Leigh M. Boehmer • Sara K. Butler • Janelle Mann
I. BACKGROUND. Traditional cytotoxic chemotherapy generally affects rapidly dividing normal and malignant cells. Recent advances in cancer biology, however, have led to the identification of numerous specific molecular targets for drug therapy. These molecular targets often play a key role in the signal transduction pathways that regulate tumor cell growth, proliferation, migration, angiogenesis, and apoptosis. Molecularly targeted therapy is a broad term encompassing several classes of agents, including tyrosine kinase inhibitors and monoclonal antibodies (MAb).
Ligand binding to the extracellular domain induces dimerization of the tyrosine kinase. This, in turn, leads to autophosphorylation of the intracellular domain, converting the tyrosine kinase to an active state. More specifically, when the intracellular domain undergoes autophosphorylation, binding sites for signaling proteins are formed. These signaling proteins are recruited to the membrane, and subsequently, multiple downstream signaling cascades are activated. Signals are conveyed from the cell membrane to the nucleus, resulting in alterations of DNA synthesis and cell growth, proliferation, migration, angiogenesis, and apoptosis. Examples of receptor tyrosine kinases include epidermal growth factor receptor (EGFR) (ErbB/HER) family members, vascular endothelial growth factor receptors (VEGFR), and platelet-derived growth factor receptors α and β(PDGFR α and β).
III. MONOCLONAL ANTIBODIES
Unconjugated MAbs directly affect signaling pathways by inhibiting ligand–receptor interactions. These are MAbs against either the receptor or its ligand. They may also indirectly stimulate host defense mechanisms, such as antibody-dependent cellular cytotoxicity (ADCC) or complement-mediated lysis, causing antitumor activity. Examples of unconjugated MAbs include rituximab, obinutuzumab, trastuzumab, cetuximab, panitumumab, and bevacizumab. Conjugated MAbs are MAbs combined with protein toxins or cytotoxic agents. These directly disrupt protein synthesis and cause tumor cell death. Examples of conjugated MAbs include brentuximab vedotin and ado-trastuzumab emtansine. Radioimmunoconjugates are MAbs in combination with radioisotopes intended to deliver a sterilizing dose of radiation to the tumor, such as ibritumomab tiuxetan.
Antibodies, or immunoglobulins, are Y-shaped molecules containing four chains—two identical light chains and two identical heavy chains. There is a fragment antigen binding (Fab) and a fragment crystalline (Fc) portion of the antibody. The Fab portion contains variable regions, including complementarity determining regions (CDR), that enable the antibody to bind to a specific antigen. The Fc portion contains constant regions that are identical in all immunoglobulins of the same isotype (i.e., IgA, IgG, and IgM) and function as binding sites for leukocytes and complement.
MAbs may be manufactured from multiple sources of B lymphocytes (i.e., murine, human, and primate). Murine MAbs are derived entirely from mice. Chimeric MAbs are composed of a murine variable region of the antibody with a constant region derived from humans, making approximately 65% to 90% of the agent of human origin. Humanized MAbs consist of variable and constant regions derived from humans with CDR derived from mice, making approximately 95% of the agent of human origin. Primatized MAbs contain variable regions from monkeys and constant regions from humans. Human MAbs are derived entirely from humans. MAbs are often manufactured by genetic manipulation to produce a humanized agent. Humanization of the agent decreases the immunogenicity of the MAb, thereby decreasing the production of human antimouse antibodies (HAMAs). HAMAs have the potential to inactivate and eliminate pure murine MAbs after repeated administration, decreasing the half-life of the agent. But HAMAs may also contribute to allergic reactions after the formation of antibody–HAMAs complexes. Pure murine MAbs also ineffectively stimulate host defense mechanisms, such as ADCC and complement-mediated lysis, because of differences between murine and human immune systems.
The United States Adopted Names (USAN) Council has developed guidelines for the nomenclature of MAbs for standardization purposes and to enable identification of the MAb composition for patient safety intent because of the potential for the development of source-specific antibodies. In general, the product source identifiers precede the suffix–mab. Also incorporated into the product name is a code syllable for the target disease state of the agent. Refer to Tables 6-1 and 6-2 for a list of product source identifiers and code syllables for the target disease states. Specific guidelines also exist for the nomenclature of radiolabeled and other conjugated MAbs.
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TABLE 6-1 |
Product Source Identifiers |
|
Source |
Identifier |
|
Human |
-u- |
|
Mouse |
-o- |
|
Rat |
-a- |
|
Humanized |
-zu- |
|
Hamster |
-e- |
|
Primate |
-i- |
|
Chimera |
-xi- |
|
TABLE 6-2 |
Code Syllables for the Targeted Disease State of the Agent |
IV. MOLECULAR TARGETS IN ONCOLOGY
i. Mechanism. Inhibits BCR-ABL tyrosine kinase, which blocks proliferation and causes apoptosis in BCR-ABL positive cell lines; inhibits stem cell factor (SCF; c-KIT) receptor tyrosine kinases, which inhibit proliferation and cause apoptosis in GIST cells that express c-KIT mutations; inhibits PDGFRα and β tyrosine kinases.
ii. Metabolism. Hepatic metabolism through CYP 3A4 to active metabolite (N-demethylated piperazine derivative). Eliminated primarily in the feces (68%) with some urinary excretion (13%) as metabolite and unchanged drug.
i. Common. Nausea, vomiting, diarrhea, erythema multiforme rash, fluid retention/edema, fatigue, pyrexia, headache, hepatotoxicity, hemorrhage, myelosuppression, arthralgia, myalgia, cough, and dyspnea.
ii. Occasional. Alopecia, gastrointestinal (GI) hemorrhage, ascites, increased transaminases and/or bilirubin, blurred vision, conjunctivitis, pruritus, chest pain, and upper respiratory tract infection.
iii. Rare. Central nervous system (CNS) hemorrhage, angioedema, aplastic anemia, migraine, pulmonary fibrosis, Stevens–Johnson syndrome, syncope, electrolyte disturbances, and peripheral neuropathy.
i. FDA-approved dose. Chronic phase CML dose is 400 mg orally daily, may be increased to 600 mg daily. Accelerated phase or blast crisis dose is 600 mg once daily, may be increased to 800 mg daily (400 mg twice daily). Dosing for Ph+ ALL is 600 mg orally daily. Dosing for GIST is 400 to 800 mg daily.
ii. Dose modification. Dose adjustment for severe hepatic impairment, hematologic and hepatotoxic adverse events, and inadequate hematologic or cytogenetic response.
iii. Supplied as 100- and 400-mg tablets.
i. Mechanism. Inhibits BCR-ABL tyrosine kinase, which blocks proliferation and causes apoptosis in BCR-ABL positive cell lines; inhibits SRC family (including SRC, LYN, and HCK); has activity in many imatinib-resistant BCR-ABL mutations (exceptions T315I and V299L).
ii. Metabolism. Hepatic metabolism through CYP 3A4 to primarily inactive metabolites. Eliminated primarily in the feces (91%) with minimal urinary excretion (3%).
i. Common. Edema, fever, fatigue, headache, rash, decreased bicarbonate, hypermagnesemia, hypomagnesemia, diarrhea, nausea, vomiting, abdominal pain, decreased appetite, thrombocytopenia, anemia, neutropenia, increased transaminases, arthralgia, back pain, weakness, cough, and dyspnea.
ii. Occasional. Chest pain, pericardial effusion, dizziness, pain, pruritis, acne, urticarial, dehydration, hypophosphatemia, uric acid elevation, hypocalcemia, gastritis, hepatotoxicity, tinnitus, renal failure, pleural effusion, and hypersensitivity reaction.
iii. Rare. Anaphylactic shock, fixed drug eruption, GI hemorrhage, pancreatitis, QTc prolongation, and pulmonary hypertension.
i. FDA-approved dose. Chronic phase CML dose is 500 mg orally once daily. May be increased to 600 mg once daily if complete response not achieved.
ii. Dose modification. Dose adjustment for hepatic impairment, hematologic and hepatotoxic adverse events, inadequate hematologic or cytogenetic response.
iii. Supplied as 100- and 500-mg tablets.
i. Mechanism. Multitargeted tyrosine kinase inhibitor affecting BCR-ABL, the SRC family, c-KIT, EPHA2, and PDGFRβ kinases; binds to both active and inactive ABL kinase domains.
ii. Metabolism. Extensive hepatic metabolism through CYP 3A4. Primarily fecal elimination. 0.1% and 19% of the dose eliminated unchanged in the urine and feces, respectively.
i. Common. Myelosuppression, fluid retention/edema, nausea, vomiting, diarrhea, abdominal pain, headache, hemorrhage, chest pain, arrhythmia, fatigue, pyrexia, rash, pruritus, mucositis, constipation, myalgia, arthralgia, dyspnea, cough, infection, and neuropathy.
ii. Occasional. Congestive heart failure, pericardial effusion, pulmonary edema, ascites, febrile neutropenia, electrolyte abnormalities, and elevated transaminases.
iii. Rare. QTc prolongation, elevated bilirubin.
i. FDA-approved dose. Chronic phase CML: 100 mg orally once daily with optional dose escalation to 140 mg once daily. Accelerated or blast phase CML: 140 mg orally once daily. ALL, Ph+: 140 mg orally once daily.
ii. Dose modification. Dose adjustment for hematologic toxicity or other non-hematologic adverse events. Consider when administered with strong CYP 3A4 enzyme inducers or inhibitors, or if inadequate hematologic or cytogenetic response.
iii. Supplied as 20-, 50-, 70-, 80-, 100-, and 140-mg tablets.
i. Mechanism. Inhibits BCR-ABL tyrosine kinase, which blocks proliferation and causes apoptosis in BCR-ABL positive cell lines; inhibits c-KIT and PDGFR.
ii. Metabolism. Hepatic metabolism through CYP 3A4 to inactive metabolites. Eliminated primarily in the feces (93%) with 69% being parent drug.
i. Common. Peripheral edema, hypertension, headache, fatigue, fever, insomnia, rash, pruritus, alopecia, hypophosphatemia, hyperglycemia, nausea, vomiting, diarrhea, constipation, neutropenia, thrombocytopenia, anemia, hyperbilirubinemia, elevated transaminases, arthralgia, and cough.
ii. Occasional. Arterial stenosis, cerebrovascular accident, arrhythmia, atrial fibrillation, QTc prolongation, dizziness, depression, dry skin, acne, erythema, hypokalemia, hyponatremia, hyperkalemia, and dyspepsia.
iii. Rare. Arteriosclerosis, cardiac failure, coronary artery disease, diplopia, dysuria, gastric ulcer, and hepatitis.
i. FDA-approved dose. Chronic phase CML: 300 mg orally twice daily. Chronic or accelerated phase in resistant or intolerant patients: 400 mg po twice daily.
ii. Dose modification. Dose adjustment for hepatic impairment, hematologic and hepatotoxic adverse events, inadequate hematologic or cytogenetic response.
iii. Supplied as 150- and 200-mg capsules.
i. Mechanism. Pan-inhibitor of BCR-ABL tyrosine kinase including T315I, which blocks proliferation and causes apoptosis in BCR-ABL positive cell lines; inhibits VEGFR, FGFR, PDGFR, EPH, and SRC kinases and KIT, RET, TIE2, and FLT3.
ii. Metabolism. Hepatic metabolism through CYP 3A4, 2C8, 2D6, and 3A5. Eliminated primarily in the feces (87%) with some urinary excretion (5%).
i. Common. Hypertension, peripheral edema, heart failure, arterial ischemia, fatigue, headache, fever, pain, dizziness, rash, dry skin, hyperglycemia, hypophosphatemia, hypocalcemia, abdominal pain, constipation, nausea, diarrhea, vomiting, mucositis, weight loss, neutropenia, thrombocytopenia, anemia, elevated transaminases, elevated bilirubin, arthralgia, myalgia, and peripheral neuropathy.
ii. Occasional. Myocardial infarction, SVT, atrial fibrillation, venous thromboembolism, pericardial effusion, stroke, and TIA.
iii. Rare. Ascites, atrial flutter, cerebral edema, heart block, and hepatic failure.
i. FDA-approved dose. 45 mg orally once daily.
ii. Dose modification. Dose adjustment for moderate-to-severe hepatic impairment, hematologic and hepatotoxic adverse events, inadequate hematologic or cytogenetic response.
iii. Supplied as 15- and 45-mg tablets.
In NSCLC, the EML4-ALK fusion oncogene is the most commonly reported ALK mutation. This inversion on chromosome 2 leads to a fusion of the kinase domain of ALK and EML-4 echinoderm microtubule-associated protein-like 4 region, inv(2)(p21p23). The EML4-ALK fusion mediates ligand-independent dimerization of the kinase, leading to the continuous downstream signaling of the PI3K-AKT, STAT3, and Ras-Raf-ERK pathways causing cell survival and proliferation.
Crizotinib has a classical ATP-competitive mechanism of action with dose-dependent inhibition on the phosphorylation of ALK as well as c-MET, preventing cellular proliferation and inducing apoptosis.
i. Mechanism. Binds to the ATP intracellular domain of activated ALK, which inhibits phosphorylation and subsequent downstream signaling.
ii. Metabolism. Extensive hepatic metabolism primarily through CYP 3A4. Eliminated primarily by feces (63%) with a small amount in the urine (22%).
i. Common. Vision disorder (visual impairment, photopsia, blurred vision, vitreous floaters, photophobia, and diplopia), dizziness, neuropathy, fatigue, decreased appetite, nausea, diarrhea, vomiting, edema, and constipation.
ii. Rare. Pneumonitis, pneumonia, QTc prolongation, liver function test elevations (AST/ALT, bilirubin), and hepatotoxicity.
i. FDA-approved dose. 250 mg orally twice daily.
ii. Dose modification. Recommendations regarding dose adjustment for corrected QTc >500 ms without serious signs or symptoms of arrhythmia are to hold therapy until QTc <480 ms and then resume at 200 mg orally twice daily. Dose adjustment for AST/ALT elevations of ≥5 × ULN with grade ≤1 total bilirubin is to hold until toxicity improves and then resume at 200 mg orally twice daily. Evaluate for drug interaction with strong inducers or inhibitors of CYP3A and concomitant use of QTc prolonging medications.
iii. Supplied as 200-, 250-mg capsules.
Activation of these receptor tyrosine kinases result in multiple downstream signaling pathways being activated, including the Ras/Raf mitogen-activated protein kinase (MAPK) pathway, the phosphatidylinositol 3′-kinase (PI3K)/Akt pathway, the protein kinase C pathway, and the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. These pathways affect cell proliferation, migration, differentiation, and inhibit apoptosis. The activation of EGFR also causes an upregulation of vascular endothelial growth factor (VEGF) expression, leading to an increase in angiogenesis.
EGFR tyrosine kinase inhibitors are small molecules that bind to the ATP-binding site on the tyrosine kinase domain of the receptor and inhibit the catalytic activity of the kinase or they may inhibit fusion tyrosine kinases by blocking dimerization. The available EGFR tyrosine kinase inhibitors include erlotinib and afatinib. The EGFR-targeting MAbs available, cetuximab and panitumumab, inhibit ligand binding to the receptor.
i. Mechanism. Inhibits intracellular phosphorylation of the EGFR tyrosine kinase.
ii. Metabolism. Extensive hepatic metabolism primarily through CYP 3A4. Eliminated primarily by feces (83%) with a small amount in the urine (8%).
i. Common. GI upset (diarrhea, nausea, vomiting, and anorexia), mucositis, dermatologic toxicity (acneiform rash, erythematous rash, maculopapular dermatitis, dry skin, and pruritus), fatigue, headache, depression, dizziness, insomnia, dyspnea, cough, infection, edema, eye irritation/conjunctivitis, elevated hepatic transaminases, and/or bilirubin.
ii. Occasional. Deep vein thrombosis, myocardial infarction/ischemia, cerebrovascular events, ileus, and pancreatitis.
iii. Rare. Corneal ulcerations, epistaxis, GI bleeding, interstitial lung disease–like events, and hemolytic anemia.
i. FDA-approved dose. Dose for NSCLC is 150 mg orally once daily. Dose for pancreatic cancer is 100 mg orally once daily in combination with gemcitabine. Administer at least 1 hour before or 2 hours after food.
ii. Dose modification. No adjustment for renal impairment. May need dose adjustment if severe liver impairment exists. Dose modifications may be made for intolerance or concomitant CYP 3A4 inhibitor or inducer administration.
iii. Supplied as 25-, 100-, 150-mg tablets.
i. Mechanism. Irreversibly inhibits intracellular phosphorylation of the EGFR tyrosine kinase.
ii. Metabolism. Metabolism is negligible, inhibitor/substrate of P-glycoprotein. Eliminated primarily by feces (85%) with a small amount in the urine (4%).
i. Common. GI upset (diarrhea, anorexia), stomatitis, dermatologic toxicity (acneiform rash, erythematous rash, maculopapular dermatitis, dry skin, and pruritus), paronychia, fatigue, dyspnea, cough, and eye irritation/conjunctivitis.
ii. Occasional. Elevated hepatic transaminases, hypokalemia, and cystitis.
iii. Rare. Interstitial lung disease–like events, pneumonia, sepsis, diastolic dysfunction, bullous skin eruption, and hepatotoxicity.
i. FDA-approved dose. Dose for NSCLC is 40 mg orally once daily. Administer at least 1 hour before or 2 hours after food.
ii. Dose modification. Dose adjustment for renal impairment should be considered if CrCl <59 mL/min and patient is showing intolerance to therapy. Reduce afatinib daily dose by 10 mg if patient is using concurrent P-glycoprotein inhibitor(s) and not tolerating treatment. If taking P-glycoprotein inducers, it is recommended to increase afatinib daily dose by 10 mg.
iii. Supplied as 20-, 30-, 40-mg tablets.
i. Mechanism. Binds to the extracellular domain of the EGFR inhibiting the binding of epidermal growth factor (EGF) to the receptor; inhibits cell growth and metastasis, induces apoptosis, inhibits VEGF production, causes ADCC, and downregulates EGFR.
ii. Metabolism. Elimination through EGFR binding/internalization.
i. Common. Dermatologic toxicities (acneiform rash, skin drying and fissuring, inflammatory/infectious reactions), malaise, fever, hypomagnesemia, nausea, constipation, abdominal pain, diarrhea, headache, weakness, cough, peripheral edema, alopecia, and anemia.
ii. Occasional. Sepsis, pulmonary embolism, kidney failure, dehydration, conjunctivitis, infusion-related reactions, and cardiopulmonary arrest.
iii. Rare. Interstitial lung disease, leukopenia.
i. FDA-approved dose. Initial loading dose: 400 mg/m2 intravenously on day 1. Maintenance dose: 250 mg/m2 intravenously once a week starting on day 8.
ii. Dose modification. Dose adjustment for toxicities. No adjustment needed for renal or hepatic impairment.
iii. Supplied as 100-mg vials.
i. Mechanism. Binds to the extracellular domain of the EGFR inhibiting the binding of EGF and other ligands to the receptor; inhibits cell growth, survival, proliferation, and transformation.
ii. Metabolism. Elimination through EGFR binding/internalization.
i. Common. Dermatologic toxicities (acneiform rash, skin drying and fissuring, inflammatory/infectious reactions), peripheral edema, fatigue, hypomagnesemia, abdominal pain, nausea, diarrhea, constipation, vomiting, ocular toxicity, and cough.
ii. Occasional. Infusion-related reactions, stomatitis, mucositis, conjunctivitis, eyelash growth, and antibody formation.
iii. Rare. Sepsis, pulmonary fibrosis, and skin necrosis.
i. FDA-approved dose. 6 mg/kg intravenously every 14 days.
ii. Dose modification. Dose adjustment for toxicities. No adjustment needed for renal or hepatic impairment.
iii. Supplied as 100- and 400-mg vials.
i. Mechanism. Dual tyrosine kinase inhibitor against EGFR and HER2 blocking phosphorylation and activation of downstream second messengers.
ii. Metabolism. Hepatic via extensively CYP3A4/5 and to a lesser extent via CYP2C19 and 2C8 to oxidized metabolites.
i. Common. Fatigue, headache, hand–foot syndrome, rash, dry skin, alopecia, nail disorder, diarrhea, nausea, vomiting, abdominal pain, stomatitis, dyspepsia, anemia, neutropenia, thrombocytopenia, increased transaminases, increased bilirubin, limb pain, and weakness.
ii. Occasional. Left ventricular dysfunction, insomnia.
iii. Rare. Anaphylaxis, hepatotoxicity, interstitial lung disease, pneumonitis, and QTc prolongation.
i. FDA-approved dose. In combination with capecitabine: 1,250 mg orally daily; in combination with letrozole: 1,500 mg orally daily; in combination with trastuzumab: 1,000 mg orally daily.
ii. Dose modification. Recommend decreased dose for severe hepatic impairment.
iii. Supplied as 250-mg tablets.
i. Mechanism. Binds to the extracellular domain of the HER2/neu protein. It mediates several intracellular effects including internalization of the HER2 receptor and downregulation of surface HER2 expression; alters downstream signaling pathways and leads to a decrease in cell proliferation and VEGF production, induces apoptosis, and potentiates chemotherapy. It also causes several extracellular effects including interference with homodimer and heterodimer formation between HER-family receptors and induces antibody-dependent cellular toxicity against cells that overproduce HER2.
ii. Metabolism. Elimination through internalization after receptor binding.
i. Common. Infusion-related reactions (fever, chills), rash, headache, diarrhea, myelosuppression, and infections.
ii. Occasional. Left ventricular dysfunction, cardiomyopathy, congestive heart failure, and arthralgia.
iii. Rare. Severe hypersensitivity reactions (anaphylaxis, urticaria, bronchospasm, angioedema, and/or hypotension), severe infusion-related reactions (fever, chills, nausea, vomiting, pain at the tumor site, headache, dizziness, dyspnea, hypotension, rash, and asthenia), pulmonary events (dyspnea, pulmonary infiltrates, pleural effusions, noncardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome [ARDS], pneumonitis, and pulmonary fibrosis).
i. FDA-approved dose. Weekly dosing: initial loading dose is 4 mg/kg intravenously on day 1. Maintenance dose is 2 mg/kg intravenously once weekly starting on day 8. Every 3-week dosing: initial loading dose is 8 mg/kg intravenously on day 1. Maintenance dose is 6 mg/kg intravenously every 3 weeks starting on day 22.
ii. Dose modification. Recommended to hold for at least 4 weeks for LVEF ≥16% decrease from baseline or LVEF below normal limits and ≥10% decrease from baseline.
iii. Supplied as a 440-mg vial.
i. Mechanism. Targets the extracellular HER2/neu dimerization domain and inhibits HER2 dimerization blocking downstream signaling. Binds to a different HER2 epitope than trastuzumab, resulting in a more complete inhibition of HER2 signaling when combined with trastuzumab.
ii. Metabolism. Elimination through internalization after receptor binding.
i. Common. Fatigue, headache, fever, dizziness, rash, diarrhea, mucosal inflammation, nausea, stomatitis, vomiting, neutropenia, anemia, and infusion reactions.
ii. Occasional. Paronychia, anorexia.
iii. Rare. Heart failure, insomnia, left ventricular ejection fraction decreased, peripheral edema, and pleural effusion.
i. FDA-approved dose. In combination with docetaxel and trastuzumab: 840 mg intravenously on day 1 followed by 420 mg intravenously every 3 weeks.
ii. Dose modification. No dose adjustments recommended.
iii. Supplied as a 420-mg vial.
Binding to VEGFR-3 (Flt-4) induces lymphangiogenesis. VEGF also plays a key role in the induction of angiogenesis, or the growth of new blood vessels from existing vasculature, which helps sustain tumor growth and survival by supplying nutrients and oxygen. The overexpression of VEGF occurs in various tumor types including colorectal, breast, cervical, endometrial, gastric, renal, pancreatic, and hepatic cancers, and NSCLC, melanoma, glioblastoma, and AML. Several factors may upregulate VEGF expression including hypoxia, acidosis, embryogenesis, endometriosis, wound healing and various growth factors (PDGF, fibroblast growth factor [FGF], epidermal growth factor [EGF], tumor necrosis factor [TNF], transforming growth factor beta, interleukin 1 [IL-1]). Within tumor cells, hypoxia is the key mediator of VEGF overexpression. Agents with effects on VEGF/VEGFRs include axitinib, pazopanib, sunitinib, bevacizumab, and ziv-aflibercept.
i. Mechanism. Blocks angiogenesis and tumor growth by inhibiting VEGFR 1, 2, and 3.
ii. Metabolism. Hepatic, primarily through CYP 3A4/5 and to a lesser extent via CYP 1A2, CYP 2C19, and UGT 1A1. Primarily excreted in the feces (41%) with a smaller amount excreted renally (23%).
i. Common. Hypertension, fatigue, dysphonia, headache, hand–foot syndrome, rash, hypocalcemia, hyperglycemia, hypernatremia, hypoalbuminemia, decreased bicarbonate, diarrhea, nausea, increased lipase/amylase, weight loss, vomiting, constipation, myelosuppression, increased liver function tests (LFTs), weakness, arthralgias, increased creatinine, proteinuria, and cough.
ii. Occasional. Venous/arterial thrombotic events, transient ischemic attack, dizziness, dry skin, pruritus, alopecia, erythema, hyperthyroidism, dyspepsia, hemorrhoids, myalgias, tinnitus, hematuria, and epistaxis.
iii. Rare. Cerebral bleeding, cerebrovascular crisis, reversible posterior leukoencephalopathy syndrome, and heart failure.
i. FDA-approved dose. 5 mg orally twice daily with or without food with a glass of water. If dose is tolerated for at least 2 consecutive weeks, may increase the dose to 7 mg orally twice daily, and then further increase (using the same criteria) to 10 mg orally twice daily.
ii. Dose modification. For adverse events, reduce dose from 5 mg orally twice daily to 3 mg orally twice daily; further reduction to 2 mg orally twice daily can be performed. Avoid concomitant administration with strong CYP 3A4 inhibitors. If strong CYP 3A4 inhibitors are used, a 50% dosage reduction is recommended. No dose adjustment necessary for mild to severe renal dysfunction. No dose adjustment necessary for Child–Pugh class A; 50% dose reduction for Child-Pugh class B; and has not been studied in Child–Pugh class C.
iii. Supplied as 1- and 5-mg tablets.
i. Mechanism. Blocks angiogenesis and tumor growth by inhibiting VEGFR 1, 2, and 3, PDGFR, FGFR-1 and 3, cKIT, interleukin-2 receptor inducible T-cell kinase, leukocyte-specific protein tyrosine kinase (LcK), and c-Fms.
ii. Metabolism. Hepatic, primarily through CYP 3A4 and to a lesser extent via CYP1A2, CYP2C8, and UGT 1A1. Primarily excreted in the feces with a smaller amount excreted renally (<4%).
i. Common. Hypertension, edema, fatigue, headache, dizziness, hair discoloration, hand–foot syndrome, rash, hyperglycemia, hypophosphatemia, hyponatremia, increased TSH, diarrhea, nausea, weight loss, vomiting, constipation, myelosuppression, increased LFTs, weakness, and cough.
ii. Occasional. Venous/arterial thrombotic events, transient ischemic attack, chest pain, QTc prolongation, insomnia, chills, dyspepsia, and blurred vision.
iii. Rare. Cerebral bleeding, cerebrovascular crisis, reversible posterior leukoencephalopathy syndrome, and heart failure.
i. FDA-approved dose. 800 mg orally once daily on an empty stomach.
ii. Dose modification. Modify doses for moderate-to-severe hepatic impairment.
iii. Supplied as 200-mg tablets.
i. Mechanism. Inhibits multiple tyrosine kinases including VEGFR 1, 2, and 3; SCF receptor (c-KIT); PDGFR α and β; and Fms-like tyrosine kinase-3 (Flt-3).
ii. Metabolism. Hepatic through CYP 3A4 to the active N-desethyl metabolite SU12662. Primarily excreted in the feces (61%) with a small amount excreted renally (16%).
i. Common. Hypertension, rash, hand–foot syndrome, alopecia, skin discoloration (yellow–orange), hair pigmentation changes, dry skin, diarrhea, nausea, vomiting, mucositis/stomatitis, constipation, dyspepsia, dyspnea, cough, edema, fever, fatigue, hyperuricemia, increased LFTs, increased amylase/lipase, myelosuppression, arthralgia, myalgia, increased serum creatinine, decreased left ventricular ejection fraction (LVEF), and hemorrhage.
ii. Occasional. Electrolyte disturbances, hypothyroidism, oral pain, thromboembolism, myocardial ischemia/infarction, anorexia, and peripheral neuropathy.
iii. Rare. Febrile neutropenia, pancreatitis, reversible posterior leukoencephalopathy syndrome, and seizure.
i. FDA-approved dose. 50 mg orally once daily with or without food for 4 weeks in a 6-week treatment cycle (4 weeks on, 2 weeks off) for GIST and advanced RCC. Dosing for PNET is 37.5 mg orally once daily with or without food; maximum daily dose used in clinical trials: 50 mg.
ii. Dose modification. Dose reductions to 37.5 mg daily (GIST/RCC) or 25 mg daily (PNET) should be considered with concomitant use of strong CYP 3A4 inhibitors. Dosage increment to 87.5 mg daily (GIST/RCC) or 62.5 mg daily (PNET) should be considered with concomitant use of strong CYP 3A4 inducers.
iii. Supplied as 12.5-, 25-, and 50-mg capsules.
i. Mechanism. Recombinant, humanized MAb that binds to and neutralizes VEGF.
i. Common. Hypertension, headache, abdominal pain, nausea, vomiting, diarrhea, anorexia, constipation, proteinuria, leukopenia, weakness, exfoliative dermatitis, stomatitis, epistaxis, dyspnea, upper respiratory infection, and wound healing.
ii. Occasional. Venous thromboembolic events, hemorrhagic events, GI perforation, arterial thromboembolic events, left ventricular dysfunction, and infusion-related reactions.
iii. Rare. CNS hemorrhage, nephrotic syndrome, fistula development, severe or fatal hemorrhage, necrotizing fasciitis, and wound dehiscence.
i. FDA-approved dose. For metastatic colorectal cancer: 5 mg/kg intravenously every 2 weeks (in combination with bolus-IFL); 10 mg/kg intravenously every 2 weeks (in combination with FOLFOX4). 5 mg/kg intravenously every 2 weeks or 7.5 mg/kg intravenously every 3 weeks (in combination with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin–based regimen). For metastatic nonsquamous NSCLC: 15 mg/kg intravenously every 3 weeks (in combination with paclitaxel and carboplatin). For metastatic RCC: 10 mg/kg intravenously every 2 weeks (in combination with interferon alfa).
ii. Dose modification. Temporary suspension of therapy is warranted in patients with moderate or severe proteinuria or severe, uncontrolled hypertension. Permanent discontinuation is recommended for wound dehiscence requiring intervention, GI perforation, hypertensive crisis, serious bleeding, severe arterial thromboembolic events, or nephrotic syndrome.
iii. Supplied as 100- and 400-mg vials.
i. Mechanism. Recombinant fusion protein, comprised of portions of binding domains for VEGFR 1 and 2 attached to the Fc portion of human IgG1, which acts as a decoy receptor for VEGF-A, -B, and placental growth factor that prevent VEGFR binding/activation to their receptors, leading to angiogenesis and tumor regression.
i. Common. Hypertension, fatigue, dysphonia, hand–foot syndrome, diarrhea, stomatitis, decreased appetite, weight loss, abdominal pain, myelosuppression, increase AST/ALT, weakness, proteinuria, increased creatinine, epistaxis, and dyspnea.
ii. Occasional. Venous/arterial thromboembolic events, reversible posterior encephalopathy syndrome (RPLS), hyperpigmentation, dehydration, hemorrhoids, neutropenic fever, oropharyngeal pain, pulmonary embolism, and fistula formation.
iii. Rare. Hypersensitivity resections, thrombotic microangiopathy, and impaired wound healing.
i. FDA-approved dose. 4 mg/kg intravenously every 2 weeks (in combination with FOLFIRI).
ii. Dose modification. Temporary suspension of therapy is warranted in patients with uncontrolled hypertension, neutropenia, or moderate-to-severe proteinuria. Permanent discontinuation is recommended for arterial thrombotic events, fistula formation, GI perforation, serious bleeding, hypertensive crisis, nephrotic syndrome or thrombotic microangiopathy, RPLS, or wound dehiscence requiring intervention.
iii. Supplied as 100- and 200-mg vials.
i. Mechanism. Inhibits several intracellular Raf kinases including C-Raf, wild-type B-Raf, and mutant B-Raf. Also inhibits several cell surface kinases including VEGFR1-3, PDGFRα, c-KIT, RET, and Flt-3. These inhibitory effects decrease tumor cell proliferation and angiogenesis.
ii. Metabolism. Hepatic metabolism primarily through CYP 3A4 and glucuronidation by UGT1A9. Elimination occurs primarily by the fecal route (77%; 51% as unchanged drug); 19% of the dose undergoes urinary excretion.
i. Common. Rash, hand–foot syndrome, diarrhea, hypertension, elevations in amylase/lipase, bleeding events, fatigue, hypophosphatemia, alopecia, pruritus, dry skin, diarrhea, nausea, vomiting, constipation, dyspnea, cough, myelosuppression, and neuropathy.
ii. Occasional. Cardiac ischemia/infarction, mucositis/stomatitis, headache, hypokalemia, and dyspepsia.
iii. Rare. GI perforation, thromboembolism, interstitial lung disease, and RPLS.
i. Common. Hypertension, fatigue, dysphonia, pain, headache, fever, hand–foot syndrome, rash, alopecia, hypocalcemia, hypophosphatemia, hyponatremia, hypothyroidism, increased lipase, diarrhea, nausea, vomiting, elevations in AST/ALT, and proteinuria.
ii. Occasional. Taste disturbance, xerostomia, gastroesophageal reflux, tremor, and myocardial ischemia.
iii. Rare. GI fistula, hypertensive crisis, RPLS, and skin cancer (squamous cell carcinoma or keratoacanthoma).
i. FDA-approved dose. 160 mg orally once daily for the first 21 days of each 28-day cycle with a low-fat (<30% fat) breakfast.
ii. Dose modification. Modifications recommended for skin toxicities. No adjustments in mild or moderate preexisting renal impairment; not studied in severe renal dysfunction. No adjustments necessary for Child–Pugh Class A or B hepatic dysfunction; not studied in Child–Pugh Class C.
iii. Supplied as 40-mg tablets.
i. Mechanism. Inhibits BRAF V600E and blocks downstream phosphorylation in BRAF-mutated cells
ii. Metabolism. Hepatic metabolism occurs via CYP3A4. Elimination occurs primarily by the fecal route (94%); 1% of the dose undergoes urinary excretion.
i. Common. Alopecia, papilloma, photosensitivity, pruritus, rash, nausea, arthralgia, and fatigue.
ii. Occasional. Prolonged QT interval, squamous cell carcinoma of the skin, Stevens–Johnson syndrome, toxic epidermal necrolysis, and hand–foot syndrome.
iii. Rare. Immune hypersensitivity reaction, malignant melanoma.
i. FDA-approved dose. 960 mg orally twice daily
ii. Dose modification. Modifications recommended for QT prolongation. No adjustments in mild or moderate preexisting renal impairment; not studied in severe renal dysfunction. No adjustments necessary for Child–Pugh Class A or B hepatic dysfunction; not studied in Child–Pugh Class C.
iii. Supplied as 240-mg tablets.
i. Mechanism. Inhibits BRAF V600E kinase, as well as BRAF V600K, BRAF V600D, and wild-type BRAF and CRAF kinases and competitively blocks phosphorylation at the ATP-binding site of these kinases.
ii. Metabolism. Hepatic metabolism primarily through CYP 2C8 and CYP3A4. Elimination occurs primarily by the fecal route (71%); 23% of the dose undergoes urinary excretion.
i. Common. Peripheral edema, alopecia, hand–foot syndrome, hyperkeratosis, night sweats, papilloma, rash, hyperglycemia, hypoalbuminemia, hypokalemia, hypophosphatemia, abdominal pain, constipation, decreased appetite, diarrhea, nausea, vomiting, anemia, leukopenia, neutropenia, elevated liver enzymes, lymphocytopenia, arthralgia, myalgias, headache, cough, fatigue, pyrexia, and shivering.
ii. Occasional. Cardiomyopathy, deep venous thrombosis, pancreatitis, interstitial nephritis, and renal failure.
iii. Rare. New primary cutaneous malignancies, febrile drug reaction, hemolytic anemia in G6PD-deficient patients, uveitis, and iritis.
i. FDA-approved dose. 150 mg orally twice daily taken 1 hour before or 2 hours after a meal.
ii. Dose modification. May be considered based on side effects. No data exist to guide dose adjustments in patients with renal or hepatic insufficiencies; however, dose adjustments are not recommended for mild-to-moderate renal dysfunction or mild hepatic dysfunction. It is recommended to avoid strong inhibitors and inducers of CYP3A4, CYP2C8, and p-glycoprotein.
iii. Supplied as 50- and 75-mg capsules.
i. Mechanism. Inhibitor that reversibly inhibits mitogen-activated extracellular regulated kinase 1 (MEK1) and MEK2 activation and of MEK1 and MEK2 activity. It also inhibits BRAF V600 mutation-positive cells when used in combination with dabrafenib.
ii. Metabolism. Predominantly metabolized via deacetylation alone or with mono-oxygenation in combination with glucuronidation. Elimination occurs primarily by the fecal route (80%); 20% of the dose undergoes urinary excretion.
i. Common. Peripheral edema, night sweats, rash, hyperglycemia, hypoalbuminemia, hypokalemia, hypophosphatemia, abdominal pain, constipation, decreased appetite, diarrhea, nausea, vomiting, anemia, leukopenia, neutropenia, thrombocytopenia, elevated liver enzymes, lymphedema, arthralgia, myalgias, cough, fatigue, pyrexia, and shivering.
ii. Occasional. Cardiomyopathy, prolonged QT interval, interstitial nephritis, and renal failure.
iii. Rare. New primary cutaneous malignancies, febrile drug reaction, retinal pigment epithelial detachment, thrombosis of retinal vein, pulmonary embolism, and interstitial lung disease.
i. FDA-approved dose. 2 mg orally once daily taken 1 hour before or 2 hours after a meal.
ii. Dose modification. May be considered based on side effects. Reduce, hold, or discontinue doses based on organ-specific toxicities, specifically cutaneous, cardiac, ocular, and pulmonary toxicities.
iii. Supplied as 0.5- and 2-mg tablets.
i. Mechanism. Binds to the FK binding protein-12 to form a complex that inhibits activation of mTOR serine-threonine kinase activity, which leads to reduced protein synthesis and cell proliferation. Also inhibits VEGF and hypoxia-inducible factor, thereby reducing angiogenesis.
ii. Metabolism. Extensively metabolized in the liver via CYP 3A4; forms six weak metabolites. Elimination occurs via feces (80%) and urine (∼5%).
i. Common. Peripheral edema, hypertension, fatigue, headache, fever, seizure, behavioral changes, insomnia, dizziness, rash, acneiform eruption, pruritus, xeroderma, contact dermatitis, excoriation, hypercholesterolemia, hyperglycemia, hypertriglyceridemia, hypophosphatemia, hypocalcemia, diabetes mellitus, hypomagnesemia, stomatitis, constipation, nausea, diarrhea, gastroenteritis, myelosuppression, abnormal liver function tests, weakness, arthralgias, limb pain, otitis, increased serum creatinine, epistaxis, cough, dyspnea, and rhinitis.
ii. Occasional. Chest pain, depression, migraine, paresthesia, chills, eczema, alopecia, hand–foot syndrome, hypermenorrhea, menstrual disease, gastritis, vaginal hemorrhage, increased serum bilirubin, muscle spasm, tremor, jaw pain, pleural effusion, pneumonia, and rhinitis.
iii. Rare. Cardiac arrest, azoospermia, fluid retention, intrahepatic cholestasis, pulmonary embolism, thrombotic microangiopathy, and thrombotic thrombocytopenic purpura.
i. FDA-approved dose. 10 mg orally once daily with or without food with a glass of water. To reduce variability, take consistently with regard to food.
ii. Dose modification. No dosage adjustment necessary for renal dysfunction. For Child–Pugh class A, reduce dose to 7.5 mg orally once daily; if not tolerated, may further reduce to 5 mg orally once daily. For Child–Pugh class B, reduce dose to 5 mg orally once daily; if not tolerated, may further reduce to 2.5 mg orally once daily. For Child–Pugh class C, if potential benefit outweighs risks, a maximum dose of 2.5 mg orally once daily may be considered.
iii. Supplied as 2.5-, 5-, 7.5-, and 10-mg tablets.
i. Mechanism. Binds to the FK binding protein-12 to form a complex that inhibits activation of mTOR serine-threonine kinase activity, which leads to reduced protein synthesis and cell proliferation. Also inhibits VEGF and hypoxia-inducible factors, thereby reducing angiogenesis.
ii. Metabolism. Primarily hepatic metabolism via CYP 3A4 to sirolimus (active metabolite) and four minor metabolites. Excretion occurs via feces (78%) and the urine (<5%).
i. Common. Edema, chest pain, fever, pain, headache, insomnia, rash, pruritus, nail thinning, dry skin, hyperglycemia, hypercholesterolemia, hypophosphatemia, hyperlipidemia, hypokalemia, mucositis, nausea, anorexia, stomatitis, constipation, weight loss, vomiting, myelosuppression, abnormal liver function tests, weakness, back pain, arthralgia, increased creatinine, dyspnea, cough, epistaxis, and infections.
ii. Occasional. Hypertension, venous thromboembolism, acne, impaired wound healing, hyperbilirubinemia, bowel perforation, myalgias, conjunctivitis, interstitial lung disease, and hypotension.
iii. Rare. Acute renal failure, glucose intolerance, angioneurotic edema, pericardial effusion, pleural effusion, pneumonitis, and seizure.
i. FDA-approved dose. 25 mg intravenously once weekly until disease progression or unacceptable toxicity. Avoid concomitant administration with CYP 3A4 inhibitors. If a strong CYP 3A4 inhibitor cannot be avoided, consider dose reduction to 12.5 mg intravenously once weekly. If a strong CYP 3A4 inducer is concomitantly used, consider dose adjustment up to 50 mg intravenously once weekly.
ii. Dose modification. No renal dose adjustments are necessary; has not been studied in dialysis. For mild hepatic dysfunction (bilirubin >1–1.5 times upper limit of normal (ULN) or AST >ULN with bilirubin ≤ULN), reduce dose to 15 mg intravenously once weekly. Use is contraindicated in moderate-to-severe hepatic dysfunction.
iii. Supplied as 25-mg vials.
i. Mechanism. Potent and irreversible binding of Bruton’s tyrosine kinase, resulting in decreased malignant B-cell proliferation and survival.
ii. Metabolism. Metabolized in the liver via CYP 3A (major) and CYP2D6 (minor) to an active metabolite. Elimination occurs via feces (80%) and urine (<10%).
i. Common. Peripheral edema, fatigue, skin rash, diarrhea, nausea, constipation, thrombocytopenia, neutropenia, anemia, musculoskeletal pain, and dyspnea.
ii. Occasional. Dehydration, stomatitis, dyspepsia, arthralgias, increased serum creatinine, sinusitis, and epistaxis.
iii. Rare. Malignant neoplasm of skin, renal failure.
i. FDA-approved dose. CLL: 420 mg orally once daily; Mantle cell lymphoma: 560 mg orally once daily. Administer with water at approximately the same time each day.
ii. Dose modification. Avoid concurrent use with moderate or strong inhibitors of CYP3A. If concomitant use is necessary, reduce dose to 140 mg orally once daily.
iii. Supplied as 140-mg capsules.
i. Mechanism. Binds to CD52, resulting in complement-mediated and/or antibody-dependent cellular cytotoxicity.
ii. Metabolism. Initial half-life is 11 hours but increases to 6 days after repeated dosing (due to depletion of CD52-positive cells).
i. Common. Hypotension, fever, chills, headache, rash, nausea, vomiting, diarrhea, rigors, chest pain, dyspnea, pharyngitis, infection, neutropenia, thrombocytopenia, and anemia.
ii. Occasional. Pancytopenia, autoimmune idiopathic thrombocytopenia, and hemolytic anemia.
iii. Rare. Pulmonary fibrosis, bone fracture, tumor lysis syndrome, and electrolyte disturbances.
i. FDA-approved dose. Initial dose is 3 mg intravenously once daily, which is then increased to 10 mg intravenously once daily as tolerated. Once the 10-mg dose is tolerated, the dose is increased to 30 mg intravenously once daily. Most patients can tolerate dose escalation in 4 to 7 days. The maintenance dose is 30 mg intravenously once daily, three times per week, on alternate days for 12 weeks. If therapy is interrupted for more than 7 days, dose escalation should gradually be reinitiated.
ii. Dose modification. Hematologic toxicities.
iii. Supplied as 30-mg vials.
i. Mechanism. Binds to CD20, which regulates cell cycle initiation. Obinutuzumab induces complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity.
ii. Metabolism. Not appreciably metabolized. Elimination is uncertain, but it may undergo phagocytosis by the reticuloendothelial system.
i. Common. Cytokine release syndrome (fever, chills, dyspnea, bronchospasm, hypoxia, hypotension, urticaria, and angioedema), hypocalcemia, hyperkalemia, hyponatremia, hypoalbuminemia, hypokalemia, leukopenia, lymphocytopenia, neutropenia, thrombocytopenia, increased transaminases, antibody development, infection, and increased serum creatinine.
ii. Occasional. Tumor lysis syndrome, cough, fever
iii. Rare. Progressive multifocal leukoencephalopathy, reactivation of HBV.
i. FDA-approved dose. Cycle 1: 100 mg intravenously on day 1, followed by 900 mg intravenously on day 2, followed by 1,000 mg intravenously weekly for 2 doses (days 8 and 15). Cycles 2 to 6: 1,000 mg intravenously on day 1 every 28 days for 5 doses.
ii. Dose modification. No specific recommendations.
iii. Supplied as 1,000-mg vials.
i. Mechanism. Binds to extracellular (large and small) loops of CD20, which regulates cell cycle initiation. Ofatumumab induces complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity.
ii. Metabolism. Not appreciably metabolized. Elimination is uncertain, but it may undergo phagocytosis by the reticuloendothelial system.
i. Common. Cytokine release syndrome (fever, chills, dyspnea, bronchospasm, hypoxia, hypotension, urticaria, and angioedema), fatigue, rash, diarrhea, nausea, neutropenia, anemia, infection, cough, and dyspnea.
ii. Occasional. Peripheral edema, hypertension, hypotension, tachycardia, chills, insomnia, headache, back pain, and sinusitis.
iii. Rare. Abdominal pain, hemolytic anemia, hepatitis B, hypoxia, progressive multifocal leukoencephalopathy, and thrombocytopenia.
i. FDA-approved dose. Initial dose: 300 mg intravenously on week 1, followed 1 week later by 2,000 mg intravenously once weekly for 7 doses (doses 2 to 8), followed 4 weeks later by 2,000 mg intravenously once every 4 weeks for 4 doses (doses 9 to 12).
ii. Dose modification. No specific recommendations.
iii. Supplied as 100- and 1,000-mg vials.
i. Mechanism. Binds to CD20, which regulates cell cycle initiation. Rituximab induces complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity.
ii. Metabolism. Not appreciably metabolized. Elimination is uncertain, but it may undergo phagocytosis by the reticuloendothelial system.
i. Common. Cytokine release syndrome (fever, chills, dyspnea, bronchospasm, hypoxia, hypotension, urticaria, and angioedema), headache, GI upset (nausea, vomiting, and diarrhea), myelosuppression, weakness, cough, rhinitis, infusion-related reactions (hypotension, angioedema, hypoxia, and bronchospasm), infections, rash, arthralgia, myalgia, and hypersensitivity reactions (hypotension, angioedema, bronchospasm).
ii. Occasional. Edema, hypertension, dyspnea, sinusitis, and tumor lysis syndrome.
iii. Rare. Severe infusion-related reactions (pulmonary infiltrates, ARDS, myocardial infarct, ventricular fibrillation, and cardiogenic shock), optic neuritis, serum sickness, severe mucocutaneous reactions (paraneoplastic pemphigus, Stevens–Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis), and acute renal failure.
i. FDA-approved dose. Refer to individual protocols. Usual dose is 375 mg/m2 intravenously once weekly for 4 to 8 doses.
ii. Dose modification. No specific recommendations.
iii. Supplied as 100- and 500-mg vials.
i. Mechanism. MAb drug conjugate directed at HER2, which incorporates the HER2-targeted actions of trastuzumab with the microtubule inhibitor DM1 (a maytansine derivative) resulting in cell cycle arrest and apoptosis.
ii. Metabolism. DM1 undergoes hepatic metabolism via CYP 3A4/5.
i. Common. Fatigue, headache, fever, insomnia, rash, nausea, constipation, diarrhea, abdominal pain, vomiting, xerostomia, stomatitis, thrombocytopenia, anemia, increased transaminases, increased bilirubin, pain, peripheral neuropathy, arthralgia, weakness, myalgia, and cough.
ii. Occasional. Peripheral edema, hypertension, left ventricular systolic dysfunction, dizziness, chills, pruritus, dysgeusia, neutropenia, and blurred vision.
iii. Rare. Anaphylaxis, hepatic encephalopathy, hepatotoxicity, and portal hypertension.
i. FDA-approved dose. 3.6 mg/kg intravenously every 3 weeks until disease progression or toxicity.
ii. Dose modification. No recommendation for renal and/or hepatic impairment.
iii. Supplied as 100- and 160-mg vials.
i. Mechanism. MAb drug conjugate directed at CD30, made up of three components: (1) a CD30-specific IgG1 antibody; (2) a microtubule-disrupting agent, monomethylauristatin E (MMAE); and (3) a protease cleavable dipeptide linker. After binding to cells that express CD30, the complex is internalized and releases MMAE, which binds to tubules and causes cell cycle arrest and apoptosis.
ii. Metabolism. MMAE: minimal, primarily via CYP 3A4/5-mediated oxidation.
i. Common. Peripheral edema, fatigue, pain, headache, insomnia, dizziness, anxiety, rash, pruritus, alopecia, nausea, diarrhea, abdominal pain, constipation, weight loss, myelosuppression, peripheral sensory neuropathy, myalgias, arthralgias, dyspnea, oropharyngeal pain, and infusion reactions (fever, chills, rigors, and sweats).
ii. Occasional. Supraventricular arrhythmia, dry skin, limb pain, muscle spasms, pyelonephritis, pneumonitis, pulmonary embolism, and septic shock.
iii. Rare. Anaphylaxis, progressive multifocal leukoencephalopathy, tachycardia, and tumor lysis syndrome.
i. FDA-approved dose. 1.8 mg/kg intravenously (maximum dose: 180 mg) every 3 weeks for a maximum of 16 cycles. For patients weighing >100 kg, doses should be calculated using a weight of 100 kg.
ii. Dose modification. No recommendation for renal and/or hepatic impairment.
iii. Supplied as 50-mg vials.
i. Mechanism. Ibritumomab is joined through covalent bonds to tiuxetan, a chelating agent. The chelator tightly binds to the radioisotopes indium 111 (111In) or yttrium 90 (90Y). Ibritumomab binds to the CD20 antigen found on normal and malignant B cells while allowing the emission of radiation against the target and neighboring cells. The agent causes antibody-dependent and complement-mediated cytotoxicity and induces apoptosis.
ii. Metabolism. Primarily eliminated from circulation by binding to the tumor and metabolized through radioactive decay. The product of the radioactive decay of 90Y is 90Zr (nonradioactive); 111In decays to 111Cd (nonradioactive). Approximately 7% of the radiolabeled activity undergoes urinary excretion over 7 days.
i. Common. Chills, fever, GI upset (nausea, vomiting, abdominal pain), myelosuppression, weakness, infection, headache, dizziness, dyspnea, and cough.
ii. Occasional. Hypotension, diarrhea, constipation, insomnia, anxiety, arthralgia, myalgia, epistaxis, allergic reactions, pruritus, rash, peripheral edema, and secondary malignancies.
iii. Rare. Arthritis, encephalopathy, pulmonary edema, hemorrhagic stroke, angioedema, and pulmonary embolus.
i. FDA-approved dose. Step 1: inject 111In ibritumomab tiuxetan 5 mCi (1.6-mg total antibody dose) over 10 minutes after rituximab infusion of 250 mg/m2. Biodistribution is then assessed with a first image taken 2 to 24 hours after 111In ibritumomab tiuxetan, a second image 48 to 72 hours after the infusion, and an optional third image 90 to 120 hours after the infusion. If biodistribution is considered acceptable, proceed to step 2. Step 2 (initiated 7 to 9 days after step 1): rituximab infusion 250 mg/m2 followed by 90Y ibritumomab tiuxetan 0.4 mCi/kg over 10 minutes (if platelet count >150,000) or 0.3 mCi/kg (if platelet count between 100,000 and 149,000). Ibritumomab should not be administered if platelet count is less than 100,000 cells/mm3, and the maximum allowable whole-body dose should not exceed 32 mCi regardless of patient’s weight.
ii. Dose modification. No dosage modifications recommended for renal and/or hepatic impairment.
iii. Supplied as 3.2-mg vials.
i. Mechanism. Selective, reversible inhibitor of the 26S proteasome.
ii. Metabolism. Primarily hepatic through CYP 1A2, 2C19, and 3A4 with minor metabolism through CYP 2D6 and 2C9 to inactive metabolites. Elimination pathways in humans are unknown.
i. Common. Peripheral neuropathy, hypotension, thrombocytopenia, anemia, neutropenia, nausea, vomiting, diarrhea, constipation, pyrexia, psychiatric disorders, decreased appetite, asthenia, paresthesia, dysesthesia, anemia, headache, cough, dyspnea, rash, pain, insomnia, lower respiratory tract infections, arthralgia, myalgia, dizziness, herpes zoster, lower limb edema, blurred vision, and pneumonia.
ii. Occasional. Heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, and pulmonary edema).
iii. Rare. QT-interval prolongation, pneumonitis, interstitial pneumonia, lung infiltration, ARDS, cardiac tamponade, ischemic colitis, encephalopathy, disseminated intravascular coagulation, hepatitis, pancreatitis, and toxic epidermal necrolysis.
i. FDA-approved dose. 1.3 mg/m2 intravenously twice weekly for 2 weeks on days 1, 4, 8, and 11 in a 21-day cycle. Therapy extending beyond 8 cycles may be administered by the standard schedule or may be given once weekly for 4 weeks on days 1, 8, 15, and 22 followed by a 13-day rest (days 23 to 35). Doses given consecutively should be separated by at least 72 hours.
ii. Dose modification. No dosage adjustment for mild hepatic dysfunction; reduce initial dose to 0.7 mg/m2 in the first cycle for moderate hepatic dysfunction (bilirubin >1.5 to 3 times upper limit of normal). No dosage adjustment necessary for renal dysfunction. Recommend administration post-dialysis, given that dialysis may decrease bortezomib concentrations. Monitor closely for toxicity.
iii. Supplied as 3.5-mg vials.
i. Mechanism. Selective, irreversible inhibitor of the 20S proteasome.
ii. Metabolism. Primarily metabolized via peptidase and epoxide hydrolase activity. Elimination pathways in humans are unknown, but most likely extrahepatic clearance.
i. Common. Peripheral neuropathy, thrombocytopenia, anemia, neutropenia, nausea, vomiting, diarrhea, constipation, headache, backache, cough, dyspnea, rash, pain, insomnia, upper respiratory tract infections, elevated serum creatinine, fatigue, and pyrexia.
ii. Occasional. Congestive heart failure, acute renal failure, pneumonia, pulmonary hypertension, pulmonary complications, and infusion reactions.
iii. Rare. Dyspnea, cardiac arrest, myocardial ischemia, liver failure, tumor lysis syndrome, and febrile neutropenia.
i. FDA-approved dose. 20 mg/m2/day intravenously on days 1, 2, 8, 9, and 16 to be given every 28 days for cycle 1. If cycle 1 is well tolerated, may increase dose to 27 mg/m2/day on the same schedule. Utilize actual body weight and cap BSA at 2.2 m2.
ii. Dose modification. Recommendations on modifying or holding therapy based on the following toxicities, hematologic, cardiac, pulmonary, hepatic, renal, and peripheral neuropathy.
iii. Supplied as 3.5-mg vials.
i. Mechanism. Inhibition of histone deacetylase results in accumulation of acetyl groups, leading to changes in chromatin structure and transcription factor activation causing termination of cell growth and apoptosis.
ii. Metabolism. Primarily hepatic via CYP 3A4, and to a lesser degree CYP 3A5, 1A1, 2B6, and 2C19.
i. Common. ST-T wave changes, hypotension, fatigue, fever, headache, chills, pruritus, dermatitis, hypocalcemia, hyperglycemia, hypoalbuminemia, hypermagnesemia, hyperuricemia, hypokalemia, hypophosphatemia, hyponatremia, nausea, diarrhea, constipation, taste alteration, weight loss, abdominal pain, myelosuppression, AST/ALT increase, cough, and dyspnea.
ii. Occasional. Peripheral edema, tachycardia, dehydration, stomatitis, hyperbilirubinemia, hypoxia, and pulmonary embolism.
iii. Rare. Acute renal failure, atrial fibrillation, cardiopulmonary failure, cardiogenic shock, and septic shock.
i. FDA-approved dose. 14 mg/m2 intravenously on days 1, 8, and 15 of a 28-day cycle.
ii. Dose modification. No dosage adjustments necessary for renal impairment. Use has not been studied, however, in patients with end stage renal disease. For mild hepatic dysfunction, no dosage adjustments are provided. Use with caution in patients with moderate-to-severe hepatic impairment.
iii. Supplied as 10-mg vials.
i. Mechanism. Inhibition of histone deacetylase results in accumulation of acetyl groups, leading to changes in chromatin structure and transcription factor activation causing termination of cell growth and apoptosis.
ii. Metabolism. Glucuronidated and hydrolyzed (followed by beta-oxidation) to inactive metabolites. Excretion occurs via the urine (52%) as both inactive metabolites (∼52%) and unchanged drug (<1%).
i. Common. Peripheral edema, fatigue, chills, dizziness, headache, fever, alopecia, pruritus, hyperglycemia, diarrhea, nausea, taste alteration, anorexia, vomiting, decreased appetite, muscle spasm, myelosuppression, proteinuria, increased creatinine, and cough.
ii. Occasional. QTc prolongation, squamous cell carcinoma, and pulmonary embolism.
iii. Rare. Angioneurotic edema, cholecystitis, deafness, diverticulitis, exfoliative dermatitis, GI bleeding, hemoptysis, MI, neutropenia, renal failure, sepsis, and ischemic stroke.
i. FDA-approved dose. 400 mg orally once daily until disease progression or unacceptable toxicity.
ii. Dose modification. Dosing was not studied in renal dysfunction; based on the minimal renal clearance, however, the need for adjustment is not expected. For patients with mild-to-moderate hepatic dysfunction, reduce dose to 300 mg orally once daily. For patients with severe hepatic dysfunction (bilirubin >3 times upper limit of normal), doses of 100 to 200 mg orally daily have been studied in a limited number of cases.
iii. Supplied as 100-mg capsules.
Ipilimumab is a first-in-class human monoclonal antibody against CTLA-4. Ipilimumab inhibits CD80 and CD 86 on antigen-presenting cell forms binding to CTLA-4 on T cells. The blockade of CTLA-4 signaling results in prolonged T-cell activation, proliferation and amplifies immunity.
i. Mechanism. Binds to CTLA-4, which blocks the interaction of CTLA-4 with its ligands. This leads to T-cell activation and proliferation.
i. Common. Pruritus, rash, colitis, diarrhea, nausea, vomiting, injection site reaction, pyrexia, and fatigue.
ii. Occasional. Hypothyroidism, enterocolitis, hepatotoxicity.
iii. Rare. Pericarditis, dermatitis, adrenal insufficiency, disorder of endocrine system, hypogonadism, hypopituitarism, perforation of intestine, eosinophilia, hemolytic anemia, myositis, polymyositis, encephalitis, Guillain–Barré syndrome, meningitis, neuropathy, peripheral motor neuropathy, iritis, orbital myositis, uveitis, nephritis, renal failure, and pneumonitis.
i. FDA-approved dose. 3 mg/kg intravenously every 21 days for a total of 4 doses. Discontinue treatment if therapy cannot be completed in 16 weeks.
ii. Dose modification. Moderate immune-mediated reactions require holding therapy until resolution and dosing with prednisone therapy. No dose adjustments required for renal impairment. Dose adjustments are not required for mild hepatic impairment. No data for moderate or severe hepatic impairment.
iii. Supplied as 5 mg/mL solution.
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