Adct-602, a CD22 Targeting Antibody Drug Conjugate Bound to PBD Toxin in Adult Patients with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia: A Phase 1 Trial

Introduction: Outcomes of patients (pts) with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) remain dismal. CD22 is expressed on lymphoblasts in >90% of pts with B-ALL and is an established therapeutic target. Inotuzumab ozogamicin is an approved CD22 targeting antibody for pts with R/R B-ALL; however, the toxin calicheamicin can lead to veno-occlusive disease (VOD) of the liver, especially after allogeneic SCT (allo-SCT).

ADCT-602 is an antibody drug conjugate composed of a humanized monoclonal antibody directed against CD22 and conjugated to SG3199, a pyrrolobenzodiazepine (PBD) dimer cytotoxin. In preclinical studies, ADCT-602 demonstrated potent anti-tumor activity in mouse models of B-cell malignancies. We present here results from an ongoing phase 1/2 trial evaluating ADCT-602 in pts with R/R B-ALL (NCT03698552).

Methods: This is an investigator-initiated phase 1/2 trial of ADCT-602 monotherapy in pts with R/R B-ALL. The primary objective of the phase 1 part is to assess the safety and determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ADCT-602. The primary objective of phase 2 is to evaluate efficacy (CR/CRi rate). Eligible pts must be ≥18 years of age with R/R B-ALL with bone marrow blasts ≥5%. CD22 must be expressed in ≥20% blasts. Pts must have adequate organ function (creatinine ≤1.5 mg/dL; ALT and AST ≤2 times upper limit of normal (ULN), ≤5 times ULN if there is liver or bone involvement; total bilirubin ≤1.5 times ULN; LVEF ≥45%). A 3+3 dose-escalation design was used for phase 1. ADCT-602 was initially given IV once every 3 weeks; based on the PK data, the administration schedule was later amended to weekly infusions.

Results: From November 2018 to July 2022, 21 pts (11 women, 10 men) with R/R B-ALL were enrolled and received treatment with ADCT-602. The median age was 39 years (range, 21-82) and pts had received a median of 5 (range, 2-9) prior therapies [inotuzumab ozogamicin 12/21 (57%); blinatumomab 18/21 (86%); venetoclax 12/21 (57%)]. A total of 8/21 (38%) had a prior CD19 CAR-T, including 1 pt who had both CD19 and CD22 CAR-T. Ten (10/21, 48%) pts had a prior allo-SCT, including 3 pts with 2 prior allo-SCT. The median pretreatment bone marrow blasts were 70% (range, 16-96). The median CD22 expression on blasts was 97% (range, 33.6-100).

A total of 11 pts were treated in the Q3week schedule [30µg/kg, n=3; 60µg/kg, n=4; 90µg/kg, n=4]. As the PK data indicated rapid clearance of the antibody, the trial was amended to allow for weekly dosing. A total of 10 pts were treated at the weekly dose level [30µg/kg, n=3; 40µg/kg, n=4; 50µg/kg, n=3]. One pt (30µg/kg weekly dose level) had grade 4 thrombocytopenia possibly related to ADCT-602. One pt (50µg/kg weekly dose level) had a DLT of prolonged myelosuppression (marrow blast clearance without blood count recovery). No pt had VOD.

Notably, all 3 pts treated at the 50µg/kg weekly dose level (a dose level expected to be close to RP2D) had evidence of anti-tumor activity (2 pts achieved MRD negative CR; one pt had bone marrow blast clearance). First pt at this dose level was a 26-yr-old with R/R B-ALL with PAX5-JAK2 fusion with 5 prior therapies including 2 CD19 CAR-T and an allo-SCT who achieved MRD negative CR and is receiving ongoing therapy in Cycle 5. Second pt at this dose level was a 66-yr-old with TP53- and KRAS-mutated B-ALL with 2 prior therapies including modified BFM regimen and blinatumomab who achieved MRD negative CR and is receiving ongoing therapy in Cycle 4. Third pt at this dose level was a 21-yr-old with TP53- and KRAS-mutated B-ALL with 4 prior therapies including inotuzumab and a CD19 CAR-T who had morphologic blast clearance without blood count recovery.

Two additional pts treated at lower doses levels (1 each at 30µg/kg Q3week and 30µg/kg weekly schedule) achieved MRD negative CR. All responding pts had CD22 expression noted in >97% of the blasts by flow cytometry.

Conclusions: In this phase 1 study in pts with very heavily pretreated R/R B-ALL with a median of 5 prior lines of therapy and high baseline bone marrow tumor burden, single-agent ADCT-602 was well tolerated with one pt with DLT noted at the 50µg/kg weekly dose level. Notably, all 3 pts treated at this dose level had evidence of clinical activity with 2/3 pts achieving MRD negative CR. Due to 1 pt with DLT at this dose level, this cohort is being expanded to treat 3 additional pts. This trial continues to accrue pts and updated data will be presented at the ASH meeting.

Jain:Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel Support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel Support, Research Funding; Beigene: Honoraria; TransThera Sciences: Research Funding; Newave: Research Funding; Dialectic Therapeutics: Research Funding; Novalgen: Research Funding; Loxo Oncology: Research Funding; Medisix: Research Funding; Takeda: Research Funding; Mingsight: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Fate Therapeutics: Research Funding; Aprea Therapeutics: Research Funding; Pfizer: Research Funding; Incyte Corporation: Research Funding; Cellectis: Honoraria, Research Funding; BMS: Consultancy, Honoraria, Other: Travel Support, Research Funding; ADC Therapeutics: Research Funding; Servier Pharmaceuticals LLC: Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel Support, Research Funding; Pharmacyclics, Inc.: Consultancy, Honoraria, Other: Travel Support, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support; Genentech, Inc.: Consultancy, Honoraria, Other: Travel Support, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel Support, Research Funding; Cellectis: Honoraria, Research Funding; TG Therapeutics: Honoraria; MEI Pharma: Honoraria; Ipsen: Honoraria; CareDx: Honoraria. Jabbour:Genentech: Other: Advisory Role, Research Funding; AbbVie: Other: Advisory Role, Research Funding; Bristol Myers Squibb: Other: Advisory Role, Research Funding; Adaptive Biotechnologies: Other: Advisory Role, Research Funding; Amgen: Other: Advisory Role, Research Funding; Takeda: Other: Advisory Role, Research Funding; Spectrum: Research Funding; Pfizer: Other: Advisory Role, Research Funding. Aldoss:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Autolus Limited: Consultancy; Amgen: Consultancy; Agios: Consultancy, Honoraria; AbbVie: Consultancy, Research Funding; Kite: Consultancy. Konopleva:Reata Pharmaceuticals, Novartis and Eli Lilly: Patents & Royalties; Forty-Seven; F. Hoffman LaRoche: Honoraria; AbbVie, Genentech, F. Hoffman La-Roche, Eli Lilly, Cellectis, Calithera, Ablynx, Stemline Therapeutics, Agios, Ascentage, Astra Zeneca; Rafael Pharmaceutical; Sanofi, Forty-Seven: Research Funding; Stocks, Reata Pharmaceuticals: Current equity holder in publicly-traded company; AbbVie, Genentech, F. Hoffman La-Roche, Stemline Therapeutics, Amgen, Forty-Seven, Kisoji; Janssen: Consultancy; Stemline Therapeutics, F. Hoffman La-Roche; Janssen: Membership on an entity's Board of Directors or advisory committees. Short:AstraZeneca: Consultancy; Stemline Therapeutics: Research Funding; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria; Novartis: Consultancy; Astellas: Research Funding; Pfizer: Consultancy. Stein:Amgen: Honoraria. Pemmaraju:stemline: Consultancy; abbvie: Consultancy; immunogen: Consultancy; mustangbio: Research Funding; incyte: Consultancy; novartis: Research Funding; pacylex: Consultancy, Research Funding; samus: Research Funding; daiichi sankyo: Research Funding; cellectis: Research Funding; cellularity: Research Funding. Thompson:AbbVie, Gilead, Janssen, Pharmacyclics, Adaptive Biotechnologies, Genentech: Consultancy; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; AbbVie, Gilead, Janssen, Pharmacyclics, Adaptive Biotechnologies, Genentech, Amgen: Honoraria; AbbVie, Pharmacyclics, Adaptive Biotechnologies, Genentech: Research Funding. Ravandi:Amgen: Honoraria, Research Funding; Astex/Taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Syos: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Abbvie: Consultancy, Honoraria, Research Funding; Prelude: Research Funding; Xencor: Research Funding; AstraZeneca: Consultancy; Astellas: Consultancy, Honoraria, Research Funding; Biomea Fusion, Inc.: Research Funding. Kantarjian:Astellas Health: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Research Funding; ImmunoGen: Research Funding; Ipsen Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Research Funding; KAHR Medical Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; NOVA Research: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Honoraria.

ADCT-602 is not FDA approved