Table 1.

Dose Escalation Schemas for Momelotinib and Trametinib

	Momelotinib	Trametinib
Dose Level	Once Daily	Twice Daily	Once Daily
Momelotinib Dose Escalation
(If needed) −1	100 mg		0.5 mg
(Starting level) M1	100 mg		1.0 mg
M2	(A) 200 mg	(B) 100 mg	1.0 mg
M3		150 mg	1.0 mg
M4		200 mg	1.0 mg
End of Momelotinib Dose Escalation: Momelotinib MTD
Trametinib dose escalation
TI	Momelotinib MTD		1.5 mg
TII	Momelotinib MTD		2.0 mg

There were two 3 + 3 dose escalations. The first was conducted to determine the MTD of momelotinib in combination with trametinib, and the second dose escalation was conducted to determine the MTD of trametinib in combination with momelotinib at its MTD. A DLT within 28 days would trigger a cohort expansion. DLTs were defined as adverse events considered to be clinically significant and related to study treatment (eg, Grade 4 neutropenia or thrombocytopenia, Grade ≥ 3 neutropenia with fever; Grade ≥ 3 thrombocytopenia with bleeding; Grade ≥ 3 nonhematologic toxicity). If DLTs occurred in 0 of 3 (or <2 of 6) patients, then the next dose level was opened. The MTD was the dose level immediately below the one at which ≥2 patients had DLTs. If ≥ 2 DLTs were observed at dose level M2A but not at dose level M2B, then dose level M3 was to be opened as the last evaluated dose level for momelotinib (without precluding trametinib dose escalation). If ≥2 DLTs were observed at dose level M3, then tolerability and response would be used to decide between doses M2A and M2B as momelotinib MTD for use in the trametinib dose escalation. The trametinib dose escalation would not proceed if a trametinib-related DLT was observed during the momelotinib dose escalation. Otherwise, patients were treated with dose TI of trametinib and escalation to dose TII would move forward in the absence of DLTs. If ≥ 2 DLTs occurred at the same dose level, the MTD of trametinib would be considered to have been exceeded. Abbreviations: DLT = dose-limiting toxicity; MTD = maximum tolerated dose.