A Phase 1 Trial of SGN-CD33A As Monotherapy in Patients with CD33-Positive Acute Myeloid Leukemia (AML)
Authors: Stein Anthony S. , Walter Roland B. , Erba Harry P , Fathi Amir T. , Advani Anjali S. , Lancet Jeffrey E , Ravandi Farhad , Kovacsovics Tibor J. , DeAngelo Daniel J. , Bixby Dale , Faderl Stefan , Jillella Anand P , O'Meara Megan M. , Zhao Baiteng , Stein Eytan M 
Published: October 2019

Abstract
Background
CD33is expressed in approximately 90% of AML, representing a promising target despite age, prior therapies, or mutational heterogeneity. SGN-CD33A (or 33A) is a CD33-directed antibody conjugated to 2 molecules of a pyrrolobenzodiazepine (PBD) dimer. Upon binding, 33A is internalized and transported to the lysosomes where PBD dimer is released via proteolytic cleavage of the linker, crosslinking DNA, and leading to cell death.
Methods
The dose-escalation portion of this phase 1 study (NCT01902329) is designed to evaluate the safety, tolerability, pharmacokinetics (PK), and antileukemic activity of 33A as monotherapy. Eligible patients (ECOG 0-1) must have CD33-positive AML, and have either relapsed disease following initial remission (CR) of >3 months, or have declined conventional induction/consolidation. 33A monotherapy is administered outpatient via IV every 3 weeks for up to 2 cycles, followed by optional low-dose maintenance treatment for patients who achieve a CR/CRi. Investigator assessment of response is per IWG criteria; CRi requires either platelet count of ≥100,000/µL or neutrophils of ≥1,000/µL (Cheson 2003).
Results
To date, 87 patients (62% male) with a median age of 74 years (range, 27-89) have been treated. 34 patients had relapsed AML after 1st CR with intensive therapy; 52 had declined conventional intensive therapy (40 of these patients had received 1-2 prior low intensity therapies, primarily hypomethylating agents). Most patients had intermediate I-II (51%) or adverse (31%) risk by ELN classification and 54% of patients had AML with underlying myelodysplasia-related changes. 9% of patients displayed NPM1 mutations without FLT3 mutation (NPM1+/FLT3-). Dose levels ranged from 5-60 mcg/kg (n=75) and also included fractionated dosing of 20 mcg/kg on Day 1 and Day 4 (n=12). Five patients remain on treatment. Six dose-limiting toxicities were reported in the monotherapy escalation cohorts: 2 Grade 4 bone marrow failures (40 and 60 mcg/kg), 2 mucositis (Grade 3 at 50 mcg/kg; Grade 3 at fractionated 20+20 mcg/kg), Grade 3 pulmonary embolism (20 mcg/kg), and Grade 5 sepsis (50 mcg/kg). The most common Grade 3 or higher adverse events (AE) reported were febrile neutropenia (69%), thrombocytopenia (29%), and anemia (23%). Increased myelosuppression was observed at doses higher than 40 mcg/kg and the fractionated dosing cohort, including febrile neutropenia observed in 68% of patients and sepsis observed in 26% of patients. Other common treatment-emergent AEs regardless of relationship to study treatment were fatigue (48%), decreased appetite (28%), constipation, diarrhea, dyspnea, nausea (26% each), and peripheral edema (25%). The 30-day mortality was 6%. Across all dose levels, the CR+CRi rate was 86% in the patients with NPM1+/FLT3- disease (n=7). Of the 21 efficacy evaluable patients treated at 40 mcg/kg, 3 patients achieved a best clinical response of CR, 4 achieved CRi, and 5 had morphologic leukemia-free state (mLFS). Three of 5 treatment-naïve patients within the 40 mcg/kg dose level achieved a CR or CRi. In patients across dose levels who achieved at least mLFS, the mean time to full count recovery was 5 weeks for neutrophils (≥1,000/µL) and 6 weeks for platelets (≥100,000/µL). Median OS in patients treated at 40 mcg/kg is 10 months with 17 patients alive at the time of this data cut. Across all dose levels, 8 patients went on to receive an allogeneic SCT. PK data demonstrated generally dose-dependent increase in plasma ADC exposures and target-mediated rapid clearance.
Conclusions
Dose escalation is complete and a recommended monotherapy 33A dose of 40 mcg/kg was identified. AEs observed were generally manageable, often associated with underlying myelosuppression. 33A has demonstrated favorable antileukemic activity with 33% achieving a CR+CRi at the 40 mcg/kg dose level (60% CR+CRi in treatment naïve patients). The rapid clearance of marrow blasts in patients with poor risk factors and low 30-day mortality (6%) are encouraging. Enrollment is ongoing in multiple expansion cohorts, including previously untreated AML patients who declined intensive therapy, relapsed NPM1 mutant disease, and relapsed APL. In addition, a study evaluating 33A with intensive therapy in newly diagnosed patients with AML is ongoing.

Disclosures
Stein: Amgen: Speakers Bureau. Off Label Use: SGN-CD33A is an investigational agent being studied in patients with CD33-positive AML. SGN-CD33A is not approved for use. Walter:Pfizer, Inc.: Consultancy; Covagen AG: Consultancy; AstraZeneca, Inc.: Consultancy; CSL Behring: Research Funding; AbbVie, Inc.: Research Funding; Amgen: Research Funding; Amphivena Therapeutics, Inc.: Consultancy, Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding. Erba:GlycoMimetics; Janssen: Other: Data Safety & Monitoring Committees; Sunesis; Pfizer; Daiichi Sankyo; Ariad: Consultancy; Millennium/Takeda; Celator; Astellas: Research Funding; Seattle Genetics; Amgen: Consultancy, Research Funding; Novartis; Incyte; Celgene: Consultancy, Patents & Royalties. Fathi:Agios Pharmaceuticals: Other: Advisory Board participation; Seattle Genetics: Other: Advisory Board participation, Research Funding; Merck: Other: Advisory Board participation. Lancet:Seattle Genetics: Consultancy; Pfizer: Research Funding; Boehringer-Ingelheim: Consultancy; Kalo-Bios: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Research Funding. Kovacsovics:Seattle Genetics, Inc.: Research Funding. DeAngelo:Pfizer: Consultancy; Amgen: Consultancy; Ariad: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Consultancy; Incyte: Consultancy; Agios: Consultancy; Celgene: Consultancy. Bixby:Seattle Genetics, Inc.: Research Funding. Faderl:Onyx: Speakers Bureau; BMS: Research Funding; Seattle Genetics, Inc.: Research Funding; JW Pharma: Consultancy; Karyopharm: Consultancy, Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau; Pfizer: Research Funding; Astellas: Research Funding; Celator: Research Funding; Ambit: Research Funding. Jillella:Seattle Genetics, Inc.: Research Funding. O'Meara:Seattle Genetics, Inc: Employment, Equity Ownership. Zhao:Seattle Genetics, Inc.: Employment, Equity Ownership. Stein:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees.