Table 2.
Phase I/II studies of c-MEK inhibitors in melanoma.
| Study reference | Number of patients eligible for analysis | Study design | Primary end point | Dose and schedule - treatment arm | Responses | Survival | Toxicity |
|---|---|---|---|---|---|---|---|
| Agarwal et al. [29], | 28 (8 with melanoma) | Two-part Phase I dose escalation | Part A: 3 + 3 dose escalation Part B: relative bioavailability of the two formulations |
AZD6244 hydrogen sulfate formulation 25 – 100 mg b.i.d. | Not reported | N/A | Rash; fatigue; nausea/vomiting; diarrhea; dyspnea; peripheral edema (% not available) |
| Kirkwood et al. [30] | 200 | Phase II, open-label, multicenter, 1:1 randomized, parallel-group study | PFS | Selumetinib 100 mg b.i.d. OR TMZ 200 mg/m2/day D1 – 5 of each 28-day cycle |
ORR (all PR): 5.8% (MEK-I) vs 9.4% (TMZ) BRAF mutant cohort: 11.1% (MEK-I) vs 10.7% (TMZ) |
PFS: not calculated Time to death: 9.5 months (MEK-I) vs 12.3 months (TMZ) |
Rash 59.6% (G3/412.1 %) Diarrhea 56.6% (G3/44.0%) Nausea 50.5% (G3/43.0%) Edema 40.4% (G3/41.0%) |
| Infante et al. [34] | 84 patients (29 with melanoma, 20 evaluable) | Three-part Phase I/II study | Part 1: dose escalation Part 2: expansion in selected tumor types to evaluate RP2D Part 3: PK/PD assessment using tumor biopsies or FDG-PET |
GSK1120212 in escalating doses RP2D 2 mg/day MTD 3 mg/day |
ORR (all PR): 20% (3 mutant, 2 wild type) CBR (PR + SD): 73% (8/11 mutant) vs 56% (5/9 wild type) |
N/A | Rash 77% (G3 5%) Diarrhea 45% (G3 3%) |
| Kurzrock et al. [37] | 23 (13 evaluable) | Three-part Phase I/II study | Part 1: dose escalation Part 2: expansion in selected tumor types to evaluate RP2D Part 3: PK/PD assessment using tumor biopsies or FDG-PET |
GSK1120212 + AKT inhibitor GSK2141795 in escalating doses RP2D GSK1120212 2 mg/day MTD GSK2141795 75 mg/day RP2D/MTD for combination not identified |
ORR (all PR): 23% (3/13) | N/A | Nausea 26% (G3/40%) AST elevation 22% (G3/49%) Fatigue 22% (G3/40%) Rash 22% (G3/40%) |
AST: Aspartate aminotransferase; CBR: Clinical benefit rate; FDG-PET: Fluorodeoxyglucose positron emission tomography; MTD: Maximal tolerated dose; N/A: Not applicable; ORR: Overall response rate; PD: Pharmacodynamics; PFS: Progression-free survival; PR: Partial response; PK: Pharmacokinetics; RP2D: Recommended Phase II dosage; SD: Stable disease.