Table 5.

Schedule A DLTs

Patient's starting dose cohort	Dose when DLT occurred	AE recorded as DLT	Was the AE serious?	Severity	Relationship to MRZ/Dex	Action taken with MRZ/Dex	Outcome
0.075 mg/m2*	0.075 mg/m2	Renal failure acute	Yes	Grade 3	Possible	MRZ discontinued	Resolved
		Blood creatinine increased	Yes	Grade 4	Possible	MRZ discontinued	resolved
		Blood creatinine increased	Yes	Grade 3	Possible	MRZ discontinued	Resolved
0.7 mg/m2	0.6 mg/m2	Nausea	Yes	Grade 3	Possible	MRZ dose reduced	Resolved
		Vomiting	Yes	Grade 3	Possible	MRZ dose reduced	Resolved
0.7 mg/m2	0.6 mg/m2	Fatigue	No	Grade 3	Possible	MRZ discontinued	Resolved
0.7 mg/m2	0.7 mg/m2	Hallucinations	No	Grade 2	Possible	MRZ dose reduced	Resolved
0.7 mg/m2	0.7 mg/m2	Mental status changes	Yes	Grade 3	Possible	none	Resolved
		Balance disorder	Yes	Grade 3	Possible	none	Resolved
RP2D 0.7 mg/m2†	0.7 mg/m2	Confusional state	Yes	Grade 3	Possible	MRZ discontinued	Resolved

^*As of protocol amendment 4, >60 patients with similar baseline renal function had been treated at MRZ doses as high as 0.7 mg/m² (nearly 10-fold higher) on an identical schedule without DLT or demonstration of nephrotoxicity. Therefore, when the dose of 0.075 mg/m² was shown to be safe in a cohort of 6 new patients (without observation of DLT), the protocol permitted dose escalation to continue using dose doubling in cohorts of 1-3 patients evaluable for toxicity, until observation of grade 2 or greater drug-related toxicity. Thereafter, dose escalation increments were limited to <50% in groups of at least 3 patients evaluation for toxicity until observation of DLT.

^†Schedule A of this study was conducted in parallel with separate MRZ trials (NPI-0052-100 and NPI-0052-102) that studied doses of 0.8 and 0.9 mg/m² at the same schedule and found that MRZ, administered on days 1, 8, and 15, was generally well tolerated through 0.7 mg/m², and therefore, the parallel-run trials influenced the designation of the 0.7-mg/m² dose as the RP2D of schedule A.