancer Type: | advanced solid tumors |
| Cancer Subtype: | advanced solid tumors |
| Therapy Type: | mono |
| Therapeutic Combination Type: | NA |
| Therapeutic Combination Content: | NA |
| Study Type: | Phase I, openlabel, twocenter, nonrandomized, doseescalation study |
| Key Patients Feature: | Patients ofagemore than and equal to 18 that provided signed informed consent, with relapsed or refractory solid tumors, for which no standardtherapy existed, were eligible for the study. Other eligibilitycriteria included: Eastern Cooperative Oncology Group(ECOG) performance status (PS) of 0-1, life expectancymore than and equal to 3 months, baseline laboratory data indicating acceptablebone marrow reserve, liver, and renal function, Grade less than and equal to 1retinopathy, and the capability to swallow capsules intact.Except for prior exposure to experimental CDK2 inhibitors, prior systemic therapy was allowed if completed 4-6 weeksprior to study entry |
| Biomarker: | NA |
| Biomark Analysis: | NA |
| Control Group Info: | PHA848125AC |
| Treatment Info: | PHA848125AC was administered orally in two schedules: daily for 7 consecutive days in 2week cycles (i.e. 7 days on/7 days off q2wks; S1) or daily for 4 consecutive days a week for 3 weeks in 4week cycles (i.e. 4 days on/3 days off x 3wks q4wks; S2). |
| Primary End Point: | safety and efficacy assessment, pharmacokinetic (PK) |
| Secondary End Point: | NA |
| Patients Number: | 37 |
| Trial Results |
| DLT_MTD: | The recommendedphase II dose (RP2D) was 150 mg/day for either schedule. The doselimiting toxicities (DLTs) in S1 included ataxia (Grade 24) and tremors (Grade 23). In S2, DLTs included tremors (Grade 23), 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. |
| Objective Response Rate: | NA |
| Disease Control Rate: | Disease stabilizations were observed in 6 out of 14 (42.9%) evaluable patients treated in S1 and in 3 out of14 (21.4%) evaluable patients in S2. |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | NA |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | The most frequently reported drugrelated events were similar in both schedules and included nausea, diarrhea, vomiting, fatigue, and neurologic effects. The most frequent (more than and equal to 20%) and all the Grade 3-4 drugrelated adverse events by dose level |
| Conclusions: | The RP2D of PHA848125AC was 150 mgday on both schedules. Based on the responses noted in thymic carcinoma, aphase II study for patients with that disease is currently enrolling. |