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

Background

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). 

Methods

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.

Results

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).

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). 

	Q3wk Dosing (N=51)		Q6wk Dosing (N=9)
	Relapseda N=22	Refractoryb N=29	Relapseda N=3	Refractoryb N=6
Best 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)
Progression	5 (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 rate

a  Best response of CR/PR with most recent prior therapy

b  Best response of SD/PD with most recent prior therapy

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.   

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. 

Conclusions

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.