1490 Vol. 7, 1490–1496, June 2001 Clinical Cancer Research Report from the FDA Approval Summary: Gemtuzumab Ozogamicin in Relapsed Acute Myeloid Leukemia Peter F. Bross,1 Julie Beitz, Gang Chen, subgroup of patients over 60 years of age, the overall re- Xiao Hong Chen, Eric Duffy, Lydia Kieffer, sponse rate was 26%. Response duration was difficult to Sandip Roy, Rajeshwari Sridhara, establish because of the high prevalence of postremission therapies. Tolerability and ease of administration may be Atiqur Rahman, Grant Williams, and improved compared with conventional chemotherapy, ex- Richard Pazdur cept for hepatotoxicity, with 31% of patients exhibiting Division of Oncology Drug Products, Center for Drug Evaluation and abnormal liver enzymes. One patient died of liver failure in Research, Food and Drug Administration, Rockville, Maryland 20852 the Phase 2 trials. Conclusions: Marketing approval of gemtuzumab ozo- gamicin was granted on May 17, 2000 by the United States Abstract Food and Drug Administration under the Accelerated Ap- Purpose: Gemtuzumab ozogamicin (Mylotarg; Wyeth proval regulations. Gemtuzumab ozogamicin is indicated Laboratories, Philadelphia, PA) consists of a semisynthetic for the treatment of patients with CD33 positive AML in derivative of calicheamicin, a cytotoxic antibiotic linked to a first relapse who are 60 years of age or older and who are recombinant monoclonal antibody directed against the not considered candidates for cytotoxic chemotherapy. The CD33 antigen present on leukemic myeloblasts in most pa- 2 approved dose was 9 mg/m i.v. over 4 h and repeated in 14 tients with acute myeloid leukemia (AML). In this study, we days. Completion of the ongoing studies of gemtuzumab review the preclinical and clinical profiles of this immuno- ozogamicin in relapsed AML and initiation of randomized conjugate and the regulatory review that led to marketing clinical trials comparing the effects of gemtuzumab ozo- approval by the United States Food and Drug Administra- gamicin in combination with conventional induction chemo- tion. therapy to conventional chemotherapy alone on survival are Experimental Design: From the literature and manufac- mandated to confirm clinical benefit under the accelerated turer’s data, we review the activity, tolerability, and phar- approval Subpart H regulations. Postmarketing reports of macokinetics of gemtuzumab ozogamicin in preclinical and fatal anaphylaxis, adult respiratory distress syndrome Phase I studies and its activity, efficacy, and side effects in (ARDS), and hepatotoxicity, especially venoocclusive disease three Phase 2 trials of 142 patients with relapsed AML. (VOD) in patients treated with gemtuzumab ozogamicin, Results: In Phase I studies, the major toxicity was my- with and without associated hematopoietic stem cell trans- elosuppression, especially neutropenia and thrombocytope- plantation (HSCT), have required labeling revisions and the nia, resulting from the expression of CD33 on myeloid pro- initiation of a registration surveillance program. Tumor genitor cells. The Phase 2 dose was 9 mg/m2 infused i.v. over lysis and ARDS have been reported in patients with leuko- 4 h, repeated on day 14. A minority of patients experienced cytes above 30,000/ml treated with gemtuzumab ozogami- acute infusion-related symptoms, usually transient and oc- cin; therefore, the reduction of leukocyte counts to below casionally requiring hospitalization. The complete response 30,000/ml is recommended prior to treatment. Patients (CR) rate with full recovery of hematopoiesis was 16%. A should be carefully monitored for acute hypersensitivity, subset of patients [CRs with incomplete platelet recovery hypoxia, and delayed hepatotoxicity following treatment (CRps)] was identified with blast clearance and neutrophil with gemtuzumab ozogamicin. recovery but incomplete platelet recovery. The duration of responses of CRps appeared to be similar to those of the CRs, although the numbers were small. The question of the Introduction 2 equivalence of these response groups was a central issue in AML is a disease characterized by the proliferation of the review of this new drug application (NDA). After con- clonal precursor myeloid cells with arrested differentiation. siderable discussion, the Oncology Drugs Advisory Commit- AML affects approximately 9000 people/year in the United tee recommended allowing inclusion of CRps resulting in an States with a peak incidence in people 60–70 years of age. overall response rate in the Phase 2 studies of 30%. In the Conventional treatment with a combination of cytotoxic chemo- therapeutic agents results in remission rates of up to 85%; however, many of these patients eventually relapse (1). Treat- ment of relapsed AML patients is considerably less successful, Received 11/23/00; revised 3/1/01; accepted 3/2/01. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to 2 The abbreviations used are: AML, acute myeloid leukemia; CR, com- indicate this fact. plete response; CRp, CR with incomplete platelet recovery; OR, overall 1 To whom requests for reprints should be addressed, at Food and Drug responder; AUC, area under the curve; RFS, relapse-free survival; Administration, HFD 150, 1451 Rockville Pike, Rockville, MD 20852. HSCT, hematopoietic stem cell transplantation; VOD, venoocclusive E-mail: [email protected]. disease; NCI, National Cancer Institute. Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2001 American Association for Cancer Research. Clinical Cancer Research 1491 Preclinical Evaluation. Gemtuzumab ozogamicin showed in vitro activity against the CD33-positive (CD33ϩ) HL-60 human promyelocytic leukemia cell line and demonstrated se- lectivity for CD33ϩ target cells relative to cells not expressing the CD33 antigen, thus causing significant reduction in growth in the HL-60 xenograft tumor model. When administered weekly for six doses, gemtuzumab ozogamicin was not lethal to rats up to 7.2 mg/m2 and in monkeys up to 22 mg/m2. Marked changes in the histopathology of the testes, liver, and kidney were noted at these doses, as well as significant myelotoxicity. Free calicheamicin, as well as conjugated calicheamicin, was noted to cause liver toxicity in preclinical testing, and gemtu- zumab ozogamicin was found to be preferentially distributed to the liver. Pharmacokinetic studies were conducted in rats and mon- keys after administration of single and repeated i.v. doses of Fig. 1 Structure of gemtuzumab ozogamicin. HP67.6 represents the humanized monoclonal antibody directed against CD33. Calicheamicin gemtuzumab ozogamicin. The major excretion pathways ap- is linked to the antibody in variable molar ratios; approximately 50% of peared to be biliary, and plasma concentrations of the unconju- the antibody is unconjugated. gated calicheamicin derivatives were generally below the assay limits. Reproductive toxicology suggests the potential for ad- verse human effects on fertility, dysmorphogenesis, and fetal growth. Gemtuzumab ozogamicin was clastogenic in an in vivo especially in the elderly. Remission rates are generally reported mouse micronucleus assay, as expected from the induction of to be 20–40% in patients over 65 years of age, compared with DNA damage by calicheamicin. 40–50% in younger patients (2). Treatment of AML in the Phase I Trials. A single Phase I trial evaluated the dose elderly has been particularly problematic, because the toxicity of range, safety, and pharmacokinetics of gemtuzumab ozogamicin standard induction chemotherapy is poorly tolerated in the older in men and women 16 to 70 years of age with CD33 positive age group (3). AML who had failed to achieve remission or had a relapse after AML myeloblasts are immunophenotypically well charac- remission. A dosing interval of 2 weeks was selected because of terized and accessible to circulating antibodies (4). CD33 is a Mr the relatively long half-life of the drug (over 3 days; see “Phar- 67,000 transmembrane cell surface glycoprotein receptor that is macokinetics” section). Initially, three biweekly doses were specific for myeloid cells. CD33 expression is down-regulated studied, but this led to profound and persistent myelosuppres- with maturation of the myeloid lineage, resulting in low-level sion. Subsequently, two doses were used in the Phase 2 trials, expression on peripheral granulocytes and tissue macrophages and the dose was not adjusted for high blast counts. The dose- (5). The CD33 antigen is expressed on approximately 90% of limiting toxicity was neutropenia, and persistent thrombocyto- AML myeloblasts, including leukemic clonogenic precursors as penia occurred in half of the patients. The most common acute well as normal myeloid precursor cells, but not on CD34ϩ infusion-related clinical adverse event was a postinfusion symp- pluripotent hematopoietic stem cells (6). In vitro studies have tom complex consisting of fever and chills. This symptom documented internalization of CD33 antibodies by the target complex generally occurred within 6 h after infusion and tended cell (7). These properties enable the use of antibodies directed to be less frequent and severe with subsequent doses. The most against CD33 in the treatment of myeloid leukemia (8). common delayed infusion-related events overall in dose periods Several approaches using antibodies to CD33 in the treat- were fever (44% of patients),