Table 2.

DLTs occurring during cycle 1 in the dose-escalation and MTD expansion phases and in the DLT-evaluable population

Treatment arm	Pevonedistat dose, mg/m2	No. of patients	No. of patients with G ≥3 DLT	DLT	Management of DLTs
Arm 1: pevonedistat + docetaxel (n = 20)	15	3 (dose-escalation)	0	None	NA
	25 (MTD)	12 (dose-escalation)	2	G3 increased ALT + G3 increased AST	Dose hold and dose reduction
				G3 increased ALT + G3 increased AST	Dose hold and dose reduction
		5 (MTD expansion)	2	G3 increased ALT	Dose hold and dose reduction
				G3 increased ALT + G3 increased AST	Dose hold
Arm 2a (lead-in cohort): pevonedistat + carboplatin (n = 6)	15	6	2	G4 thrombocytopenia	Dose delayed and concomitant medication
				G3 increased AST	Dose delayed
Arm 2: pevonedistat + carboplatin + paclitaxel (n = 22)	15	5 (dose-escalation)	1	G3 febrile neutropenia	Dose reduction and concomitant medication
	25	5 (dose-escalation)	2	G3 increased ALT + G3 increased AST	Dose hold and dose reduction
				G3 increased ASTa	Dose hold and dose reduction
	20 (MTD)	6 (dose-escalation)	2	G3 increased ALT + G3 increased AST	Dose hold and dose reduction
				G3 increased ALT + G3 increased AST	Dose hold and dose reduction
		6 (MTD expansion)	1	G3 increased AST	Dose reduction
Arm 3: Pevonedistat + gemcitabine (n = 8)	25	8	3	G4 febrile neutropenia	Discontinued from study
				G3 febrile neutropenia + G5 febrile neutropenia	Concomitant medication, then discontinued from study
				G3 increased ALT + G3 increased AST	Dose hold and dose reduction

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRM, continual reassessment method; D, day; DLT, dose-limiting toxicity; G, grade; MTD, maximum tolerated dose; NA, not applicable

^aDLT was not considered related to study drug but was used in the CRM algorithm to de-escalate the next dose to 15 mg/m²