Antibody-drug Conjugate Therapeutics Research Articles

A Phase 1b Open-Label Study of Loncastuximab Tesirine in Combination with Other Anticancer Agents in Patients with Relapsed or Refractory (R/R) B-Cell Non-Hodgkin Lymphoma (LOTIS-7)

Background: Patients (pts) with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) may not respond well to single-agent therapy. Combining agents with different mechanisms of action may enhance the efficacy of single agents. Loncastuximab tesirine (loncastuximab tesirine-lpyl; Lonca) is an FDA-approved CD19-directed antibody-drug conjugate (ADC) indicated for R/R large B-cell lymphoma and showed significant antitumor activity and manageable toxicity in a phase 2 trial in pts with R/R diffuse large B-cell lymphoma (Lancet Oncol 2021;22(6):790-800). In preclinical xenograft models, Lonca in combination with gemcitabine, polatuzumab vedotin (Pola), or phosphatidylinositol 3-kinase inhibitors showed improved antitumor activity. The safety and activity of Lonca in combination with other established anticancer agents in pts with R/R B-NHL will be evaluated in LOTIS-7. Methods: LOTIS-7 is a phase 1b, open-label, multicenter, multiarm study (NCT04970901) with 2 parts: dose escalation (part 1) and dose expansion (part 2). Approximately 200 pts with B-NHL will be enrolled (part 1, 70 pts; part 2, 130 pts). Part 2 may include DLBCL, high-grade B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, and Burkitt lymphoma cohorts. The design of part 2, such as the sample size, population, etc., may be informed by data collected in part 1. For safety, tolerability, and identifying the maximum tolerated dose and/or recommended dose for part 2, primary endpoints are frequency and severity of adverse events (AE), serious adverse events, dose-limiting toxicities during cycle 1, and frequency of dose modifications due to AE. For efficacy, pharmacokinetics, and immunogenicity, secondary endpoints are overall response rate, duration of response, complete response rate, progression-free survival, relapse-free survival, overall survival, Lonca concentrations, and antidrug antibodies to Lonca titers. Multiple arms are planned; currently, enrollment is open to 1 arm, wherein patients will be treated with Lonca + Pola as an outpatient infusion every 3 weeks (Q3W). In part 1, patients will receive Lonca at escalating doses (from 90 µg/kg to 150 µg/kg) and Pola at a dose of 1.8 mg/kg on day 1 of each 3-week cycle. In part 2, patients will receive Lonca in combination with Pola at the maximum tolerated dose and/or recommended dose for expansion if favorable results in part 1 are achieved. The study has a screening period (≤28 days from the day of the first dose), a treatment (Tx) period (cycles Q3W, ≤1 year), and a follow-up period (~Q12W visits, ≤2 years after Tx discontinuation). Treatment may continue for up to 1 year or until disease progression, unacceptable toxicity, or other discontinuation criteria-whichever occurs first. Key inclusion criteria are patients age ≥18 years with a pathologic diagnosis of R/R B-NHL (2016 WHO classification) and the following: those who failed/are intolerant to any approved Tx, received ≥2 systemic Tx regimens, need systemic Tx, have an ECOG performance status of 0-2, and have measurable disease (2014 Lugano Classification). Patients who previously received any study drugs; received a stem-cell transplant within 60 days prior to the start of study drugs; have lymphoma with active CNS involvement, serious skin-related disease, ascites, edema, or effusion; and have significant medical comorbidities are excluded. Results: The study opened in December 2021, and the first patient was dosed in the Lonca + Pola arm in June 2022. Funding: ADC Therapeutics SA; medical writing: CiTRUS Health Group.

First-in-human, phase 1, open-label, dose-escalation, dose-expansion study of ADCT-901 as monotherapy in patients with select advanced solid tumors.

TPS3157 Background: Kidney associated antigen 1 (KAAG1) is highly and selectively expressed on tumor cell surface, such as ovarian, prostate, and triple negative breast cancers (TNBC), and is rapidly internalized and co-localized with a lysosomal marker, making an ideal candidate for an antibody-drug conjugate (ADC) target. ADCT-901 is an ADC composed of a humanized monoclonal antibody IgG1 against KAAG1, conjugated through a cathepsin-cleavable linker to SG3199, a pyrrolobenzodiazepine (PBD) dimer cytotoxin. In mouse xenograft models of human-derived TNBC, ovarian, and renal cancers significant tumor reduction was observed after a single dose of ADCT-901, providing the rationale for clinical development of a PBD-based ADC to treat KAAG1 expressing tumors (Zammarchi et al, AACR 2019). This study aims to identify the recommended dose and schedule for expansion and to characterize safety and tolerability of ADCT-901 in patients (pts) with selected advanced solid tumors that generally express KAAG1. Methods: ADCT-901-101 is a phase 1, multicenter, 2-part, open-label study that will enroll ̃70 pts (NCT04972981). Part 1: pts will receive escalating doses of ADCT-901 guided by a 3+3 design (1st dose: 15 µg/kg every 3 weeks [Q3W]; highest dose: 290 µg/kg Q3W). Dose escalation will be evaluated by administering the lowest dose to first 3 pts, then increasing/decreasing the dose based on dose-limiting toxicity (DLT) experienced by pts. The dose and schedule of ADCT-901 identified in part 1 will be tested in part 2 to characterize safety, tolerability, and preliminary efficacy of ADCT-901. Primary endpoints include incidence of DLTs (part 1 only), frequency/severity of adverse events (AE) and serious AE, clinically significant changes in vitals, laboratory values, overall tolerability, and frequency of dose interruptions and reductions. Secondary endpoints include overall response rate, duration of response, progression-free and overall survival, pharmacokinetic parameters of ADCT-901 total antibody, PBD-conjugated antibody, unconjugated SG3199 in serum, and frequency of confirmed positive antidrug antibody responses. Exploratory endpoints include tumor modulation and potential pharmacodynamic changes. Key inclusion criteria: pathologic diagnosis of selected solid tumor (cholangiocarcinoma, renal cell carcinoma, ovarian/fallopian tube and prostate cancers, TNBC) locally advanced or metastatic at time of screening, pts refractory or intolerant to existing therapy, tissue biopsy or available tissue sample, ECOG of 0-2, and adequate organ function based on predefined laboratory parameters. Pts with symptomatic CNS metastases and clinically significant third space fluid accumulation will be excluded. The study opened for recruitment in September 2021; enrollment is ongoing. Funding: ADC Therapeutics; medical writing: CiTRUS Health Group. Clinical trial information: NCT04972981.

Phase 3 randomized study of loncastuximab tesirine in combination with rituximab (Lonca-R) versus immunochemotherapy in patients with R/R DLBCL (LOTIS-5).

TPS7591 Background: Patients (pts) with refractory or relapsed (R/R) diffuse large B-cell lymphoma (DLBCL) have poor outcomes with standard treatment. Loncastuximab tesirine (loncastuximab tesirine-lpyl; Lonca), an antibody-drug conjugate (ADC) comprising a humanized anti-CD19 monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer toxin, is approved in R/R DLBCL based on data from the phase 2 LOTIS-2 trial (Caimi et al. Lancet Oncol 2021). Rituximab (R) is part of standard immunochemotherapy for DLBCL, both as frontline therapy and in subsequent treatments. Preclinical evidence suggests that the addition of rituximab to anti-CD19 ADC therapy may result in prolonged tumor control (Ryan et al. Blood 2017). LOTIS-5 aims to evaluate Lonca-R vs. standard immunochemotherapy of R + gemcitabine + oxaliplatin (R-GemOx) in pts with R/R DLBCL. Methods: This is a phase 3 randomized open-label, two-part, two-arm multicenter study of Lonca-R in pts with R/R DLBCL (NCT04384484). A review of safety data from the nonrandomized safety run-in (Part 1), comparing the safety of Lonca-R to previous Lonca safety data, was completed in January 2022. The trial is now continuing to the randomized phase (Part 2). In Part 2, approximately 330 pts will be randomized 1:1 to receive Lonca-R or R-GemOx. The primary objective of the study is to evaluate the efficacy of Lonca-R versus R-GemOx. The primary endpoint is progression-free survival by independent central review (ICR). Secondary endpoints include overall survival, overall response rate (by ICR using 2014 Lugano classification), complete response rate by ICR, duration of response by ICR, frequency and severity of adverse events, changes from baseline in safety laboratory and clinical variables, concentration and pharmacokinetic parameters of Lonca (conjugated and total antibody and unconjugated warhead), immunogenicity, and changes in patient-reported outcomes. The time to event endpoints will be analyzed based on the intent-to-treat population using a stratified log-rank test. The dosing regimen for Lonca-R: Lonca at 0.15 mg/kg + rituximab at 375 mg/m2 every 3 weeks (Q3W) for 2 cycles and then Lonca at 0.075 mg/kg + rituximab at 375 mg/m2 Q3W for up to 6 cycles. The dose regimen of R-GemOx: rituximab at 375 mg/m2, gemcitabine at 1000 mg/m2 Gem, and oxaliplatin at 100 mg/m2 every 2 weeks for up to 8 cycles. Key inclusion criteria include age ≥18 years, pathologic diagnosis of DLBCL (including pts with DLBCL transformed from indolent lymphoma) or high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, ≥1 line of prior systemic therapy, not being a candidate for stem cell transplantation, and measurable disease per the 2014 Lugano classification. The randomized part of LOTIS-5 commenced in January 2022, and recruitment is ongoing. Funding: ADC Therapeutics SA; medical writing: CiTRUS Health Group. Clinical trial information: NCT04384484.

Clinical Characteristics and Responses of Patients with Relapsed or Refractory High-Grade B-Cell Lymphoma Treated with Loncastuximab Tesirine in the Lotis-2 Clinical Trial

Clinical Characteristics and Responses of Patients with Relapsed or Refractory High-Grade B-Cell Lymphoma Treated with Loncastuximab Tesirine in the Lotis-2 Clinical Trial

The Anti-CD19 Antibody-Drug Conjugate Loncastuximab Tesirine Achieved Responses in Patients with Diffuse Large B-Cell Lymphoma Who Relapsed after Anti-CD19 CAR T-Cell Therapy

The Anti-CD19 Antibody-Drug Conjugate Loncastuximab Tesirine Achieved Responses in Patients with Diffuse Large B-Cell Lymphoma Who Relapsed after Anti-CD19 CAR T-Cell Therapy

Planned Interim Analysis of a Phase 2 Study of Loncastuximab Tesirine Plus Ibrutinib in Patients with Advanced Diffuse Large B-Cell Lymphoma (LOTIS-3)

Planned Interim Analysis of a Phase 2 Study of Loncastuximab Tesirine Plus Ibrutinib in Patients with Advanced Diffuse Large B-Cell Lymphoma (LOTIS-3)

Combination of Loncastuximab Tesirine and Polatuzumab Vedotin Shows Increased Anti-Tumor Activity in Pre-Clinical Models of Non-Hodgkin Lymphoma

Loncastuximab tesirine-lpyl (formerly ADCT-402) is an antibody-drug conjugate (ADC) comprising a humanised anti-CD19 monoclonal antibody conjugated to the pyrrolobenzodiazepine (PBD) dimer-based payload tesirine. Once bound to CD19 on the cell membrane, loncastuximab tesirine is rapidly internalised and the released PBD dimer warhead causes interstrand DNA crosslinks which ultimately trigger cell death. Pre-clinically, loncastuximab tesirine has shown potent and specific anti-tumor activity in lymphoma models both as single agent and in combination with other approved drugs, like venetoclax, idelalisib and bendamustine (Zammarchi, Corbett et al. 2018, Tarantelli, Spriano et al. 2019). Loncastuximab tesirine has been recently approved by the United States Food and Drug Administration (FDA) for the treatment of relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) and it is currently being tested in multiple clinical trials, either as monotherapy or in combination with other anti-lymphoma drugs.Polatuzumab vedotin is an ADC composed of a humanized anti-CD79b monoclonal antibody conjugated to monomethyl auristatin E (vcMMAE) and it is approved by the FDA for treatment of r/r DLBCL when used in combination with bendamustine and rituximab.Here, we investigated the in vitro and in vivo anti-tumor activity of loncastuximab tesirine combined with polatuzumab vedotin in pre-clinical models of non-Hodgkin lymphoma (NHL).In vitro, the combination of loncastuximab tesirine and polatuzumab vedotin was tested in three human-derived, CD19 and CD79b-positive NHL cell lines (WSU-DLCL2, TMD8 and Ramos) and it resulted in synergistic (TMD8 and Ramos) and additive (WSU-DLCL2) activity, as assessed by the Chou-Talalay method.Quantification of cell viability (propidium iodide [PI]-negative and Annexin V-negative) and early/late apoptosis (Annexin V-positive and PI-negative/ Annexin V-positive and-PI positive) on TMD8 and Ramos cells treated with loncastuximab tesirine, polatuzumab vedotin or the combination of the two agents showed a significant reduction of viable cells accompanied by an increase in apoptotic cells in the combination setting compared to the single agents.In vivo, loncastuximab tesirine was tested either alone (0.25 or 0.5 mg/kg, single dose) or in combination with polatuzumab vedotin (1 mg/kg, single dose) in the WSU-DLCL2 xenograft model. At the highest dose of loncastuximab tesirine, combination with polatuzumab vedotin resulted in improved anti-tumor activity and superior response rate compared to the 2 agents in monotherapy. All treatment regimens were well tolerated by the mice, as assessed by body weight measurements and frequent observation for signs of treatment-related side effects.In conclusion, the combination of loncastuximab tesirine and polatuzumab vedotin resulted in improved anti-tumor activity both in vitro and in vivo in lymphoma preclinical models and it was well tolerated. Altogether, these novel pre-clinical data warrant translation of the combination of loncastuximab tesirine and polatuzumab vedotin into the clinic for the treatment of NHL. DisclosuresSachini: ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Jabeen: ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. van Berkel: ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Zammarchi: ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties.

CD19-Mediated DNA Damage Boost in Lymphoma Cells Treated with Loncastuximab Tesirine in Combination with PARP Inhibitors

Overexpression of the MYC oncogene is a frequent feature of diffuse large B-cell lymphoma (DLBCL) being associated with poor prognosis following standard R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone) chemoimmunotherapy. Since MYC expression is associated with overactivation of the DNA damage response (DDR), targeting DDR pathways with selective small molecule inhibitors could be a promising strategy to circumvent the inherent resistance to exogenous DNA damage proper of MYC-positive DLBCL. Loncastuximab tesirine-lpyl (here abbreviated as Lonca) is an antibody-drug conjugate (ADC) composed of a humanized anti-CD19 antibody conjugated to a potent DNA-crosslinking pyrrolobenzodiazepine dimer toxin.We hypothesized that DDR inhibition could increase the efficacy of Lonca by selectively enhancing DNA damage induction in B-cell lymphoma cells. In a preliminary analysis of a publicly available dataset (Sha et al. J Clin Oncol 2019), we found a significant correlation between MYC and PARP1 gene expression levels, with higher PARP1 levels observed in DLBCL samples characterized by high MYC expression. Following this observation, with the aim of developing a treatment strategy for MYC-positive DLBCL, we tested the in vitro activity of 3 FDA-approved PARP inhibitors (Olaparib, Rucaparib, Talazoparib) in a panel of 13 CD19+ DLBCL cell lines (7 with MYC rearrangements). Cytotoxicity was evaluated with Cell Titer Glo assay (CTG), and all compounds showed anti-proliferative activity in a dose and time-dependent manner. Compared with Olaparib and Rucaparib, Talazoparib (Talazo) showed more potent in vitro activity as single agent, with IC50 values in the submicromolar range (100-200 nM at 5 days) observed in most cell lines, in line with its increased PARP trapping capacity. Of note, the BRCA-mutated cell line DOHH2 was the most sensitive to all 3 PARPi, in line with the known synthetic lethal interaction between BRCA mutations and PARP inhibition.Lonca showed significant cytotoxic activity in 10 of 13 cell lines, which were sensitive in the same range of clinically achievable concentrations, with IC50 values ≤ 1 ng/ml at 5 days; conversely, the B12 isotype control ADC was completely ineffective. Interestingly, BRCA-mutated DOHH2 cells were highly sensitive to single agent Lonca, and those cell lines that were resistant to Lonca (SUDHL-2, Pfeiffer, SUDHL-10) displayed also reduced sensitivity to Talazo. The combination of Talazo and Lonca produced enhanced anti-proliferative effects, with strong synergism (evaluated by combination index analysis) observed in most cell lines. Notably, those cell lines resistant to both compounds as single agents became sensitive to the combination. To investigate the mechanisms underlying these synergistic interactions, we performed 2D-cell cycle analysis by flow cytometry with bromodeoxyuridine (BrdU) and propidium iodide staining at different time points (24h-72h-5days). While single agent treatments predominantly increased the fraction of cells in G2/M phase, the combination of Talazo and Lonca clearly increased the fraction of cells in the BrdU-negative S phase of the cell cycle, (which represents cells that are not actively synthetizing DNA, S-), thus suggesting a mechanistic interaction between the two drugs (Fig. 1). Treatment with the Lonca/Talazo combination induced cell death (as measured by trypan blue assay or SubG1 fraction of the cell cycle), in the absence of significant caspase cleavage. Western blot assay showed enhanced induction of the DNA damage marker γH2AX in cells treated with the combination after 24 hours of incubation. In line with this, alkaline Comet assay confirmed enhanced DNA damage induction after 24h of combinational treatment as compared to single agents, thus confirming that DDR inhibition significantly increases the amount of DNA damage induced by Lonca. Comet assay performed on peripheral blood CD19+ B cells from healthy donors following ex-vivo treatment with Talazo, Lonca or the combination showed similar DNA damage induction patterns. Importantly, no DNA damage could be detected in CD3+ T-cells from the same healthy donors.In conclusion, these data indicate that PARP inhibition significantly enhances the efficacy of Lonca in in vitro DLBCL models, providing the rationale to develop precision therapy strategies aimed at boosting DNA damage induction in neoplastic B-cells. [Display omitted] DisclosuresZammarchi: ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. van Berkel: ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Pileri: NANOSTRING: Other: ADVISORY BOARD; ROCHE: Other: ADVISORY-BOARD; CELGENE: Other: ADVISORY BOARD. Tarella: ADC-THERAPEUTICS: Other: ADVISORY BOARD; Abbvie: Other: ADVISORY BOARD. Derenzini: TG-THERAPEUTICS: Research Funding; ASTRA-ZENECA: Consultancy, Other: ADVISORY-BOARD; BEIGENE: Other: ADVISORY BOARD; TAKEDA: Research Funding; ADC-THERAPEUTICS: Research Funding.

Encouraging Early Results from the First in-Human Clinical Trial of ADCT-402 (Loncastuximab Tesirine), a Novel Pyrrolobenzodiazepine-Based Antibody Drug Conjugate, in Relapsed/Refractory B-Cell Lineage Non-Hodgkin Lymphoma

Introduction: CD19 is expressed on the cell surface of many types of non-Hodgkin lymphoma (NHL), including follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). ADCT-402 (loncastuximab tesirine) is an antibody drug conjugate (ADC) comprising a humanized antibody (Ab) directed against human CD19 conjugated to a pyrrolobenzodiazepine (PBD) dimer toxin. Loncastuximab tesirine (Lonca-T) has demonstrated potent anti-tumor activity against CD19-expressing B-cell malignancies in preclinical models. Interim results of the first-in-human clinical study of Lonca-T in the difficult-to-treat relapsed/refractory (R/R) NHL setting are reported here.Methods: Patients (pts; ≥18 years of age) with R/R B-cell lineage NHL who have failed or are intolerant to established therapies, or have no other treatment options available, are being enrolled in this Phase 1, multicenter, open-label, two-part study. The primary objectives for Part 1 (dose escalation) are to evaluate the safety and tolerability of Lonca-T, and to determine the maximum tolerated dose (MTD) and the recommended dose(s) to use in Part 2 (dose expansion). The primary objective for Part 2 is to evaluate the safety and tolerability of the dose(s) determined in Part 1. Efficacy (measured by overall response rate [ORR], duration of response [DoR], progression-free survival [PFS] and overall survival), pharmacokinetics, pharmacodynamics, and other exploratory endpoints are also being assessed in both parts of the study. Pts receive 1-hour intravenous infusions of Lonca-T every 3 weeks (1 cycle) according to a 3+3 dose-escalation study design. No intra-patient dose escalation is allowed.Results: As of July 5, 2017, 80 pts (55 male, 25 female; median age: 65.5 years [range 24-85]; median number of previous therapies: 3 [range 1-10]) have been recruited. Diagnoses were DLBCL (n=56), mantle cell lymphoma (MCL; n=9), FL (n=6), marginal zone B-cell lymphoma (n=3), chronic lymphocytic leukemia (n=2) and other (n=4). Pts have received doses of Lonca-T ranging from 15 to 200 µg/kg (median cycles: 2 [range 1-16]). Treatment-emergent adverse events (TEAEs) were reported in 76 (95.0%) pts, and grade ≥3 TEAEs in 46 (57.5%) pts. The most common non-hematological all-grade TEAEs were fatigue (35 [43.8%] pts), peripheral edema (21 [26.3%] pts) and nausea (20 [25.0%] pts), and grade ≥3 TEAEs were increased gamma-glutamyltransferase (7 [8.8%] pts) dyspnea (4 [5.0%] pts) and fatigue (4 [5.0%] pts). Hematological abnormalities included decreased hemoglobin (74/77 [96.1%] and 9/77 [11.7%] pts with all-grade and grade ≥3 TEAEs, respectively), decreased neutrophil count (42/69 [60.9%] and 29/69 [42.0%] pts, respectively) and decreased platelet count (55/77 [71.4%] and 21/77 [27.3%] pts, respectively). TEAEs in 8 (10.0%) pts led to treatment withdrawal (increased gamma-glutamyltransferase [n=4]; increased blood alkaline phosphatase [n=1]; periorbital edema [n=1]; fatigue [n=1]; abdominal pain [n=1]; thrombocytopenia [n=1]). A dose-limiting toxicity (DLT) was reported in 1 pt (worsening of thrombocytopenia at 200 µg/kg) and the MTD has not yet been reached. Table 1 shows the best overall response by dose. At doses ≥120 µg/kg, 16/47 (34.0%) and 12/47 (25.5%) evaluable pts achieved a complete response (CR) or partial response (PR), respectively (ORR: 28/47 [59.6%]). ORR for pts with DLBCL was 20/35 (57.1%), with a CR rate of 34.3% (12/35). Figure 1 depicts the waterfall plot. Pharmacokinetic measures for total- and PBD-conjugated Ab exposures were comparable, were proportional to dose, and were associated with modest accumulation by Cycle 2. Measures for unconjugated PBD were predominantly below quantification levels for all doses and time points. Associations of exposure to safety and efficacy are reported in a companion abstract (O O'Connor et al.).Conclusions: In this Phase 1 study, Lonca-T has demonstrated encouraging single-agent anti-tumor activity and manageable toxicity in pts with R/R B-cell lineage NHL. One DLT has been reported and the MTD has not yet been reached. Evaluation in specific NHL subtypes is now warranted, and a dose expansion in pts with DLBCL is planned initially. Updated safety, tolerability, and efficacy results will be presented at the meeting.Study sponsored by ADC Therapeutics. http://clinicaltrials.gov/show/NCT02669017 [Display omitted] DisclosuresKahl:ADC Therapeutics: Research Funding; Celgene: Consultancy; Gilead: Consultancy; Seattle Genetics: Consultancy; Genentech: Consultancy. Hamadani:Takeda, Otsuka, MedImmune, Merck, ADC Therapeutics: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau; Celgene, Cellerant, Jansen, MedImmune: Consultancy. Caimi:Seattle Genetics: Equity Ownership; Incyte: Equity Ownership; Abbvie: Equity Ownership; Celgene: Speakers Bureau. Carlo-Stella:ADC Therapeutics: Research Funding. Reid:ADC Therapeutics, Millennium: Research Funding. Feingold:ADC Therapeutics: Employment, Other: Potential equity interest. Ardeshna:ADC Therapeutics: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Conference Expenses; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference Expenses, Research Funding. Radford:Takeda: Research Funding, Speakers Bureau; Seattle Genetics: Speakers Bureau; Novartis: Speakers Bureau; GlaxoSmithKline: Equity Ownership; AztraZeneca: Equity Ownership; ADC Therapeutics: Research Funding. Solh:Celgene: Speakers Bureau; Amgen: Speakers Bureau; ADC Therapeutics: Research Funding. Chung:ADC Therapeutics: Research Funding. Heffner:ADC Therapeutics: Research Funding. He:ADC Therapeutics: Employment, Other: Potential equity interest. Boni:ADC Therapeutics: Employment, Other: Potential equity interest. O'Connor:ADC Therapeutics: Research Funding.

Interim Data from a Phase 1 Study Evaluating Pyrrolobenzodiazepine-Based Antibody Drug Conjugate ADCT-402 (Loncastuximab Tesirine) Targeting CD19 for Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia

Introduction: Outcomes of patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) remain dismal, with 5-year survival <20%.Expression of CD19, which is normally restricted to B-cell developmental stages, is universally present in patients with B-ALL. ADCT-402 (loncastuximab tesirine) is an antibody drug conjugate (ADC) composed of a humanized CD19-targeting monoclonal antibody conjugated to a pyrrolobenzodiazepine (PBD) dimer cytotoxin. In preclinical studies, loncastuximab tesirine (Lonca-T) demonstrated potent anti-tumor activity in mouse models of B-cell malignancies. We present interim data from a Phase 1 study evaluating Lonca-T in patients with R/R B-ALL.Methods: A Phase 1, open-label, dose-escalation (part 1) and expansion (part 2), multicenter, US study is enrolling patients with R/R B-ALL to assess the tolerability and safety of Lonca-T. Secondary objectives include evaluation of clinical activity, characterization of the pharmacokinetic (PK) profile, and evaluation of anti-drug antibodies. Eligible patients are ≥12 years of age with R/R B-ALL and an Eastern Cooperative Oncology Group performance status of 0-2 who have failed, or are intolerant to, established therapy, or have no other treatment options available in the opinion of the investigator. In part 1, patients were assigned to treatment according to a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD). Lonca-T was given intravenously on Day 1 of each cycle. The first cohort received a dose of 15 μg/kg on a 21-day (q3w) treatment cycle. Part 2 will further evaluate the safety, tolerability, PK and clinical activity at the dose recommended from part 1.Results: As of June 23, 2017, 23 patients (14 male, 9 female) with B-ALL have been treated with Lonca-T. The median age was 57 years [range 21-80] and patients had received a median of 2 (range: 1-12) previous chemotherapies. Nine (39%) patients had received prior allogeneic stem cell transplantation. No dose-limiting toxicities were observed up to the highest evaluated dose of 150 µg/kg q3w. A total of 204 treatment-emergent adverse events (TEAEs) were reported from all patients. The most common TEAEs were nausea (n=7) and fatigue (n=6) followed by diarrhea, febrile neutropenia and headache (all n=5). Grade ≥3 TEAEs were reported in 19/23 (83%) patients, of which febrile neutropenia (n=5), bacteremia (n=3) and sepsis (n=3) were the most common. There have been no treatment-related deaths. Four patients experienced TEAEs leading to a dose delay or reduction, but no TEAEs led to treatment discontinuation. There were 16 liver toxicity events recorded in 5 patients, leading to dose delay in 1 patient; 3 patients experienced Grade ≥3 events, all of which were reversible and not related to veno-occlusive disease. Two Grade 2 and one Grade 3 infusion-related reactions were observed. Two patients achieved a complete response with no minimal residual disease (MRD), at a dose of 30 μg/kg and 120 μg/kg q3w after five and two treatment cycles, respectively. Both responders had previously received blinatumomab. PK data show PBD-conjugated antibody concentrations below quantifiable levels well before end of cycle, which in combination with the absence of dose-limiting toxicities (DLTs) support weekly dosing.Conclusions:In this Phase 1 study in patients with R/R B-ALL, single-agent Lonca-T was well tolerated with no DLTs and showed two MRD-negative complete remissions in a heavily pre-treated population. Dose escalation will continue to find the MTD for a weekly regimen. A dose-expansion phase in part 2 of the study is planned to further evaluate the tolerability, safety, PK and activity of Lonca-T.Study sponsored by ADC Therapeutics. https://clinicaltrials.gov/ct2/show/NCT02669264 DisclosuresJain:Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Celgene: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Research Funding; BMS: Research Funding; Abbvie: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding. Stock:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ungar:ADC Therapeutics: Employment, Other: Stock option interest. Zeidan:AbbVie, Otsuka, Pfizer, Gilead, Celgene, Ariad, Incyte: Consultancy, Honoraria; Takeda: Speakers Bureau; Otsuka: Consultancy. Atallah:ADC Therapeutics: Research Funding. McCloskey:ADC Therapeutics: Research Funding. Heffner:ADC Therapeutics: Research Funding; Kite: Research Funding. Kantarjian:Delta-Fly Pharma: Research Funding; Novartis: Research Funding; Bristol-Meyers Squibb: Research Funding; Pfizer: Research Funding; Amgen: Research Funding; ARIAD: Research Funding. He:ADC Therapeutics: Employment, Other: Potential equity interest. Boni:ADC Therapeutics: Employment, Other: Potential equity interest. Wieduwilt:Reata Pharmaceuticals: Equity Ownership; Sigma-Tau: Research Funding.

Elucidating Exposure-Response (Safety and Efficacy) of ADCT-402 (Loncastuximab Tesirine), a Novel Pyrrolobenzodiazepine-Containing Antibody Drug Conjugate, for Recommended Phase 2 Dose Determination in Patients with Relapsed or Refractory Non-Hodgkin Lymphoma

▪Introduction: ADCT-402 (loncastuximab tesirine) is an antibody-drug conjugate (ADC) composed of a humanized CD19-specific IgG1 antibody stochastically conjugated to a pyrrolobenzodiazepine (PBD) dimer cytotoxin via a cleavable maleimide linker. In this Phase 1 dose escalation trial of heavily pre-treated patients with B-cell non-Hodgkin lymphoma (NHL), loncastuximab tesirine (Lonca-T) 15 to 200 µg/kg was administered every 3 weeks (q3w) by intravenous infusion. The dose and pharmacokinetic (PK) exposure of Lonca-T were modeled as drivers of safety (treatment-emergent adverse events [TEAEs]) and efficacy (reduction in tumor size) for the determination of the Recommended Phase 2 Dose (RP2D).Methods:Concentrations of PBD-conjugated antibody (Ab) in serum were determined using a validated electrochemiluminescence immunoassay, then analyzed by population PK methodology using NONMEM (version 7.3, first-order conditional estimation). Associations between exposure (dose and Bayesian-estimated individual-patient exposure metrics) and the maximum severity of early (Cycle 1) and early or later (all cycles) TEAEs were evaluated for overall TEAEs, anemia, platelets, neutrophils, hemoglobin, fatigue, edema and pleural effusion. Associations of dose and PK with maximum change from baseline tumor size were also determined to identify potential relationships between exposure and activity (complete response plus partial response). For the PK population, drug concentrations were described using the log-transformed both sides approach with a 3-compartment open model and zero-order infusion. In the final population model, gender was retained as a covariate on central volume of distribution.Results: Data from 44 patients (28 males and 16 females) were included in the population PK model. Patients had a mean (range) age of 67 years (24-85) and weight of 87 kg (42-143). A positive relationship was apparent for maximum severity TEAEs, anemia, and thrombocytopenia both in Cycle 1 and in later cycles. A positive relationship was evident for neutropenia, edema and pleural effusion in later cycles only. For patients with and without Grade 3/4 TEAEs, median (5th, 95th percentile) PBD-conjugated Ab area under the curve (AUC) was 13.6 mg*Day/L (0.359, 40.8), and 6.33 mg*Day/L (0.308, 35.0), respectively. Increased exposure to Lonca-T in Cycle 1 was associated with decreased tumor size, with the model giving a dosage of 120 µg/kg q3w as a median minimum dose necessary for requisite efficacy. To achieve at least a 50% tumor size reduction from baseline, the median (min, max) PBD-conjugated Ab AUC was ~66 mg*Day/L (4.69, 294), which is close to the median AUC values of 63.9 and 66.9 mg*Day/L from patients in the 120 and 200 µg/kg cohorts, respectively.Conclusions: By quantitating the differences between exposure associated with grade of a given TEAE and the exposure necessary for efficacy, an optimal dose of Lonca-T associated with an acceptable set of toxicity thresholds was preliminarily identified. Since this trial is ongoing, supplemental pending data will be incorporated into the model, particularly for the 150 µg/kg dose, for an alternate dosage frequency (q6w), for individual patient CD19 status at baseline, and for NHL subtype, to provide the rationale for dosage and regimen selection and definition of the RP2D. DisclosuresO'Connor:ADC Therapeutics: Research Funding. Kahl:Seattle Genetics: Consultancy; ADC Therapeutics: Research Funding; Celgene: Consultancy; Gilead: Consultancy; Genentech: Consultancy. Hamadani:Takeda, Otsuka, MedImmune, Merck, ADC Therapeutics: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau; Celgene, Cellerant, Jansen, MedImmune: Consultancy. Caimi:Celgene: Speakers Bureau; ADC Therapeutics: Research Funding. Reid:ADC Therapeutics, Millennium: Research Funding. Feingold:ADC Therapeutics: Employment, Other: Potential equity interest. Havenith:ADC Therapeutics: Employment, Other: Stock option interest. He:ADC Therapeutics: Employment, Other: Potential equity interest. Mould:Projections Research Inc, a consulting company for pharmaceutical industry: Consultancy. Freedman:Projections Research Inc, Gerson Lerhrman Group: Consultancy; Freedman patent: Patents & Royalties. Boni:ADC Therapeutics: Employment, Other: Potential equity interest.

CD25 Enables Oncogenic BCR-Signaling and Represents a Therapeutic Target in B Cell Malignancies

Background and hypothesis: B cells critically depend on continuous survival and proliferation signals from a functional B cell receptor (BCR). In >50% of B cell malignancies, the tumor clone is driven by an oncogenic BCR-mimic. Oncogenic mimics of BCR-signaling include BCR-ABL1 (Ph+ ALL) and other ABL1-fusion genes (Ph -like ALL), viral oncoproteins (e.g. EBV; KSHV), BRAF- (hairy cell leukemia) and NF-κB-pathway lesions (Hodgkin's lymphoma, primary mediastinal B cell lymphoma). B cell tumors driven by oncogenic BCR-signaling represent a highly heterogeneous group of various cellular origins, genetic lesions and divergent clinical outcomes. Despite this heterogeneity, our correlative analyses showed that these B cell malignancies are uniformly characterized by high expression levels of CD25.Features of CD25 function in B cell malignancies: We found out that adults with Ph+ ALL (ECOG; MDACC) and children with Ph -like ALL (P9906) with high CD25 expression at the time of diagnosis have a particularly poor outcome (n=416; P =0.005). While CD25 mediates IL2 signaling on T cells and is highly expressed on regulatory T cells (Tregs), CD25 on B-lineage cells did not pair with IL2Rβ and was not responsive to IL2. Our genetic studies showed that BCR signaling rapidly induces CD25 cell surface translocation by PKCδ-dependent phosphorylation of the CD25 cytoplasmic tail (S268), which is further supported by transcriptional upregulation of CD25 by activation of NF-κB. Antibody mediated stimulation of surface exposed CD25 in response to BCR signaling shuttles inhibitory phosphatases (e.g. SHIP1) from the cytoplasm to the cell membrane. CD25-mediated membrane recruitment of inhibitory phosphatases limits kinase signaling (e.g. SYK, SRC and ERK) downstream of the BCR or its oncogenic mimics. Consistent with a role as negative feedback regulator, our genetic studies showed that CD25 deficient pre-B cells (Il2ra-/- ) have autonomous pre-BCR signals, resulting in uncoordinated Ca2+ oscillations of variable duration. Genetic ablation of CD25 subverted the ability of B cell leukemia cells to balance oncogenic signal strength, resulting in p53 checkpoint activation, cell cycle arrest, therefore failed initiation of B cell leukemia in transplant recipients. Importantly, reconstitution of myristoylated CD25 tail but not a mutant construct lacking the serine/threonine motif (S268A/T271A) rescued proliferation and survival defects of Il2ra-/- ALL cells.CD25 as novel therapeutic target in BCR-mimic B cell malignancies: Despite heterogeneity of B cell malignancies, we found that CD25 is an integrated biomarker of tumor clones driven by oncogenic BCR-mimics. BCR-dependent B cell tumors further exposed CD25 on the surface in response to the PKCδ activator, PEP005 (also known as Ingenol Mebutate) with rapid phosphorylation of PKCδT505, followed by CD25S268. As a strategy to eradicate CD25-expressing B cell malignancies, combined treatment of PEP005 with ADCT-301, an antibody drug conjugate (ADC) targeting CD25 with a pyrrolobenzodiazepine (PBD) dimer as the cytotoxic warhead, synergistically delayed leukemia development in recipient mice xenografted with patient-derived Ph+ ALL cells. Notably, synergistic effects of ADCT-301 were further enhanced by treatment with AZD5363, an AKT-inhibitor, which further upregulates CD25 on patient-derived Ph+ ALL cells by imitating signaling pressure leading to differentiation of large circulating pre-B to small pre-B cell fraction.Conclusion: Based on these finding, we propose CD25 as an integrated biomarker of BCR-dependent B cell tumors that are highly sensitive to established BCR signaling antagonists (e.g. Ibrutinib, Entospletinib) and as a therapeutic target in refractory B cell tumors. DisclosuresZammarchi:ADC Therapeutics: Employment. Van Berkel:ADC Therapeutics: Employment. Muschen:AbbVie: Research Funding; Pfizer: Research Funding.

Safety and Antitumor Activity Study Evaluating Loncastuximab Tesirine and Rituximab Versus Immunochemotherapy in Diffuse Large B-Cell Lymphoma

Introduction: Patients with diffuse large B-cell lymphoma (DLBCL) who fail immunochemotherapy (IC) and are unsuitable for autologous stem cell transplantation (ASCT) and those who relapse shortly after ASCT have extremely poor prognosis and need additional treatment options. Loncastuximab tesirine (Lonca) is an antibody-drug conjugate (ADC) composed of a humanized anti-CD19 antibody conjugated to a pyrrolobenzodiazepine dimer toxin. In a Phase 2 study (NCT03589469), Lonca demonstrated single-agent antitumor activity with manageable toxicity in patients with relapsed/refractory (R/R) DLBCL. Rituximab is a CD20-targeting monoclonal antibody used in front-line IC for DLBCL and in salvage regimens, such as rituximab/gemcitabine/oxaliplatin (R-GemOx). The addition of rituximab to a CD19-targeting pyrrolobenzodiazepine ADC appears to prolong tumor control in preclinical studies, providing the rationale for evaluating Lonca combined with rituximab (Lonca-R) as a treatment for R/R DLBCL. Study Design and Methods: This is a Phase 3, randomized, open-label, 2-part, 2-arm, multicenter study of Lonca-R versus standard IC in patients with R/R DLBCL (NCT04384484). Part 1 is a nonrandomized safety run-in with Lonca-R. The toxicity of Lonca-R will be compared with previous single-agent Lonca safety data after 20 patients have completed Cycle 1 in Part 1. Provided no significant increase in toxicity is observed, Part 2 will be initiated. Part 2 is a randomized study of Lonca-R versus R-GemOx (Figure 1). Key inclusion and exclusion criteria are reported in Table 1. The primary objective of Part 2 is to evaluate the efficacy of Lonca-R versus R-GemOx, using progression-free survival (PFS) as the primary endpoint. PFS will be defined as the time between randomization and first documentation of recurrence, disease progression or death (central review) and the primary analysis will compare PFS between treatment arms using stratified log-rank testing. Secondary objectives include evaluation of safety, pharmacokinetics, and immunogenicity of the combination, in addition to the impact of treatment on symptoms, patient-reported outcomes and patients' overall health. In Part 1 and in the Lonca-R arm of Part 2, patients will receive intravenous (iv) Lonca at 150 µg/kg on day 1 of each 21-day cycle for 2 cycles, then at 75 µg/kg on day 1 for up to 6 additional cycles. Rituximab 375 mg/m2 iv will be administered subsequent to Lonca infusion on day 1 of each cycle. Patients treated with Lonca-R will also be given dexamethasone 4 mg (oral, twice a day), where not contraindicated, on the day before, the day of, and the day after Lonca-R infusion. In the R-GemOx arm, patients will receive rituximab 375 mg/m2, gemcitabine 1000 mg/m2, and oxaliplatin 100 mg/m2 iv on day 1 of each 14-day cycle up to a total of 8 cycles. Patients will receive premedication and supportive care according to the respective prescribing information for rituximab, gemcitabine, and oxaliplatin. The trial is planned to open in Q3/Q4 2020, and target enrollment is 350 patients. Funding: This study is sponsored by ADC Therapeutics SA; https://clinicaltrials.gov/ct2/show/NCT04384484. Disclosures Linhares: Jazz Pharmaceuticals: Consultancy; ADC Therapeutics, Verastem Oncology, Bristol Myers-Squibb (Juno), AstraZeneca: Research Funding; Miami Cancer Institute, Baptist Health South Florida: Current Employment. Gandhi:TG Therapeutics (Advisory board), GlaxoSmithKline (Advisory board): Membership on an entity's Board of Directors or advisory committees. Adeleye:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Ungar:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Hamadani:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme, AstraZeneca: Speakers Bureau; Janssen R&amp;D; Incyte Corporation; ADC Therapeutics; Celgene Corporation; Pharmacyclics, Omeros, AbGenomics, Verastem, TeneoBio: Consultancy; Takeda Pharmaceutical Company; Spectrum Pharmaceuticals; Astellas Pharma: Research Funding. OffLabel Disclosure: Rituximab is licensed for treatment of NHL but is being used in combination with an unlicensed drug (loncastuximab tesirine) in this study

Combination of Camidanlumab Tesirine, a CD25-Targeted ADC, with Gemcitabine Elicits Synergistic Anti-Tumor Activity in Preclinical Tumor Models

Camidanlumab tesirine (ADCT-301) is an antibody-drug conjugate (ADC) comprised of HuMax®-TAC, a monoclonal antibody directed against human CD25, conjugated to the pyrrolobenzodiazepine dimer payload tesirine[1]. Currently, camidanlumab tesirine is being evaluated in a pivotal Phase 2 clinical trial in patients with relapsed or refractory Hodgkin lymphoma (HL) (NCT04052997) and in a Phase 1b clinical trial in patients with advanced solid tumors (NCT03621982). In pre-clinical studies, camidanlumab tesirine demonstrated strong and durable single agent activity in CD25-expressing lymphoma xenograft models[1] and in vitro it synergised with selected targeted agents[2]. Moreover, CD25-ADC, a mouse CD25 cross-reactive surrogate of camidanlumab tesirine, induced potent anti-tumor immunity against established syngeneic solid tumor models by depleting CD25-positive tumor-infiltrating T regulatory cells (Tregs) and it showed synergistic activity when combined with PD-1 blockade[3]. Here, we investigated the in vitro and in vivo anti-tumor activity of camidanlumab tesirine combined with gemcitabine, a common standard-of-care chemotherapeutic agent used both in a hematological and solid tumor clinical setting. In vitro, the combination of camidanlumab tesirine and gemcitabine was evaluated in three human-derived cancer cell lines (two HL and one anaplastic large cell lymphoma, ALCL) and resulted in synergistic activity as determined by the Chou-Talalay method. In vivo, camidanlumab tesirine was tested either alone (0.05 or 0.1 mg/kg, single dose) or in combination with gemcitabine (80 mg/kg, q3dx4) in the CD25-expressing ALCL Karpas299 xenograft model. At both ADC dose levels, combination with gemcitabine resulted in synergistic anti-tumor activity (coefficient of drug interaction (CDI) 0.51 and 0.17, respectively), better response rates and increased survival compared to monotherapy with camidanlumab tesirine. In order to extend the investigation to solid tumor models, CD25-ADC was tested in the CT26 syngeneic model, a colorectal cancer model with CD25-expressing tumor-infiltrating Tregs. CD25-ADC was administered either alone (0.1, 0.5 or 1 mg/kg, single dose) or in combination with gemcitabine (80 mg/kg, q3dx4). At the 0.1 mg/kg dose of CD25-ADC, combination with gemcitabine resulted in synergistic anti-tumor activity (CDI 0.68). Moreover, at 0.5 and 1 mg/kg, the combination of CD25-ADC and gemcitabine resulted in more durable anti-tumor activity and better response rates compared to both monotherapy treatments. In conclusion, the combination of camidanlumab tesirine and gemcitabine was synergistic both in vitro and in vivo in lymphoma preclinical models. Synergistic anti-tumor activity was also demonstrated in a colorectal cancer model using CD25-ADC, a mouse-cross-reactive version of camidanlumab tesirine, in combination with gemcitabine. Altogether, these novel pre-clinical data warrant translation of the combination between camidanlumab tesirine and gemcitabine into the clinic. 1.Flynn, M.J., et al., ADCT-301, a Pyrrolobenzodiazepine (PBD) Dimer-Containing Antibody-Drug Conjugate (ADC) Targeting CD25-Expressing Hematological Malignancies. Mol Cancer Ther, 2016. 15(11): p. 2709-2721. 2.Spriano, F., et al., The anti-CD25 antibody-drug conjugate camidanlumab tesirine (ADCT-301) presents a strong preclinical activity both as single agent and in combination in lymphoma cell lines. Hematological Oncology, 2019. 37(S2): p. 323-324. 3.Zammarchi, F., et al., A CD25-targeted antibody-drug conjugate depletes regulatory T cells and eliminates established syngeneic tumors via antitumor immunity. Journal for ImmunoTherapy of Cancer, 2020. In press. Disclosures Jabeen: ADC Therapeutics: Current Employment. Hartley:ADC Therapeutics: Consultancy, Current equity holder in publicly-traded company, Research Funding. Van Berkel:ADC-Therapeutics: Current Employment, Current equity holder in publicly-traded company. Zammarchi:ADC-Therapeutics: Current Employment, Current equity holder in publicly-traded company.

Clinical Profile of IMGN632, a Novel CD123-Targeting Antibody-Drug Conjugate (ADC), in Patients with Relapsed/Refractory (R/R) Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

Clinical Profile of IMGN632, a Novel CD123-Targeting Antibody-Drug Conjugate (ADC), in Patients with Relapsed/Refractory (R/R) Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

Interim Futility Analysis of a Phase 2 Study of Loncastuximab Tesirine, a Novel Pyrrolobenzodiazepine-Based Antibody-Drug Conjugate, in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Interim Futility Analysis of a Phase 2 Study of Loncastuximab Tesirine, a Novel Pyrrolobenzodiazepine-Based Antibody-Drug Conjugate, in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Safety and Anti-Tumor Activity Study of Loncastuximab Tesirine and Ibrutinib in Diffuse Large B-Cell or Mantle Cell Lymphoma

Introduction: Loncastuximab tesirine (Lonca) is an antibody-drug conjugate (ADC) comprising a humanized anti-CD19 antibody conjugated to a pyrrolobenzodiazepine dimer toxin. In a Phase 1, first-in-human study (ADCT-402-101), Lonca demonstrated single agent anti-tumor activity with manageable toxicity in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). Ibrutinib is a small-molecule inhibitor of Bruton's tyrosine kinase (BTK), a mediator of the B-cell-receptor signaling pathway implicated in the pathogenesis of B-cell cancers. BTK plays a crucial role in B-cell-receptor signaling, resulting in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. In vitro data show synergy between the two compounds, providing the rationale for studying them in combination. Study Design and Methods: This is a Phase 1b (ADCT-402-103; NCT03684694), open-label, dose escalation (Part 1) and expansion (Part 2) trial of Lonca combined with ibrutinib in patients with R/R DLBCL or MCL. The key inclusion and exclusion criteria for this study are reported in Table 1. This trial will evaluate the safety and tolerability, preliminary anti-tumor activity, pharmacokinetics, pharmacodynamics, and immunogenicity of this combination. Patients will receive Lonca once every 3 weeks for a total of 2 doses, and ibrutinib daily for up to 1 year. Patients with a partial response or stable disease at the second disease evaluation may receive 2 additional doses of lonca. During Part 1, the dose of Lonca will be escalated using a classic 3+3 design. The dose of ibrutinib will be fixed. Part 2 will consist of up to 2 expansion cohorts, one for each of the DLBCL and MCL populations. All patients in Part 2 will receive the dose of Lonca determined in Part 1, with a fixed dose of ibrutinib. The trial opened in February 2019 and recruitment is ongoing. Study sponsored by ADC Therapeutics SA, with the support of Pharmacyclics LLC, an AbbVie company, which supplies ibrutinib (http://clinicaltrials.gov/show/NCT03684694). Disclosures Ungar: ADC Therapeutics: Employment, Other: Stock options;equity interest. Dautaj:ADC Therapeutics: Employment, Other: Stock options. Wagner-Johnston:Jannsen: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Safety and Anti-Tumor Activity Study of Loncastuximab Tesirine and Durvalumab in Diffuse Large B-Cell, Mantle Cell, or Follicular Lymphoma

Introduction: Loncastuximab tesirine (Lonca) is an antibody-drug conjugate (ADC) comprising a humanized anti-CD19 antibody (Ab) conjugated to a pyrrolobenzodiazepine dimer toxin. In a Phase 1, first-in-human ADCT-402-101 clinical study, Lonca demonstrated single-agent anti-tumor activity with manageable toxicity in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and follicular lymphoma (FL). Durvalumab is a human monoclonal Ab of the immunoglobulin G-1 kappa subclass that blocks the interaction of programmed death-ligand 1 (PD-L1) with PD-1 on T-cells and with CD80 (B7.1) on other immune cells. Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, including those that may result in tumor elimination. Preclinical data, as well as early results from clinical trials combining ADCs and checkpoint inhibitors, show potentially increased effectiveness of these therapeutics when used in combination and provide the rationale for the current trial. Study Design and Methods: This is a Phase 1b, open-label, dose escalation (Part 1) and expansion (Part 2) trial of Lonca combined with durvalumab in patients with R/R DLBCL, MCL, or FL (NCT03685344). The key inclusion and exclusion criteria for the ADCT-402-104 study are reported in Table 1, and the dosing schema is presented in Figure 1. This trial will evaluate the safety and tolerability, preliminary anti-tumor activity, pharmacokinetics, pharmacodynamics, and immunogenicity of Lonca combined with durvalumab. Patients will receive Lonca once every 3 weeks for 2 doses in total, and durvalumab every 4 weeks for up to 1 year. Patients with only partial response or stable disease at the second disease evaluation may receive 2 additional doses of Lonca given once every 3 weeks. During Part 1, the dose of Lonca will be escalated using a classic 3+3 design with a fixed dose of durvalumab. Part 2 will consist of up to 3 expansion cohorts, one for each of the DLBCL, MCL, and FL populations. All patients in Part 2 will receive the dose of Lonca determined in Part 1, with a fixed dose of durvalumab. The trial opened in February 2019 and recruitment is ongoing. Study sponsored by ADC Therapeutics SA with the support of MedImmune Limited, a wholly-owned subsidiary of AstraZeneca Pharmaceuticals PLC, which supplies durvalumab (http://clinicaltrials.gov/show/NCT03685344). Disclosures Moskowitz: ADC Therapeutics: Research Funding; Merck: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Ungar:ADC Therapeutics: Employment, Other: Stock options. equity interest. Dautaj:ADC Therapeutics: Employment, Other: Stock options.

Pre-Clinical Development of Adct-402, a Novel Pyrrolobenzodiazepine (PBD)-Based Antibody Drug Conjugate (ADC) Targeting CD19-Expressing B-Cell Malignancies

Human CD19 antigen is a 95 kilodalton type I transmembrane glycoprotein belonging to the immunoglobulin superfamily (Wang, Wei, & Liu, 2012). The role of CD19, both in health and disease, is well studied, and the therapeutic efficacy and safety of CD19 modulation have been well defined over several decades (Scheuermann & Racila, 1995). In normal human tissue, expression of CD19 is limited to the various stages of B-cell development and differentiation (except plasma cells) and its expression is maintained on the majority of B-cell malignancies, including B-cell leukemia and non-Hodgkin lymphomas of B-cell origin. CD19 has rapid internalization kinetics and it is not shed into the circulation (Blanc et al., 2011; Gerber et al., 2009). All these features make CD19 an attractive target for the development of an ADC to treat B-cell malignancies.ADCT-402 is an ADC composed of a humanized antibody directed against human CD19, stochastically conjugated via a valine-alanine cleavable, maleimide linker to a PBD dimer cytotoxin. PBD dimers are highly efficient anticancer drugs that covalently bind in the minor groove of DNA and form cytotoxic DNA interstrand cross-links. The average drug to antibody ratio of ADCT-402 is 2.3 ± 0.3, as shown by hydrophobic interaction chromatography and reverse-phase HPLC.In vitro, ADCT-402 demonstrated potent cytotoxicity in a panel of human-derived cell lines of differing levels of CD19, while its potency was strongly reduced in CD19-negative cell lines.In vivo, ADCT-402 demonstrated dose-dependent anti-tumor activity in a subcutaneously implanted human Burkitt's lymphoma-derived Ramos xenograft model, where a single dose at 0.33 mg/kg induced significantly delayed tumor growth compared to the vehicle-treated mice and at 0.66 mg/kg and 1 mg/kg gave 4/10 and 10/10 tumor-free survivors, respectively. In the same model, ADCT-402 showed remarkably superior anti-tumor activity compared to both maytansinoid- and auristatin-based CD19-targeting ADCs, when they were tested at the same dose and schedule (1 mg/kg, single dose). Moreover, ADCT-402 mediated an impressive increase in survival compared to both vehicle-treated and isotype control ADC-treated mice in the disseminated Ramos xenograft model when tested as a single dose at 0.33 mg/kg or 1 mg/kg. For example, a single dose of ADCT-402 at 1 mg/kg resulted in 10/10 survivors at day 91, while there were 0/10 survivors at day 19 in the group of animals treated with either the vehicle control or with a single dose of the non-binding, control ADC at 1 mg/kg.In rat, a single dose of ADCT-402 at 2 mg/kg was well tolerated with no adverse signs or hematologic effects.Altogether, these data show the potent and specific anti-tumor activity of ADCT-402 against CD19-expressing B-cell malignancies, both in vitro and in vivo, and warrant further development of this ADC into the clinic. DisclosuresZammarchi:ADC Therapeutics: Employment. Williams:Spirogen/Medimmune: Employment. Adams:Spirogen/Medimmune: Employment, Equity Ownership. Havenith:ADC Therapeutics: Employment. Chivers:ADC Therapeutics: Employment. D'Hooge:Spirogen/Medimmune: Employment, Equity Ownership. Howard:ADCT Spirogen/Medimmune: Employment, Equity Ownership, Patents & Royalties. Hartley:ADCT Spirogen/Medimmune: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. van Berkel:ADC Therapeutics: Employment, Equity Ownership, Patents & Royalties.

Abstract 2645: Advantages of polyacetal polymer-based ADCs: Application to low expression targets

Abstract The application of biodegradable polymers to antibody-drug conjugate (ADC) design can provide numerous advantages, including significantly higher drug-antibody ratios, the use of alternative payloads with potencies considered insufficient for direct conjugation, the improvement of ADC physico-chemical properties, especially for highly hydrophobic payloads, and the potential expansion of protein recognition scaffolds beyond the commonly used IgGs. The basis of the novel polymer-based conjugation system described herein is a hydrophilic, fully biodegradable polyacetal carrier, (poly(1-hydroxymethylethylene hydroxymethylformal) or PHF) modified with chemically orthogonal linkers. A bioconjugation linker is used for efficient covalent attachment of a targeting moiety to the PHF scaffold, while a second, chemically distinct linker is used to attach multiple copies of a drug payload to the polymer to control the mechanism and rate of drug release. Utilizing multiple copies of a proprietary dolastatin derivative chemically conjugated to PHF, we have developed a potent and effective drug conjugation platform for ADC application, which has been named Dolaflexin™. Here, we report the preparation and characterization of a novel trastuzumab DolaflexinTM ADC, employing a maleimide-based bioconjugation approach. The resulting ADC, with a drug-antibody ratio of 20, exhibits enhanced stability and improved pharmacokinetics, with a prolonged plasma half-life and tumor-specific accumulation. Active drug release and accumulation in tumor tissue was also confirmed by LC/MS/MS methods. The activity of this novel trastuzumab-dolaflexin ADC was evaluated in multiple tumor xenograft models with significant variations in target antigen expression levels. Models including BT474 breast cancer, NCI-N87 gastric cancer, and JIMT1 breast cancer models were utilized, and comparisons to a variety of controls and ADC reference standards were made. Significant advantages of the polyacetal polymer-based ADCs in comparison to conventional ADCs, particularly in models with low target antigen expression, were observed. Details of these studies and potential applications for the development of new ADC therapeutics based on this approach will be presented. Citation Format: Alex Yurkovetskiy, Natalya Bodyak, Mao Yin, Joshua D. Thomas, Patrick Conlon, Cheri A. Stevenson, Alex Uttard, LiuLiang Qin, Dmitry R. Gumerov, Elena Ter-Ovaneysan, Venu R. Gurijala, Dennis McGillicuddy, Roberta E. Glynn, Michael DeVit, Laura L. Poling, Peter U. Park, Timothy B. Lowinger. Advantages of polyacetal polymer-based ADCs: Application to low expression targets. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2645. doi:10.1158/1538-7445.AM2014-2645