A Phase 1 Study of Denintuzumab Mafodotin (SGN-CD19A) in Relapsed/Refactory B-Lineage Non-Hodgkin Lymphoma

<jats:title>Abstract</jats:title> <jats:p>Background</jats:p> <jats:p>Denintuzumab mafodotin (SGN-CD19A) is a novel 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 expressed in the vast majority of patients (pts) with B-cell non-Hodgkin lymphoma (NHL).</jats:p> <jats:p>Methods</jats:p> <jats:p>An ongoing phase 1, dose-escalation study is investigating the safety, tolerability, pharmacokinetics (PK), and antitumor activity of denintuzumab mafodotin in pts with relapsed or refractory (R/R) B-cell NHL (NCT 01786135). Eligible pts were ≥12 yrs of age and were R/R to ≥1 prior systemic regimens; pts with diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma grade 3 (FL3) also received intensive salvage therapy ± autologous stem cell transplant (ASCT), unless they refused or were ineligible. Denintuzumab mafodotin was administered IV every 3 weeks (q3wk; 0.5-6 mg/kg) for dose escalation and every 6 weeks (q6wk; 3 mg/kg) in a subsequent expansion cohort. A modified continual reassessment method was used for dose allocation and maximum tolerated dose (MTD) estimation in the q3wk dosing schedule. Archived tissue was collected to assess potential biomarkers of response.</jats:p> <jats:p>Results</jats:p> <jats:p>To date, 62 pts have been treated, including 53 pts (85%) with DLBCL (of whom 16 had transformed DLBCL), 5 (8%) with mantle cell lymphoma, and 3 (5%) with FL3. Median age was 65 yrs (range, 28-81). Pts had received a median of 2 prior systemic therapies (range, 1-6); 15 pts (24%) had prior ASCT. Thirty-seven pts (60%) were refractory to the most recent prior therapy. Fifty-two pts were treated in the q3wk schedule (0.5-6 mg/kg), and 10 pts were treated with 3 mg/kg q6wk. Five pts remain on treatment (2 q3wk pts, 3 q6wk pts).</jats:p> <jats:p>Overall, 20 (33%) of 60 efficacy-evaluable pts achieved objective responses, including 13 (22%) with CRs. Eighteen of the 20 objective responses were achieved by the end of Cycle 2 (15 q3wk pts, 3 q6wk pts). Table.Q3wk Dosing (N=51)Q6wk Dosing (N=9)RelapsedaN=22RefractorybN=29RelapsedaN=3RefractorybN=6Best clinical response, n (%)Complete remission (CR)7 (32)3 (10)3 (100)-Partial remission (PR)4 (18)3 (10)--Stable disease (SD)6 (27)7 (24)-3 (50)Progression5 (23)16 (55)-3 (50)ORR (CR+PR), % (95% CI)50 (28, 72)21 (8, 40)100 (29, 100)-CR rate, % (95% CI)32 (14,55)10 (2, 27)100 (29, 100)-ORR=objective response rateaBest response of CR/PR with most recent prior therapybBest response of SD/PD with most recent prior therapy</jats:p> <jats:p>Median duration of objective response in the q3wk schedule was 39 wks for relapsed pts (95% CI: 11.6, - [range, 0.1+ to 73+ wks]) and 41 wks for refractory pts (95% CI: 13.7, 67 [range, 13.7 to 67 wks]); this included 2 pts who maintained their responses for >15 mos. Data for the q6wk schedule are not yet mature.</jats:p> <jats:p>The MTD was not reached at 0.5-6 mg/kg q3wk, and only 1 DLT was observed (G3 keratopathy at 3 mg/kg). Toxicity profiles were similar across both dosing schedules; the most frequently reported adverse events (AEs) were blurry vision (65%), dry eye (52%), fatigue and keratopathy (35% each), constipation (29%), photophobia (27%), and nausea (26%). Ocular symptoms and corneal exam findings consistent with superficial microcystic keratopathy were observed in 52 pts (84%); 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 ~5 wks (range, 1-17) in pts for whom there was sufficient follow-up. ADC PK demonstrated a mean terminal half-life of ~2 wks, and accumulation was observed following multiple dose administrations in both schedules.</jats:p> <jats:p>Conclusions</jats:p> <jats:p>Denintuzumab mafodotin is generally well tolerated and demonstrates encouraging activity with durable responses in heavily pre-treated pts with B-cell NHL. In relapsed pts, 56% achieved objective responses with a CR rate of 40% across both the q3wk and q6wk schedules. The low rate of myelosuppression and neuropathy suggests that denintuzumab mafodotin could be incorporated into novel combination regimens in earlier lines of therapy. A randomized phase 2 trial is being initiated to evaluate RICE (rituximab, ifosfamide, carboplatin, etoposide) ± denintuzumab mafodotin pre-ASCT as second-line treatment for pts with DLBCL.</jats:p> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>Moskowitz: Seattle Genetics, Inc.: Consultancy, Research Funding; Merck: Research Funding; Genentech: Research Funding. Off Label Use: Denintuzumab ma ...