Pocket Oncology (Pocket Notebook Series), 1st Ed.

MISCELLANEOUS AGENTS

Salma Afifi

All-Trans Retinoic Acid, ATRA, Tretinoin (Vesanoid)

Dosing/dose adjustments: 45 mg/m2/d in 2 divided doses × 30–90 d. No renal dose adjustments recommended. Hepatic: AST/ALT 5× ULN: Hold.

PK/PD: Good oral absorption (↑ absorption w/food), does not cross BBB, hepatically metabolized, renal excretion (63%), T1/2 0.5–2 h

Adverse effects: APL differentiation syndrome (BBW, 25%, fever, dyspnea, ≠ wt, pulm infiltrates) leukocytosis (BBW, 40%), peripheral edema, HA, dry skin, ↑ wt, ↑ cholesterol, ↑ LFTs

DDI: Oral contraceptives (↓ effect of oral contraceptives), immunosuppressants (↑ effect of immunosuppressants)

Clinical pearls: APL differentiation syndrome tx: High dose steroids (dexamethasone 10 mg IV every 12 h for 3–5 d); consider stopping Rx

Arsenic Trioxide, ATO (Trisenox)

Dosing/dose adjustments: 0.15 mg/kg/d IV until BM remission (max: 60 doses), same dose for consolidation (max: 25 doses over 5 wks). No renal or hepatic dose adjustments recommended.

PK/PD: Widely distributes into body & CNS, hepatically metabolized, renal excretion (15% as unchanged drug), T1/2 10–14 h

Adverse effects: APL differentiation syndrome (BBW, fever, dyspnea, wt gain, pulm infiltrates), QT prolongation (BBW), ↓ K/Mg, hyperglycemia, leukocytosis, rash, pain, ↑ LFTs, hearing loss

DDI: QTc-prolonging agents (↑ QTc interval)

Clinical pearls: Baseline then weekly 12-lead ECG & monitor electrolytes. APL differentiation syndrome tx: High-dose steroids (dexamethasone 10 mg IV every 12 h for ≥3 d); most pts may continue ATO.

Asparaginase, E. coli (Elspar)/Erwinia (Erwinaze)

Dosing/dose adjustments: E. coli: 6000 units/m2/dose IV/IM 3×/wk × 6–9 doses or 1000 units/kg/d × 10 d. Erwinia: 25000 units/m2 for each planned asparaginase dose. No renal or hepatic dose adjustments recommended.

PK/PD: Peak IM blood level 50% of IV, <1% CSF penetration, T1/2 E. coli: IM 39–49 h & IV 8–30 h, Erwinia: IM ∼16 h

Adverse effects: HSR (35% E. coli & 17% Erwinia), coagulopathy, ↑ glu, seizures, pancreatitis, thrombotic events (may be dose limiting)

DDI: Dexamethasone (↑ serum conc. of dexamethasone)

Clinical pearls: Test dose is recommended prior to first dose to test for HSR. W/E. coli form, IV greatly ↑ risk of allergic rxns. Up to 33% of pts who have HSR to E. coli will also react to Erwinia or pegaspargase.

Pegaspargase (Oncaspar)

Dosing/dose adjustments: 2500 units/m2 IM/IV, no more than every 14 d. No renal or hepatic dose adjustments recommended.

PK/PD: Slow IM absorption, systemically degraded, T1/2 IM ∼5.5–6 d & IV 7 d (longer in pts w/previous HSR to native asparaginase)

Adverse effects: HSR (no prior asparaginase HSR: 1–10%; prior HSR: 32%), coagulopathy (7%), ↑ glu, edema, pancreatitis (1–2%), thrombosis

DDI: Immunosuppressants (↑ immunosuppressant effects)

Clinical pearls: Indicated for pts w/HSR to native asparaginase but shown that 32% w/h/o HSR to E. coli form have HSR to pegaspargase

Info. based on publicly available drug inserts from Roche, Cephalon, Lundbeck, Jazz Pharmaceuticals & Enzon Pharmaceuticals.

Bortezomib (Velcade)

Dosing/dose adjustments: 1.3 mg/m2 SC or IV twice weekly (d 1, 4, 8, 11) for 21 d cycle or longer for 42 d cycle. No renal or hepatic dose adjustments recommended.

PK/PD: Distributes to peripheral tissues, hepatically metabolized via CYP2C19 & CYP3A4, T1/2 single dose 9–15 h; multiple doses 76–108 h

Adverse effects: Myelosuppression (nadir d 11), herpes reactivation, peripheral neuropathy, constipation/diarrhea, ↓ BP, HF (<1%)

DDI: CYP3A4/2C19 inhibitors/inducers (↑/↓ conc. of bortezomib), ascorbic acid & green tea (↓ bortezomib effect)

Clinical pearls: ↓ peripheral neuropathy w/SC route

Carfilzomib (Kyprolis)

Dosing/dose adjustments: 20 mg/m2 IV × 2 consecutive d every wk × 3 wks then 27 mg/m2 IV × 2 consecutive d every wk × 3 wks. No renal or hepatic dose adjustments recommended.

PK/PD: Extensive metabolism via hydrolysis (little metabolism via CYP450)

Adverse effects: Myelosuppression, HSR (w/in 24 h of infusion), peripheral edema, HTN, peripheral neuropathy, herpes reactivation, N/V (mod. emetogenic potential), ↓ K/Mg, ↑ SCr & AST

DDI: P-gp inhibitors/inducers (↑/↓ conc. of carfilzomib)

Clinical pearls: Less peripheral neuropathy (14%) compared to bortezomib. Hydrate w/250–500 mL NS & premedicate w/dexamethasone in cycle 1.

Everolimus (Afinitor, Zortress)

Dosing/dose adjustments: 10 mg PO daily. No renal or hepatic dose adjustments recommended.

PK/PD: Fast absorption, extensive hepatic metabolism (CYP3A4), T1/2 30 h

Adverse effects: Myelosuppression, edema, mucositis, HTN, rash, ↑ cholesterol/TG/glu, electrolyte imbalances

DDI: Strong CYP3A4 inducers (avoid use, ↓ conc. of everolimus), strong CYP3A4 & P-gp inhibitors (avoid use, ↑ conc. of everolimus)

Temsirolimus (Torisel)

Dosing/dose adjustments: 25 mg IV weekly. No renal dose adjustments recommended. Hepatic: TBili > 1–1.5 × ULN or AST > ULN: 15 mg weekly, TBili > 1.5 × ULN: Contraindicated

PK/PD: Hepatically metabolized via CYP3A4 to active metabolite (sirolimus)

Adverse effects: Myelosuppression, HSR, edema, mucositis, HTN, rash, ↑ cholesterol/TG/glu, electrolyte imbalances

DDI: Strong CYP3A4 inducers (avoid use, ↓ conc. of temsirolimus), strong CYP3A4 & P-gp inhibitors (avoid use, ↑ conc. of temsirolimus)

Clinical pearls: Premedicate w/H1 antagonist 30 min prior to infusion

Ziv-Aflibercept (Zaltrap)

Dosing/dose adjustments: 4 mg/kg IV every 2 wks. No renal or hepatic dose adjustments recommended.

PK/PD: T1/2 ∼6 d

Adverse effects: GI perforation (BBW), hemorrhage (BBW), impaired wound healing (BBW), proteinuria, HTN, thromboembolism, ↑ LFTs

DDI: Contraindicated w/clozapine (↑ risk of agranulocytosis)

Clinical pearls: Monitor CBC, urine protein, BP & signs of bleeding. Hold Rx at least 4 wks prior & 4 wks after major elective surgery.

Info. based on publicly available drug inserts from Millennium Pharmaceuticals, Onyx Pharmaceuticals, Novartis Pharma, BDI Pharma & Sanofi-Aventis.