Final Results Of a Phase I Study Of The Anti-CD79b Antibody-Drug Conjugate DCDS4501A In Relapsed Or Refractory (R/R) B-Cell Non-Hodgkin Lymphoma (NHL)
Authors: Palanca-Wessels Maria Corinna , Salles Gilles Andre , Czuczman Myron S. , Assouline Sarit E. , Flinn Ian W. , Sehn Laurie H. , Patel Manish , Sangha Randeep , Tilly Herve , Advani Ranjana , Casasnovas Olivier , Press Oliver W. , Yalamanchili Sreeni , Kahn Robert , Lu Dan , Chai Akiko , Chu Yu-Waye , Morschhauser Franck 
Published: October 2019

Abstract

Background
DCDS4501A (DCDS), an anti-CD79b monoclonal antibody (Ab), is conjugated to the anti-mitotic agent MMAE. We previously determined a recommended Phase II dose (RP2D) of 2.4 mg/kg every 21 days (q21d), and clinical activity in R/R B-cell NHL at doses ≥ 1.8 mg/kg (Palanca-Wessels et al. ASH 2012). Here we update results from patients (pts) treated at 1.8 mg/kg and from the 2.4 mg/kg expansion cohort.

Methods
We evaluated ongoing safety, tolerability, pharmacokinetics (PK) and activity of DCDS with or without rituximab (RTX) at 375 mg/m2 q21d in pts with R/R DLBCL and indolent (i)NHL.

Results
Sixty pts were treated with DCDS (6 at 1.8 mg/kg, 45 at 2.4 mg/kg) and DCDS+RTX (9, DCDS at 2.4 mg/kg). Median age 68 yrs (range 20-86); 82% ECOG PS<2; median 4 prior regimens (range 1-14); 97% had prior RTX; 28% had prior autologous stem cell transplant. The DCDS+RTX safety profile did not differ from DCDS monotherapy. Patients received a median of 7 cycles (range 1-20) of DCDS and 10 cycles (range 1-17) of DCDS + RTX; 18 patients continue to receive study treatment. Treatment-emergent adverse events (TEAEs) included neutropenia (50%), diarrhea (45%), nausea (40%), pyrexia (38%), peripheral neuropathy (25%), peripheral sensory neuropathy (20%), and hypokalemia (20%). Grade ≥ 3 AEs in ≥5% of pts included neutropenia (43%), anemia (13%), thrombocytopenia (7%), hyperglycemia (7%), fatigue (5%) and diarrhea (5%). Grade ≥ 3 infection was reported in 8 (13%) pts. Twenty-two (37%) pts reported a serious AE. TEAEs related to peripheral neuropathy (PN) were reported in 32 (53%) pts with median time to first onset of 63 days. 22/32 pts (69%) had worsening PN with median time to worsening of 49 days. Grade ≥ 3 peripheral neuropathy/peripheral sensory neuropathy/peripheral motor neuropathy was reported in 5 (8%) patients. PN was managed with dose delays and dose reductions resulting in complete reversal in 7 (22%) pts. Treatment discontinuations for AEs were reported in 25 (42%) pts including 17 for PN. Seven pts (12%) had ≥ 1 dose reduction including 3 for PN and 2 for neutropenia. Twenty-six patients (43%) had ≥ 1 dose delay including 14 for neutropenia and 6 for PN. Six deaths were reported within 60 days of last study treatment assessed as unrelated to DCDS. Exposure of Ab-conjugated (ac) MMAE, total Ab, and unconjugated MMAE increased with dose. Maximal concentrations of unconjugated MMAE were >100-fold lower than acMMAE with an average Cycle 1 value of 5-9 ng/mL at the 2.4 mg/kg ADC dose level. Moderate accumulation of acMMAE and total Ab on the q21d dosing schedule was observed with no accumulation of free MMAE. Overall objective responses were observed in 27/51 (53%) DCDS and 7/9 (78%) DCDS+RTX pts. Objective (OR) and complete responses (CR) by histology were as follows:
The median PFS for DLBCL patients treated with DCDS or DCDS + RTX was 149 days. The median PFS for iNHL patients treated with DCDS or DCDS + RTX was 241 days.

Conclusions
DCDS and DCDS+RTX were generally well-tolerated. Neutropenia and PN were the principal toxicities. PN was reversible in some patients with dose delays and reductions. Encouraging anti-tumor activity was observed in heavily pretreated pts with R/R NHL. Updated results from this Phase I study will be presented. An ongoing randomized Phase II study of DCDS+RTX versus a CD22-directed ADC (DCDT2980S) with the same linker-cytotoxic agent in patients with R/R DLBCL and follicular lymphoma will further assess the efficacy of DCDS in the treatment of NHL. Additional studies of DCDS combined with immunochemotherapy are being planned.

Disclosures:
Palanca-Wessels: Genentech, inc.: Research Funding. Off Label Use: anti-CD79b Antibody-Drug Conjugate in r/r B-cell NHL. Salles:Genentech, inc.: Consultancy. Czuczman:Genentech, inc.: Consultancy, Honoraria. Flinn:Genentech, inc.: Research Funding. Sehn:Genentech, inc.: Consultancy, Honoraria, Research Funding. Tilly:Genentech, inc.: Honoraria. Advani:Genentech, inc.: Research Funding. Casasnovas:Genentech, inc.: Research Funding. Press:Genentech, inc.: Consultancy, Research Funding. Yalamanchili:Genentech, inc.: Employment. Kahn:Genentech, inc.: Employment. Lu:Genentech, inc.: Employment. Chai:Genentech, inc.: Employment. Chu:Genentech, inc.: Employment. Morschhauser:Genentech, inc.: Honoraria, Research Funding.