A Phase 1 Study of Denintuzumab Mafodotin (SGN-CD19A) in Adults with Relapsed or Refractory B-Lineage Acute Leukemia (B-ALL) and Highly Aggressive Lymphoma

Abstract

Background Denintuzumab mafodotin (SGN-CD19A) is an antibody-drug conjugate (ADC) composed of a humanized anti-CD19 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin F (MMAF) via a maleimidocaproyl linker. CD19 is a B cell-specific marker that is expressed in nearly all patients (pts) with B-lineage acute leukemia or lymphoma. Methods A phase 1 dose-escalation study is ongoing to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of denintuzumab mafodotin in pts with relapsed or refractory (R/R) B-ALL, B-cell lymphoma (B-LBL), or Burkitt leukemia/lymphoma (NCT 01786096). Eligible pts are ≥1 year of age and are R/R to ≥1 prior systemic regimen; patients with Philadelphia chromosome-positive (Ph+) disease must have failed a 2nd-generation TKI. A modified continual reassessment method was used for dose allocation and maximum tolerated dose (MTD) estimation. The study evaluated 2 dosing schedules: first weekly (Days 1 and 8 of 21-day cycles) and then once every 3 weeks (q3wk). This report presents data from the adult subset of pts in the study (≥18 years). Results To date, 71 adult pts with R/R B-ALL (n=59), B-LBL (n=6) or Burkitt leukemia/lymphoma (n=6) have been treated; median age is 45 years (range 18−77). Pts received a median of 2 prior therapies (range 1−8); 20 pts (28%) had prior allogeneic stem cell transplant. On the weekly schedule (0.3−3 mg/kg), 40 pts received a median of 2 cycles (range 1−27); 2 pts remain on treatment. On the q3wk schedule (4−6 mg/kg), 31 pts received a median of 3 cycles (range 1−6); 4 pts remain on treatment. An MTD was identified at 5 mg/kg q3wk and was not reached with weekly dosing. Best clinical responses to date for pts with B-ALL are summarized below: Table 1.Response category per Cheson 2003Efficacy-evaluable adult pts with B-ALLweekly dosing, N=32 n (%)q3wk dosing, N=23 n (%)Complete remission (CR)6 (19)3 (13)CR with incomplete platelet recovery (CRp)−3 (13)CR with incomplete blood recovery (CRi)−2 (9)Partial remission (PR)1 (3)−Resistant disease with clinical benefit15 (47)12 (52)Resistant disease without clinical benefit2 (6)-Progression8 (25)3 (13)CRc (CR+CRi+CRp), % (95% CI)19% (95% CI 7, 36)35% (95% CI 16, 57) In the q3wk schedule, the CRc rate was similar at 4, 5, and 6 mg/kg. The median duration of response across schedules is currently 27 weeks (95% CI 7, −). Of 12 pts with CRc and available minimal residual disease (MRD) assessment, 7 were MRD negative. 3 patients with MRD-negative CRs have been in remission for >1 year, 2 of whom have been on continuous treatment for 19 and 22 months. In the subset of pts with Ph+ B-ALL, 4 of 8 pts achieved CR and 1 pt a PR. In 6 pts with Burkitt leukemia/lymphoma, 1 achieved a CR. In 6 pts with B-LBL, objective responses were 1 CR and 2 PR. The adverse event (AE) profiles were similar across both dosing schedules; the most frequently reported AEs were pyrexia (54%), nausea (52%), fatigue (51%), headache (44%), chills (38%), vomiting (37%), blurred vision (35%), and anemia (34%). Ocular symptoms and corneal exam findings consistent with superficial microcystic keratopathy were observed in 40 pts (56%); symptoms were less severe than the associated corneal exam findings. Keratopathy was managed with topical steroids and dose modifications, and improved/resolved within a median of ~3 wks (range 1-17) in pts with sufficient follow-up. ADC exposures increased with dose, and in leukemia patients, target-mediated disposition was observed that diminished with higher doses in the q3wk schedule. Post treatment, flow cytometry data demonstrate that unbound CD19 on peripheral blasts inversely correlates with ADC concentration in circulation, and is present in the majority of evaluable patients at the end of the q3wk cycle. Conclusions Denintuzumab mafodotin is generally well tolerated and demonstrates activity in heavily pretreated adult pts with B-ALL and B-lineage highly aggressive lymphomas, including durable MRD-negative responses. The results of this trial indicate that the q3wk schedule, with a CRc rate of 35% in B-ALL, warrants further clinical investigation. Based on the encouraging responses observed to date in Ph+ B-ALL (CRs in 4 of 8 pts), an expansion cohort of these pts is currently enrolling on the q3wk schedule. Disclosures Fathi: Exelexis: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy; Takeda Pharmaceuticals International Co.: Research Funding. Off Label Use: SGN-CD19A is an investigational agent being studied in patients with B-cell malignancies. SGN-CD19A is not approved for use.. Borate:Seattle Genetics: Research Funding; Genoptix: Consultancy; Alexion: Speakers Bureau; Gilead: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Speakers Bureau. DeAngelo:Agios: Consultancy; Incyte: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; Ariad: Consultancy; Novartis: Consultancy. O'Brien:Seattle Genetics, Inc.: Research Funding. Trippett:OSI Pharmaceuticals: Research Funding; Seattle Genetics, Inc.: Research Funding. Shah:NCCN: Consultancy; SWOG: Consultancy; Seattle Genetics: Research Funding; Acetylon Pharmaceuticals, INC: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Speakers Bureau; Bayer: Honoraria; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau; DeBartolo Institute for Personlaized Medicine: Research Funding; Rosetta Genomics: Research Funding; Plexus Communications: Honoraria; Spectrum: Speakers Bureau. Hale:Seattle Genetics, Inc.: Research Funding; Hyundai: Research Funding; V Foundation: Research Funding. Silverman:Seattle Genetics, Inc.: Research Funding. Pauly:Seattle Genetics, Inc.: Research Funding. Kim:Bayer: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding; Eli Lilly: Consultancy. Kostic:Seattle Genetics, Inc.: Employment, Equity Ownership. Huang:Seattle Genetics, Inc.: Employment, Equity Ownership. Pan:Seattle Genetics, Inc.: Employment, Equity Ownership. Chen:Genentech: Consultancy, Speakers Bureau; Seattle Genetics, Inc.: Consultancy, Other: Travel expenses, Research Funding, Speakers Bureau; Millennium: Consultancy, Research Funding, Speakers Bureau.

Driving Toward Precision Medicine for Acute Leukemias: Are We There Yet?

“…Targeted by an antibody-drug conjugate: gemtuzumab ozogamicin (since voluntarily withdrawn from the U.S. market in 2010, its use remains investigational, projected to be reintroduced back into U.S. market) Addition of gemtuzumab ozogamicin to intensive chemotherapy may be predictive for improved outcomes in CBF-AML (investigational) CD 19 (expressed ubiquitously in leukemic blasts of B-cell ALL) [99][100][101] Modulates B-cell activation and signaling; in vitro studies suggested that mechanisms of action include antibody-dependent cellular cytotoxicity and proliferation inhibition with cross linking Its ubiquity makes a convenient target of all developmental stages for B-cell ALL CD19-positive pre-B ALL can be targeted by:…”

“…98 Thus a therapeutic approach directed at modulating acetylation is of potential interest in ALL. Table 5 provides a synopsis of monoclonal antibodies targeting leukemic surface antigens that have regulatory approval as well as key investigational agents: CD33, 65, 66 CD19, [99][100][101] CD20, 102-104 CD22, [105][106][107] and CD52. [108][109][110][111] Of note, rituximab requires the combination with conventional chemotherapy for efficacy, whereas others may be given as a single agent.…”

Preclinical activity of the antibody‐drug conjugate denintuzumab mafodotin (SGN‐CD19A) against pediatric acute lymphoblastic leukemia xenografts

“…45 By contrast, approximately 20% of more than 100 patients with relapsed/refractory ALL achieved complete response (with or without platelet recovery) to denintuzumab mafodotin. 15,37 This lack of clinical success against ALL for ADCs with tubulin-targeted payloads raises questions about CD19 targeting using an ADC therapeutic strategy for this patient population. Does the lack of clinical activity comparable to that of other ALL immunotherapy approaches indicate that CD19 is a poorer target for ADCs compared to other lymphoid surface antigens possibly due to less efficient CD19 internalization compared with, for example, CD22?…”

“…12 Therefore, CD19-directed therapies offer enormous clinical potential regardless of disease subtype, as evidenced by the clinical success of CD19-specific chimeric antigen receptor T cells and the bispecific T-cell engager (BiTE) blinatumomab. [13][14][15][16] The ADC denintuzumab mafodotin (SGN-CD19A), comprising a humanized anti-CD19 monoclonal antibody (mAb) conjugated to the antimitotic agent monomethyl auristatin F, showed promising results in early clinical trials. In a dose-escalation study assessing weekly (0.3-3 mg/kg) and 3-weekly (4-6 mg/kg) dosing schedules, nine of 55 evaluable adult B-ALL patients achieved complete remission (CR), three achieved CR with incomplete platelet recovery (CRp), three achieved CR with incomplete blood recovery (CRi), and one achieved a partial remission (PR).…”

“…In a dose-escalation study assessing weekly (0.3-3 mg/kg) and 3-weekly (4-6 mg/kg) dosing schedules, nine of 55 evaluable adult B-ALL patients achieved complete remission (CR), three achieved CR with incomplete platelet recovery (CRp), three achieved CR with incomplete blood recovery (CRi), and one achieved a partial remission (PR). 15 Therefore, it was of interest for the Pediatric Preclinical Testing Program (PPTP) to assess the activity of denintuzumab mafodotin against CD19 + pediatric ALL patient-derived xenografts (PDXs). Eight PDXs were selected to represent diverse high-risk B-ALL subtypes, including Philadelphia chromosome-positive (Ph + )-ALL, Philadelphia chromosome-positive-like (Ph-like) ALL, and mixed-lineage leukemia (MLL)-rearranged infant ALL (MLLr-ALL).…”