10. Everolimus
(Afinitor)Dose adjustments:
Dose modifications based on treatment-associated toxicity and trough levels of everolimus:
Toxicity
No toxicity Grade 1 Grade 2* Grade 3 Grade 4
TL < 10.0 ng/mL: increase one dose level
TL < 10.0 ng/mL: increase one dose level
TL < 10.0 ng/mL: increase one dose level
Withhold dose until toxicity is ≤ grade 1 (or ≤ grade 2 in case of hematologic toxicity). For treatment related toxicity: reduce dose by one dose level and resume treatment**
Withhold dose until toxicity is ≤ grade 1 (or ≤ grade 2 in case of hematologic toxicity). For treatment related toxicity: reduce dose by one dose level and resume treatment**
TL ≥ 10.0 ng/mL: continue at the same dose level
TL ≥ 10.0 ng/mL: continue at the same dose level
TL ≥ 10.0 ng/mL: continue at the same dose level
Withhold dose until toxicity is ≤ grade 1 (or ≤ grade 2 in case of hematologic toxicity). For treatment related toxicity: reduce dose by one dose level and resume treatment**
Withhold dose until toxicity is ≤ grade 1 (or ≤ grade 2 in case of hematologic toxicity). For treatment related toxicity: reduce dose by one dose level and resume treatment**
TL = trough level everolimus
* If grade 2 toxicities are persistent or unbearable, consider treating them as grade 3.
** Patients who develop grade 4 hyperuricemia or grade 3 hypophosphatemia without clinical symptoms may continue treatment without interruption at the discretion of the investigator. Nausea, vomiting or diarrhea must persist at grade 3 or 4 despite maximal medical therapy. Patients who develop grade 3 or 4 lymphopenia without other dose-limiting events (e.g. opportunistic infection) may continue treatment without interruption. For specific dose modification guidelines see below.
Dose modifications based on treatment-associated toxicity in weeks without potential dose modifications based on trough levels of everolimus:
Toxicity
No toxicity Grade 1 Grade 2* Grade 3 Grade 4
Continue at the same dose level
Continue at the same dose level
Continue at the same dose level
Withhold dose until toxicity is ≤ grade 1 (or ≤ grade 2 in case of hematologic toxicity). For treatment related toxicity: reduce dose by one dose level and resume treatment**
Withhold dose until toxicity is ≤ grade 1 (or ≤ grade 2 in case of hematologic toxicity). For treatment related toxicity: reduce dose by one dose level and resume treatment**
* If grade 2 toxicities are persistent or unbearable, consider treating them as grade 3.
** Patients who develop grade 4 hyperuricemia or grade 3 hypophosphatemia without clinical symptoms may continue treatment without interruption at the discretion of the investigator. Nausea, vomiting or diarrhea must persist at grade 3 or 4 despite maximal medical therapy. Patients who develop grade 3 or 4 lymphopenia without other dose-limiting events (e.g. opportunistic infection) may continue treatment without interruption. For specific dose modification guidelines see below.
Specific dose modification guidelines
Adverse event Grade Recommended everolimus dose adjustment Non-infectious pneumonitis 2 Consider interruption of therapy until symptoms
improve to ≤ grade 1. Reduce dose by one dose level or to the previous dose level in case of previous dose escalation. Discontinue treatment if failure to recover within 4 weeks.
3 Withhold dose until ≤ grade 1. Consider resuming treatment with a dose reduction of one dose level or to the previous dose level in case of previous dose escalation. If toxicity recurs at grade 3, consider discontinuation.
4 Discontinue treatment with everolimus permanently.
Stomatitis 2 Withhold dose until ≤ grade 1. Resume treatment at the same dose level. If stomatitis recurs at grade 2, withhold dose until ≤ grade 1, reduce dose by one dose level or to the previous dose level in case of previous dose escalation and resume treatment.
3 Withhold dose until ≤ grade 1, reduce dose by one dose level or to the previous dose level in case of previous dose escalation and resume treatment.
4 Discontinue treatment with everolimus permanently.
Other non-hematological toxicities (excluding metabolic events)
2 If toxicity is tolerable, no dose adjustment required.
If toxicity becomes intolerable, withhold dose until
≤ grade 1 and resume treatment at the same dose level. If toxicity recurs at grade 2, interrupt dose
until recovery to ≤ grade 1, reduce dose by one dose level or to the previous dose level in case of
previous dose escalation and resume treatment.
3 Withhold dose until ≤ grade 1, reduce dose by one dose level or to the previous dose level in case of previous dose escalation and resume treatment. If toxicity recurs at grade 3, consider discontinuation.
4 Discontinue treatment with everolimus permanently.
Metabolic events (e.g.
hyperglycaemia, dyslipidaemia)
2 No dose adjustment required.
3 Withhold dose temporarily, reduce dose by one dose level or to the previous dose level in case of previous dose escalation and resume treatment.
4 Discontinue treatment with everolimus permanently.
Thrombocytopenia 2 Withhold dose until ≤ grade 1 (≥ 75 * 109/L) and resume treatment at the same dose level.
3 – 4 Withhold dose until ≤ grade 1 (≥ 75 * 109/L), reduce dose by one dose level or to the previous dose level in case of previous dose escalation and resume treatment.
Neutropenia 2 No dose adjustment required.
3 Withhold dose until ≤ grade 2 (≥ 1.0 * 109/L) and resume treatment at the same dose level.
4 Withhold dose until ≤ grade 2 (≥ 1.0 * 109/L), reduce dose by one dose level or to the previous dose level in case of previous dose escalation and resume treatment.
Febrile neutropenia 3 Withhold dose until ≤ grade 2 (≥ 1.25 * 109/L) and no fever, reduce dose by one dose level or to the previous dose level in case of previous dose escalation and resume treatment.
4 Discontinue treatment with everolimus permanently.
PK samples
- 4, 8 and 12 weeks after treatment initiation - 4 weeks after every dose adjustment
- every 12 weeks until treatment discontinuation