Table 1 Protocol-defined dose modifications for etirinotecan pegol in subsequent cycles based on worst toxicity in prior cycle

Hematologic (thrombocytopenia, anemia, neutropenia, febrile neutropenia)

 Grade 1–2 (except ANC)

Maintain dose level

 Grade 2 (ANC <1500/mm³)

First occurrence

• Hold until ANC >1500/mm³

• If screening ANC >2000/mm³; restart at reduced dose of 120 mg/m²

• Do not dose reduce if screening ANC was ≥1500 but <2000/mm³

Second occurrence

• Decrease one dose level (to 90 or 120 mg/m²)

Third occurrence

• Discontinue treatment

 Grade 3 (platelets <50 K or Hgb <8 g/dl)

First occurrence

• Hold until resolved; restart at 120 mg/m²

Second occurrence

• Decrease additional dose level to 90 mg/m²

Third occurrence

• Discontinue treatment

 Grade 4 (ANC <500/mm³ or platelets <25 K or Hgb <6.5 g/dl)

First occurrence

• Hold until resolved (ANC >1500/mm³; Hgb >8 g/dl; platelets >50 K)

• Restart at reduced dose of 120 mg/m²

Second occurrence

• Decrease additional dose level to 90 mg/m²

Third occurrence

• Discontinue treatment

 Febrile neutropenia (grade 3: ANC <1000/mm³ with a single temperature >38.3 °C or a sustained temperature of ≥38 °C for more than 1 h)

First occurrence

• Hold until resolved until grade 0–1 toxicity

• Restart at reduced dose of 120 mg/m²

Second occurrence

• Decrease additional dose level to 90 mg/m²

Third occurrence

• Discontinue treatment

Diarrhea

 All grades

Confirm that diarrhea has been resolved for at least 7 days without use of supportive care prior to retreatment

 Grade 1

Maintain dose level; consider prophylactic anti-diarrheal supportive care

 Grade 2

First occurrence

• Decrease one dose level to 120 mg/m²

• Consider prophylactic anti-diarrheal supportive care

Second occurrence

• Decrease additional dose level to 90 mg/m²

Third occurrence

• Discontinue treatment

 Grade 3–4

First occurrence:

• Decrease two dose levels to 90 mg/m²

• Use prophylactic anti-diarrheal supportive care

Second occurrence

• Provided that adequate supportive care was given previously, discontinue treatment

• If the patient did not receive adequate prior supportive care, retreatment may be attempted if 2nd episode of grade 3 diarrhea

• Discontinue treatment for 2nd episode of grade 4 diarrhea

Dehydration

 Grade 1

• Maintain dose level and consider appropriate prophylactic anti-emetic or anti-diarrheal supportive care

 Grade 2

• Maintain dose level or decrease to 120 mg/m² after first occurrence; consider appropriate prophylactic anti-emetic or anti-diarrheal supportive care

• Decrease one dose level (to 120 or 90 mg/m²) after second occurrence; use appropriate prophylactic anti-emetic or anti-diarrheal supportive care

• Up to two dose reductions are allowed

 Grade 3–4

• Delay treatment until resolution to baseline or to grade 0

• Decrease dose level to 90 mg/m² after first occurrence; use appropriate prophylactic anti-emetic or anti-diarrheal supportive care

• Discontinue after 2nd occurrence

Nausea/vomiting/abdominal pain

 Grade 1–2

• Maintain dose level and consider prophylactic anti-emetic supportive care

 Grade 3

• Delay treatment until resolution to baseline or to grade 0

• Decrease one dose level to 120 mg/m² after first occurrence and use prophylactic anti-emetic supportive care

• Decrease an additional dose level to 90 mg/m² after second occurrence

• Discontinue treatment after third occurrence

 Grade 4

• Delay treatment until resolution to baseline or to grade 0

• Decrease dose level to 90 mg/m² after first occurrence and use prophylactic anti-emetic supportive care

• Discontinue treatment after second occurrence