| General information |
| Database: | DB00816 |
| Objective: | PF299804 is a potent, orally available, irreversible inhibitor of tyrosine kinase human epidermal growth factor receptors (HER) 1 (EGFR), human epidermal growth factor receptor 2, and HER4. This firstinhuman study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF299804 in patients with advanced solid malignancies. |
| Authors: | J nne PA, et al |
| Title: | Phase I doseescalation study of the panHER inhibitor, PF299804, in patients with advanced malignant solid tumors. |
| Journal: | Clin Cancer Res. |
| Year: | 2011 |
| PMID: | 21220471 |
| Trial Design |
| Clinical Trial Id: | NCT00225121 |
| Agent: | PF299804
|
| Target: | epidermal growth factor receptors (HER) 1 (EGFR), human epidermal growth factor receptor 2, and HER4
|
| 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 doseescalation study |
| Key Patients Feature: | patients with advanced malignant solid tumors. |
| Biomarker: | EGFR mutation |
| Biomark Analysis: | Four patients, all previously treated with gefitinib or erlotinib (2 with exon 19 deletions, 1 with exon 20 insertion, 1 mutational status unknown), had a partial response to PF299804. |
| Control Group Info: | single arm |
| Treatment Info: | PF299804 was administered once daily continuously (schedule A) and intermittently (schedule B). Dose escalation proceeded until intolerable toxicities occurred. Skin biopsies were taken predose and after 14 days of treatment to establish a pharmacokinetic/pharmacodynamic relationship. Tumor response was measured once every 2 cycles. |
| Primary End Point: | MTD, DLT and safety |
| Secondary End Point: | NA |
| Patients Number: | 121 |
| Trial Results |
| DLT_MTD: | Initially, no DLTs were observed below 60 mg. At 60 mg, three of six patients experienced DLT (stomatitis, palmar-plantar erythema, and dehydration; all grade 3, n = 1 each). Consequently, this dose was considered intolerable as the DLT rate exceeded 33%. The next lotheyst dose, 30 mg, was then expanded and one of 13 patients experienced DLT (grade 3 oral mucositis). The dose was then escalated to 45 mg. At this dose, one of six patients experienced DLT (grade 3 rash, n = 1), and the MTD was established at 45 mg. Only one additional DLT (grade 3 acne) was observed in the MTD expansion cohort, making the total number of DLTs at 45 mg two of 52 (4%) treated patients (Table 2). Additional DLTs were observed in the 45 mg loadingdose MTD expansion cohort; two of 19 patients experienced grade 3 rash (n = 1) and grade 2 mucositis (n = 1), making the total number of DLTs at 45 mg four of 71 (6%) treated patients. |
| Objective Response Rate: | NA |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | NA |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | frequently observed grade 1-3 AEs attributed to study drug included diarrhea, rash, fatigue, and nausea. |
| Conclusions: | The MTD of PF299804 is 45 mgd. Both continuous and intermittent treatment schedules were well tolerated, and encouraging signs of antitumor activity were observed in gefitiniberlotinib treated non small cell lung cancer patients. |