Final Results Of a Phase I Study Of The Anti-CD22 Antibody-Drug Conjugate (ADC) DCDT2980S With Or Without Rituximab (RTX) In Patients (Pts) With Relapsed Or Refractory (R/R) B-Cell Non-Hodgkin’s Lymphoma (NHL)
Authors: Advani Ranjana , Chen Andy I. , Lebovic Daniel , Brunvand Mark W. , Goy Andre , Chang Julie E. , Hochberg Ephraim , Yalamanchili Sreeni , Kahn Robert , Lu Dan , Chai Akiko , Chu Yu-Waye , Cheson Bruce D. 
Published: October 2019

Abstract

Background
DCDT2980S (DCDT) is an anti-CD22 monoclonal antibody (Ab) conjugated to MMAE, a potent anti-microtubule inhibitor. We have previously reported clinical activity and acceptable toxicity in pts with R/R B-cell NHL treated at DCDT doses of 1.8 and 2.4 mg/kg. The maximum tolerated dose (MTD) was defined as 2.4 mg/kg either as a single agent or in combination with RTX (375 mg/m2) every 21 days (q21d) (Advani et al. ASH 2012, abstract 59). In this report, we provide updated results from pts treated at 1.8 mg/kg as well as an expanded cohort treated at 2.4 mg/kg.

Methods
We evaluated safety, tolerability, pharmacokinetics (PK), and activity of DCDT q21d with or without RTX (375 mg/m2) in pts with R/R B-cell NHL. Expanded cohorts of pts with R/R diffuse large cell lymphoma (DLBCL) or indolent (i)NHL were evaluated at the single-agent MTD of 2.4 mg/kg q21d.

Results
Forty-six pts enrolled in DCDT ≥ 1.8 mg/kg (7 at 1.8 mg/kg, 39 at 2.4 mg/kg) and 16 in the DCDT+RTX cohort (5 at 1.8 mg/kg, 11 at 2.4 mg/kg). Median age was 66 yrs; 92% had an ECOG PS<2; median of 3 prior regimens (range 1-11); 100% prior RTX, 8% prior stem cell transplant. Patients received a median of 5 cycles (range 1, 24) of DCDT and 6 cycles (range 1, 15) of DCDT + RTX; 7 patients continue to receive study treatment. The DCDT+RTX safety profile did not differ from DCDT monotherapy and toxicities were mostly Grade 1-2. Grade ≥ 3 treatment-emergent adverse events (TEAEs) in ≥5% of pts included neutropenia (26%), hyperglycemia (10%), peripheral sensory neuropathy (10%), fatigue (5%), and diarrhea (5%). Febrile neutropenia and Grade 3-4 infection occurred in 1 pt and 7 pts respectively. The median time to first onset peripheral neuropathy (PN) was 50 days. Worsening PN (at least one grade increase) occurred in 18/33 pts (55%) with median time to worsening of 48 days. PN was managed with dose delays and dose reductions resulting in complete reversal in 5 (15%) pts. Serious AEs were seen in 37% of pts, the most common (≥ 3 pts) included pyrexia (3), pneumonia (3) and dyspnea (3). Treatment discontinuations for AEs were reported in 16 (26%) pts including 12 for peripheral neuropathy. Twenty-four pts (39%) had at least one dose delay including 10 for neutropenia and 5 for peripheral neuropathy. Twelve pts (19%) had at least one dose reduction including 8 for peripheral neuropathy and 7 for neutropenia. Three deaths occurring within 60 days of the last dose of DCDT judged unrelated to DCDT were reported. 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 average Cycle 1 value of 5-7 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. Concurrent RTX administration did not impact DCDT PK. Overall objective responses were observed in 19/46 (41%) DCDT and 5/16 (31%) DCDT+RTX pts. Objective (OR) and complete responses (CR) by histology were as follows:
The median PFS for DLBCL patients treated with DCDT or DCDT + RTX was 115 days. The median PFS for iNHL patients treated with DCDT or DCDT + RTX was 227 days.

Conclusions
DCDT alone or combined with RTX was generally well-tolerated. PN and neutropenia are the principal toxicities associated with DCDT. PN was reversible in some patients with dose delays and reductions. Encouraging antitumor activity was observed in heavily pre-treated pts with R/R NHL. Updated results from this Phase I study will be presented. The addition of rituximab does not appear to enhance the efficacy of DCDT based on the small number of patients treated with the combination and continues to be evaluated in an ongoing randomized Phase II study in patients with R/R DLBCL and FL of DCDT+RTX versus a CD79b-directed ADC (DCDS4501A) with the same linker-cytotoxic agent. Additional studies of DCDT combined with immunochemotherapy are planned.

Disclosures:
Advani: Genentech, inc.: Research Funding. Off Label Use: Anti-CD22 Antibody-Drug Conjugate. Chen:Genentech, inc.: Consultancy, Research Funding. Lebovic:Genentech, inc.: Speakers Bureau. Brunvand:Genentech, inc.: Speakers Bureau. Goy:Genentech, inc.: Research Funding. Chang:Genentech, inc.: Research Funding. Hochberg:Genentech, inc.: Consultancy. Yalamanchili:Genentech, inc.: Employment. Kahn:Genentech, inc.: Employment. Lu:Genentech, inc.: Employment. Chai:Genentech, inc.: Employment. Chu:Genentech, inc.: Employment.