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216 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

Program: Oral and Poster Abstracts
Type: Oral
Session: 614. Acute Lymphoblastic Leukemias: Therapies, Excluding Transplantation and Cellular Immunotherapies: Clinical Trials
Hematology Disease Topics & Pathways:
Research, clinical trials, Lymphoid Leukemias, ALL, Biological therapies, Antibody Therapy, adult, Clinical Research, Diseases, Therapies, Lymphoid Malignancies, Study Population, Human
Saturday, December 10, 2022: 3:15 PM

Nitin Jain, MD1, Elias Jabbour, MD1, Ibrahim Aldoss, MD2, Marina Konopleva, MD, PhD1, Nicholas Short, MD3, Anthony S. Stein, MD2*, Naveen Pemmaraju, MD1, Philip A. Thompson, MBBS1, Farhad Ravandi, MD1 and Hagop Kantarjian, MD4

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA
3Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX
4Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX

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.

Disclosures: 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: MacroGenics: Research Funding; Sobi: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Autolus: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. 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: Plexxikon: Research Funding; LFB Biotechnologies: Honoraria; Roche Diagnostics: Honoraria; SagerStrong Foundation: Research Funding; Affymetrix: Research Funding; Cellectis: Research Funding; Daiichi Sankyo: Research Funding; Samus Therapeutics: Research Funding; Pacylex Pharmaceuticals: Consultancy; Novartis: Honoraria, Research Funding; Incyte: Research Funding; MustangBio: Honoraria; AbbVie: Honoraria, Research Funding; Stemline Therapeutics: Honoraria, 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: Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; NOVA Research: Honoraria; KAHR Medical Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Research Funding; Ipsen Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; ImmunoGen: Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Astellas Health: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Honoraria.

OffLabel Disclosure: ADCT-602 is not FDA approved

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