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1237 A Phase 1 Trial of Adct-602, a CD22 Targeting Antibody Drug Conjugate Bound to PBD Toxin in Adult Patients with Relapsed or Refractory CD22+ B-Cell Acute Lymphoblastic Leukemia

Program: Oral and Poster Abstracts
Session: 614. Acute Lymphoblastic Leukemias: Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster I
Hematology Disease Topics & Pathways:
Clinical Trials, Lymphoid Leukemias, ALL, Biological therapies, Antibody Therapy, Adults, Workforce, Diversity, Equity, Inclusion, and Accessibility (DEI/DEIA) , Diseases, Therapies, Lymphoid Malignancies, Study Population
Saturday, December 11, 2021, 5:30 PM-7:30 PM

Nitin Jain, MD1, Elias Joseph Jabbour, MD2, Marina Konopleva, MD, PhD1, Naveen Pemmaraju, MD1, Philip A. Thompson1, Nicholas Short, MD3, Tapan M. Kadia, MD4, Gautam Borthakur, MD5, Naval Daver, MD6, Courtney D. DiNardo, MD, MSCE1, Ibrahim Aldoss, MD7, Robin Cook, RN1*, Farhad Ravandi, MB Bs3 and Hagop Kantarjian, MD1

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Leukemia, University of Texas M.D. Anderson Cancer Ctr., Houston, TX
3Department of Leukemia, The University of Texas MD Anderson Cancer Center, HOUSTON, TX
4Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX
5MD Anderson Cancer Center, The University of Texas, Houston, TX
6MD Anderson Cancer Center, Houston, TX
7Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA

Introduction: Outcomes of patients (pts) with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) remain dismal, with 5-year survival <20%. CD22 is expressed on lymphoblasts in >90% of pts with B-ALL and is an established therapeutic target. 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 interim data 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). Secondary objectives include duration of response (DOR), progression-free survival (PFS) and overall survival (OS), and characterize the pharmacokinetic (PK) profile of ADCT-602. 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%). In part 1, pts were assigned to treatment according to a 3+3 dose-escalation design. ADCT-602 was initially given IV once every 3 weeks; recently, based on the PK data, the administration schedule was amended to weekly infusions.

Results: From November 2018 to June 2021, 14 pts (8 male, 6 female) with B-ALL have been treated with ADCT-602. The median age was 39.5 years (range, 22-82) and pts had received a median of 5 (range, 2-7) prior therapies [inotuzumab ozogamicin 10/14 (71%); blinatumomab 13/14 (93%); venetoclax 10/14 (71%); CD19 CAR 5/14 (36%)]. Seven (7/14, 50%) pts had a prior allogeneic stem cell transplant (allo-SCT), including 3 pts with 2 prior allo-SCT. The median pretreatment bone marrow blasts were 70.5% (range, 16-95). The median CD22 expression on blasts was 90.5% (range, 33.6-99.9).

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 (shown below) indicated rapid clearance of the antibody, the trial was amended to allow for weekly dosing and 3 pts have been treated at 30µg/kg weekly dose level. No pt had a DLT. Two pts (one each at 60µg/kg and 90µg/kg every 3 weeks schedule) did not complete the DLT window due to rapid disease progression and were taken off treatment prior to day 28. One pt (in the weekly schedule) had grade 4 thrombocytopenia possibly related to ADCT-602. No pt had veno-occlusive disease.

Two pts achieved MRD-negative remission. One pt was 35-year-old with R/R B-ALL (complex karyotype, NRAS mutation) with several prior lines of therapy (HCVAD, pegasparaginase-based therapy, allo-SCT, inotuzumab, POMP). Baseline bone marrow blasts were 87% with 99.9% CD22 expression. Pt received ADCT-602 at 30µg/kg Q3week schedule and achieved MRD negative CRp after Cycle 1 which improved to MRD negative CR after Cycle 2. He received a total of 6 cycles of ADCT-602 before transitioning to second allo-SCT. Another pt was 22-year-old with R/R B-ALL (complex karyotype) with multiple prior therapies (including 2 prior allo-SCT, CD19 CAR-T, inotuzumab, blinatumomab, pegasparaginase, venetoclax) received ADCT-602 at 30µg/kg weekly schedule. Baseline bone marrow blasts were 24% with 97% CD22 expression. Pt achieved MRD negative CRp after Cycle 1 and is currently receiving Cycle 2.

PK data, available for 9 pts treated at every 3-week schedule [30 mcg/kg, n=3; 60 mcg/kg, n=4; 90 mcg/kg, n=2] showed rapid clearance of antibody with mean apparent half-life of <1 day during Cycle 1. This supported transitioning ADCT-602 administration to the weekly dosing.

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 no DLTs noted. Two pts achieved MRD-negative remission. Dose escalation in the weekly schedule continues and 2 additional dose levels (40µg/kg weekly and 50µg/kg weekly) are planned.

Disclosures: Jain: Aprea Therapeutics: Research Funding; Janssen: Honoraria; ADC Therapeutics: Honoraria, Research Funding; TG Therapeutics: Honoraria; Incyte: Research Funding; Cellectis: Honoraria, Research Funding; Beigene: Honoraria; Adaptive Biotechnologies: Honoraria, Research Funding; Servier: Honoraria, Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Precision Biosciences: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Konopleva: Sanofi: Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Calithera: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Cellectis: Other: grant support; Stemline Therapeutics: Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; KisoJi: Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Agios: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Ascentage: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding. Pemmaraju: Celgene Corporation: Consultancy; LFB Biotechnologies: Consultancy; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Sager Strong Foundation: Other; Plexxicon: Other, Research Funding; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; DAVA Oncology: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; CareDx, Inc.: Consultancy; Aptitude Health: Consultancy; Springer Science + Business Media: Other; Roche Diagnostics: Consultancy; MustangBio: Consultancy, Other; Incyte: Consultancy; Affymetrix: Consultancy, Research Funding; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Thompson: Amgen: Other: Institution: Honoraria, Research Grant/Funding; Gilead: Other: Institution: Advisory/Consultancy, Honoraria; Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony; Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Janssen: Consultancy, Honoraria. Short: Astellas: Research Funding; AstraZeneca: Consultancy; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy; Novartis: Honoraria; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Kadia: Cellonkos: Other; Pulmotech: Other; Pfizer: Consultancy, Other; Novartis: Consultancy; Genentech: Consultancy, Other: Grant/research support; Amgen: Other: Grant/research support; BMS: Other: Grant/research support; Cure: Speakers Bureau; Dalichi Sankyo: Consultancy; Agios: Consultancy; Jazz: Consultancy; Liberum: Consultancy; AbbVie: Consultancy, Other: Grant/research support; Sanofi-Aventis: Consultancy; Ascentage: Other; Genfleet: Other; Astellas: Other; AstraZeneca: Other. Borthakur: GSK: Consultancy; Protagonist: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; University of Texas MD Anderson Cancer Center: Current Employment; ArgenX: Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; Ryvu: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Daver: Daiichi Sankyo: Consultancy, Research Funding; Novimmune: Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Consultancy; Pfizer: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Glycomimetics: Research Funding; Trillium: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Hanmi: Research Funding; FATE Therapeutics: Research Funding; Trovagene: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. DiNardo: Takeda: Honoraria; ImmuneOnc: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Forma: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Ravandi: Jazz: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Prelude: Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria, Research Funding. Kantarjian: Astellas Health: Honoraria; Daiichi-Sankyo: Research Funding; Ascentage: Research Funding; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Immunogen: Research Funding; Aptitude Health: Honoraria; NOVA Research: Honoraria; Amgen: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria; Astra Zeneca: Honoraria; Ipsen Pharmaceuticals: Honoraria; BMS: Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria.

OffLabel Disclosure: ADCT-602 is not approved for B-ALL

*signifies non-member of ASH