ADC Review

The information on this page is limited to commercially available antibody-drug conjugates (ADCs) approved by the U.S. Food and Drug Administration (FDA) and intended for healthcare professionals (HCP) only. If you are not a U.S. healthcare professional, do not continue on this page.

Drug	Year Approved	Brand name	Company
Gemtuzumab ozogamicin	2000; withdrawn 2010; Reapproval 2017	Mylotarg® Prescribing information	Pfizer (Wyeth)
NDC:	0008-4510-01
J-Code:	J9203	Injection, gemtuzumab ozogamicin (Mylotarg®), 0.1 mg
Black Box Warning	Hepatotoxicity, including severe or fatal hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), has been reported in association with the use of Gemtuzumab ozogamicin as a single agent, and as part of a combination chemotherapy regimen. Monitor frequently for signs and symptoms of VOD after treatment with Gemtuzumab ozogamicin. Check the Highlights of Prescribing information for additional information
Indication:	Gemtuzumab ozogamicin is a CD33-directed antibody-drug conjugate indicated for: Treatment of newly-diagnosed CD33-positive acute myeloid leukemia (AML) in adults Treatment of relapsed or refractory CD33-positive AML in adults and in pediatric patients 2 years and older
Dosage Forms & Strength:	For Injection: 4.5 mg as a lyophilized cake or powder in a single-dose vial for reconstitution and dilution
Dosage + Administration:	Newly-diagnosed, de novo AML (combination regimen): Induction: 3 mg/m2 (up to one 4.5 mg vial) on Days 1, 4, and 7 in combination with daunorubicin and cytarabine Consolidation: 3 mg/m2 on Day 1 (up to one 4.5 mg vial) in combination with daunorubicin and cytarabine. Newly-diagnosed AML (single-agent regimen): Induction: 6 mg/m2 on Day 1 and 3 mg/m2 on Day 8 Continuation: For patients without evidence of disease progression following induction, up to 8 continuation courses of Gemtuzumab ozogamicin 2 mg/m2 on Day 1 every 4 weeks Relapsed or refractory AML(single-agent regimen): 3 mg/m2 on Days 1, 4, and 7. Premedicate with a corticosteroid, antihistamine, and acetaminophen 1 hour before Gemtuzumab ozogamicin
Dosage Modifications for Toxicities	Monitor blood counts frequently to resolve cytopenias. Monitor blood counts and chemistries at least three times per week through recovery from treatment-related toxicities. Management of some adverse reactions may require dose interruptions or permanent discontinuation of Gemtuzumab ozogamicin Check the prescribing information for specific dose modification guidelines for hematologic and nonhematologic toxicities.
Contraindications:	Hypersensitivity to Gemtuzumab ozogamicin or any of its components. Gemtuzumab ozogamicin is contraindicated in patients with a history of hypersensitivity to the active substance in Gemtuzumab ozogamicin or any of its components or to any of the excipients. Reactions have included anaphylaxis.
Warning & Precautions:	Infusion-related reactions (including anaphylaxis): Premedicate with a corticosteroid, acetaminophen, and diphenhydramine. Monitor patients during the infusion and for at least 1 hour after the infusion ends. Interrupt the infusion, administer steroids or antihistamines, or permanently discontinue treatment as necessary. Hemorrhage: Severe, including fatal, hemorrhage may occur when Gemtuzumab ozogamicin is used at recommended doses. Monitor platelet counts frequently. Embryo-fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and the use of effective contraception.
Adverse Reactions:	The most common adverse reactions (>15%) were hemorrhage, infection, fever, nausea, vomiting, constipation, headache, increased AST, increased ALT, rash, and mucositis. These adverse reactions were most commonly seen when Gemtuzumab ozogamicin was given in combination with daunorubicin and cytarabine (which may affect more than 3 in 10 people), including bleeding and severe infections. These adverse reactions can be serious in more than 1 in 10 people. Other serious side effects with the combination therapy are liver disease, including veno-occlusive disease (a liver injury), and tumour lysis syndrome (a complication due to the breakdown of cancer cells). For the full list of side effects and restrictions with Gemtuzumab ozogamicin, check the Highlights of Prescribing Information.
Description	Gemtuzumab ozogamicin is an antibody-drug conjugate (ADC) composed of the CD33-directed monoclonal antibody (hP67.6; recombinant humanized immunoglobulin [Ig] G4, kappa antibody produced by mammalian cell culture in NS0 cells) that is covalently linked to the cytotoxic agent N-acetyl gamma calicheamicin. Gemtuzumab ozogamicin consists of conjugated and unconjugated gemtuzumab. The conjugated molecules differ in the number of activated calicheamicin derivative moieties attached to gemtuzumab. The number of conjugated calicheamicin derivatives per gemtuzumab molecule ranges from predominantly zero to 6, with an average of 2 to 3 moles of calicheamicin derivative per mole of gemtuzumab.
Mechanism of Action:	Gemtuzumab ozogamicin is a CD33-directed antibody-drug conjugate (ADC). The antibody portion (hP67.6) recognizes the human CD33 antigen. The small molecule N-acetyl gamma calicheamicin is a cytotoxic agent covalently attached to the antibody via a linker. Nonclinical data suggest that the anticancer activity of gemtuzumab ozogamicin is due to the binding of the ADC to CD33-expressing tumor cells, followed by internalization of the ADC-CD33 complex, and the intracellular release of N-acetyl gamma calicheamicin dimethyl hydrazide via hydrolytic cleavage of the linker. Activation of N-acetyl gamma calicheamicin dimethyl hydrazide induces double-strand DNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death.
Mechanism of Action: Patient Summary	The active substance of Gemtuzumab ozogamicin consists of two parts: a cytotoxic (cell-killing) substance and a monoclonal antibody (a type of protein). The monoclonal antibody component (gemtuzumab) has been designed to bind CD33. When the antibody attaches to CD33 on leukaemia cells, the cancer cells absorb the antibody, as well as the cytotoxic substance to which it is attached. Inside the cancer cells, the cytotoxic substance calicheamicin is released. Calicheamicin then breaks the cells’ DNA, eventually killing them.
Saftey	OSHA Hazardous Drugs
Additional Background Information	SWOG S0106 (NCT00085709) In May 2000, the United States Food and Drug Administration (FDA) granted accelerated approval of gemtuzumab ozogamicin. This approval was based on three phase 2 pilot studies in 142 adult individuals diagnosed with AML. This study aimed to examine the CR rate with the addition of gemtuzumab ozogamicin with standard induction chemotherapy compared to standard chemotherapy alone. Disease-free survival post-consolidation of the two comparator groups was also evaluated. The purpose of this randomized phase 3 trial was to compare two different regimens of chemotherapy and monoclonal antibody therapy to see how well they work in treating patients with previously untreated de novo acute myeloid leukemia. Individuals were randomized (stratified by age <35 vs ≥35) to receive induction therapy with daunorubicin (45 mg/m2 days 1-3), cytarabine (100mg/m2 on days 1-7) and gemtuzumab ozogamicin (6 mg/m2 on day 4) versus standard induction therapy with daunorubicin (60 mg/m2 days 1-3) and cytarabine (100mg/m2/ days 1- 7). The results showed that 150 of 277 (66%) individuals treated in the gemtuzumab ozogamicin cohort achieved CR. This compared with 159/229 (69%) of individuals who achieved CR with chemotherapy alone (p < 0.0025). Disease-free survival was not improved, and fatal toxicity for individuals in the gemtuzumab ozogamicin cohort vs. standard chemotherapy was 16/283 (16%) vs. 4/281 (1.4%), respectively. In 2010, Pfizer (Wyeth) voluntarily withdrew the drug from the U.S. market after confirmatory trials failed to confirm benefit and demonstrated safety concerns, including early mortality and VOD. In 2017, Gemtuzumab ozogamicin was re-approved by the FDA. This approval includes a lower recommended dose and schedule of gemtuzumab ozogamicin than those previously approved by the FDA in 2000, as well as a different patient population. This re-approval was based on three studies: ALFA-0701 (NCT00927498) was a randomized, open-label phase 3 trial involving 271 individuals newly diagnosed with de novo AML aged 50 to 70 years. Individuals were randomized (1:1) in receiving standard chemotherapy with gemtuzumab ozogamicin, and those with just standard chemotherapy. Efficacy was assessed by EFS (event-free survival), measured from the date of randomization until induction failure, relapse, or death from any cause. Individuals received induction therapy consisting of daunorubicin 60mg/m2 on Days 1-3, cytarabine 200mg/m2 on Days 1-7, and gemtuzumab ozogamicin at 3mg/m2 on Days 1, 4, and 7 (with or without as a comparator). Results showed that the estimated median EFS was 17.3 months for individuals receiving the therapy combination, compared with 9.5 months with standard chemotherapy alone. The hazard ratio was 0.66 (95% CI: 0.42-0.76). AML-19 (NCT00091234; other study ID EORTC-0603). This study was a randomized, open-label, phase 3 trial with 237 participants that compared gemtuzumab ozogamicin monotherapy with best supportive care. Individual criteria included older individuals who were ≥ 75 years of age or between 61 and 75 years with a World Health Organization performance status (WHO-PS) greater than 2, or who were unwilling to receive intensive chemotherapy. Individuals in the gemtuzumab ozogamicin arm got induction therapy of 6mg/m2, then 3mg/m2 on at 2mg/m2 on Day 1 every 4 weeks for a total of 8 courses. Efficacy was established on improvement in overall survival (OS). Hazard ratio for OS was 0.69 (95%CI: 0.53-0.90). The median OS was 4.9 months (gemtuzumab ozogamicin cohort) vs. 3.6 months (best supportive care). MyloFrance-1: This was a phase 2, single-arm, open-label study of 57 individuals with CD33-positive r/r AML. Individuals received a single dose of gemtuzumab ozogamicin 3mg/m2 on days 1, 4, and 7 of therapy. Consolidation therapy consisted of cytarabine q12h for 3 days. Efficacy was established based on CR and remission duration. Fifteen (26%; 95% CI: 16% - 40%) patients achieved complete response (CR) following a single course of gemtuzumab ozogamicin. Median relapse-free survival, measured from the first documentation of CR to the date of relapse or death, was 11.6 months.

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