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Table 3 Summary of the physicians’ guidelines for IMP’s temporary interruption and permanent discontinuation in case of immune-related adverse events. PI: principal Investigator

From: PRIME-HCC: phase Ib study of neoadjuvant ipilimumab and nivolumab prior to liver resection for hepatocellular carcinoma

Toxicity Hold treatment for grade Timing for restarting treatment
Diarrhoea/
Colitis
2–3 Toxicity resolves to Grade 0–1
4 Permanently discontinue
AST, ALT, or Increased Bilirubin 2 Toxicity resolves to Grade 0–1
3–4 Permanently discontinue (see exception below)a
Type 1 diabetes mellitus (if new onset) or Hyperglycaemia T1DM or
3–4
Hold the IMP for new onset Type 1 diabetes mellitus or Grade 3–4 hyperglycemia associated with evidence of beta cell failure
Hypophysitis 2–4 Toxicity resolves to Grade 0–1. Therapy with IMP can be continued while endocrine replacement therapy is instituted
Hyperthyroidism 3 Toxicity resolves to Grade 0–1
4 Permanently discontinue
Hypothyroidism N/A Therapy with IMP can be continued while thyroid replacement therapy is instituted
Infusion Reaction 2b Toxicity resolves to Grade 0–1
3–4 Permanently discontinue
Pneumonitis 2 Toxicity resolves to Grade 0–1
3–4 Permanently discontinue
Renal Failure or Nephritis 2 Toxicity resolves to Grade 0–1
3–4 Permanently discontinue
All Other Drug-Related Toxicityc 3 or Severe Toxicity resolves to Grade 0–1
4 Permanently discontinue
  1. Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event
  2. a For participants who begin treatment with Grade 2 AST or ALT at Cycle 1 Day 1 of treatment, if AST or ALT increases by greater than or equal to 50% relative to baseline and lasts for at least 1 week then participants should be discontinued
  3. b If symptoms resolve within one hour of stopping IMP infusion, the infusion may be restarted at 50% of the original infusion rate (e.g., from 100 mL/hr. to 50 mL/hr). Otherwise dosing will be held until symptoms resolve and the participant should be pre-medicated for the next scheduled dose
  4. c Participants with intolerable or persistent Grade 2 drug-related AE may hold study medication at PI/delegate discretion