| General information |
| Database: | DB00183 |
| Objective: | Background: Only a few small studies investigated the association between postmenopausal breast cancer and metabolic syndrome (MetS) as a single entity |
| Authors: | W. H. Sharfman, et al |
| Title: | Results from the firstinhuman (FIH)phase I study of the oral RAF inhibitor RAF265 administered daily to patients with advanced cutaneous melanoma |
| Journal: | J Clin Oncol |
| Year: | 2011 ASCO Annual Meeting |
| PMID: | https://www.researchgate.net/publication/285143156_Results_from_the_firstinhuman_FIH_phase_I_study_of_the_oral_RAF_inhibitor_RAF265_administered_daily_to_patients_with_advanced_cutaneous_melanoma |
| Trial Design |
| Clinical Trial Id: | NA |
| Agent: | RAF265
|
| Target: | mRNA of RAF protooncogene serine/threonineprotein kinase
|
| Cancer Type: | melanoma |
| Cancer Subtype: | advanced cutaneous melanoma |
| Therapy Type: | mono |
| Therapeutic Combination Type: | NA |
| Therapeutic Combination Content: | NA |
| Study Type: | the firstinhuman (FIH)phase I study |
| Key Patients Feature: | patients with advanced cutaneous melanoma |
| Biomarker: | Mutations in BRAF and NRAS |
| Biomark Analysis: | NA |
| Control Group Info: | single arm |
| Treatment Info: | use different schedules for its administration: Daily (QD), weekly and intermittent. Results for QD dosing are presented here, where pts were treated by a loading dose (LD) follotheyd by continuous QD RAF265 oral solution at escalated dose levels (DLs). |
| Primary End Point: | the maximum tolerated dose (MTD), safety, PK, PD and antitumor activity |
| Secondary End Point: | NA |
| Patients Number: | 76 |
| Trial Results |
| DLT_MTD: | The MTD of oral RAF265 on a continuous daily schedule was defined at 48mg. |
| Objective Response Rate: | The overall response rate by RECIST 1.0 was 6/37 (16%) for mut BRAF pts and 4/30 (13%) for wt (3)/unknown (1) BRAF pts. |
| Disease Control Rate: | Mutations in BRAF and NRAS were detected 59% and 16% of evaluated tumor samples (n=70), respectively. 18FFDG uptake decrease from baseline (2.6 to 57.2%) was noted in 16/31 (52%) mut BRAF pts, with partial tumor metabolic response (SUVmax more than and equal to 25%) in 8/31 (26%). Plasma angiogenesis markers showed decreases of sVEGFR2 and increases in PlGF across DLs. |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | NA |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | Of 71 evaluable pts, six experienced dose limiting toxicities within 1st cycle (28 days): Pulmonary embolism (2), visual disturbances (2), hyperlipasemia (1), diarrhea (1) and ataxia (1). Thrombocytopenia Grade 3 (6) and 4 (2) occurred at 67mg QD in 2nd cycle and was also considered dose limiting. |
| Conclusions: | The MTD of oral RAF265 on a continuous daily schedule was defined at 48mg. Clinical activity was observed at multiple dose cohorts in pts with BRAF mut and wt melanoma. Since RAF265 QD at 67mg consistently caused delayed dose limiting hematologic toxicity, an intermittent schedule is being explored. |