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

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:

Response category per Cheson 2003	Efficacy-evaluable adult pts with B-ALL
	weekly 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 benefit	15 (47)	12 (52)
Resistant disease without clinical benefit	2 (6)	-
Progression	8 (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.