Supplementary Materials

Dose-Limiting Toxicity Criteria

A dose-limiting toxicity (DLT) was defined as an adverse event (AE) occurring during cycle1 (the first 6weeks of treatment) that was considered at least possibly related to the study drug, was considered dose-dependent, and fulfilled any1 of the following criteria (using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 [NCICTCAE v4.0]):

  • Grade ≥3 nonhematological toxicity, with exceptions made for the following:
  • Grade 3 nausea, vomiting, diarrhea, fatigue, anorexia, or constipation lasting 2days or less or that could have been controlled with treatment
  • Grade 3 alopecia
  • transient Grade 3 elevations of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), without evidence of other hepatic injury, in the setting of preexisting hepatic metastasis (baseline elevation of these values may not have been considered a DLT if agreed on by the study investigator and medical monitor)
  • an infusion-related event (and/or cytokine-release event) that was not considered dose related
  • Grade 4 thrombocytopenia lasting for at least 5 days and/or complicated with bleeding
  • Grade ≥3 febrile neutropenia
  • Grade 4 neutropenia of >5 days’ duration
  • increase of at least 1 grade from a preexisting Grade 1 valvular insufficiency or any new Grade ≥2 valvular toxicity
  • left ventricular ejection fraction decrease of 10% in absolute value or 16% in relative value, which was confirmed 1 week after the first documentation of decrease, or any value going below the lower limit of normal thatdid not recover within 4 weeks
  • increase in right ventricular systolic pressure dysfunction from mild to moderate or from moderate to severe
  • increase in left atrial or ventricular chamber size of ≥2 cm and ≥1 cm, respectively
  • any other life-threatening toxicity related to LY3022859
  • any other significant morphologic or functional changes on cardiac echocardiogram, in the opinion of the investigator
  • any major ocular event, observed in at least 1 eye, as defined by:
  • funduscopic evidence of retinal bleeding resulting in a visual acuity change as reflected by a change (worsening) of at least 3 lines (and not recovered within 14days) on the Snellen chart (when retinal or macular hemorrhage affecting vision adversely occurred in the presence of a Grade 4 thrombocytopenia, it was not to be considered an ocular event but a “general bleeding event”)
  • funduscopic evidence of serious retinal detachment reducing vision 3 lines or worse (Snellen chart), which did not improve in 14 days, or other types of retinal detachment requiring intervention (such as laser treatment or surgery) unless the expert ophthalmologist considered the detached retina as an unrelated event to the study treatment
  • any visual change, or intraocular hemorrhage (excluding subconjunctival hemorrhage) resulting in a visual acuity change as reflected by a change (worsening) of at least 3 lines on the Snellen chart that had not recovered within 14days

Investigators, together with the medical monitor, could declare a DLT if a patient was experiencing increasing toxicity during treatment and it became clear that it was not going to be possible to complete the treatment without exposing the patient to excessive risk.

A DLT-equivalent toxicity was defined as an AE occurring in cycle 2 for a patient enrolled in partA or in cycles 1 to 2 for a patient enrolled in part B, which would have met the criteria for a DLT if it had occurred during cycle 1 for a patient enrolled in part A.