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
Authors: Jain Nitin , Jabbour Elias J. , Konopleva Marina , Pemmaraju Naveen , Thompson Philip A. , Short Nicholas J. , Kadia Tapan M. , Borthakur Gautam , Daver Naval , DiNardo Courtney D. , Aldoss Ibrahim , Cook Robin , Ravandi Farhad , Kantarjian Hagop 
Published: November 2021

Abstract
Introduction: Outcomes of patients (pts) with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) remain dismal, with 5-year survival &lt;20%. CD22 is expressed on lymphoblasts in &gt;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 &lt;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: Genentech: Consultancy, Other: Grant/research support; Pfizer: Consultancy, Other; AstraZeneca: Other; Cure: Speakers Bureau; BMS: Other: Grant/research support; Jazz: Consultancy; Liberum: Consultancy; Sanofi-Aventis: Consultancy; Pulmotech: Other; Astellas: Other; Genfleet: Other; Ascentage: Other; Cellonkos: Other; Novartis: Consultancy; Dalichi Sankyo: Consultancy; Amgen: Other: Grant/research support; Aglos: Consultancy; AbbVie: Consultancy, Other: Grant/research support. 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