A Phase I Study of DCDT2980S, an Antibody-Drug Conjugate (ADC) Targeting CD22, in Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma (NHL)
Authors: Advani Ranjana , Lebovic Daniel , Brunvand Mark , Chen Andy I. , Goy Andre , Chang Julie E. , Maeda Lauren S , Ho William , Kahn Robert , Lu Dan , Su Zheng , Chu Yu-Waye , Cheson Bruce D. 
Published: October 2019

Abstract
Abstract 59

Introduction:
CD22 is a lineage marker expressed in most B-cell lymphomas. DCDT2980S is an ADC consisting of an anti-CD22 monoclonal antibody conjugated to monomethyl auristatin E (MMAE), a potent microtubule disrupting agent linked to the antibody via a protease-cleavable peptide linker. DCDT2980S exhibits potent anti-tumor activity in murine xenograft models of B-cell lymphoma and is being evaluated in a Phase I study to assess the safety, tolerability, pharmacokinetics (PK), and biologic activity in patients (pts) with relapsed/refractory B-cell NHL.

Methods:
Pts receive DCDT2980S intravenously every 21 days at dose levels 0.1 to 3.2 mg/kg until disease progression or unacceptable toxicity. Intrapatient dose escalation based on tolerability at higher doses is permitted. Following determination of the recommended Phase II dose (RP2D) based on protocol-defined dose-limiting toxicities (DLTs) occurring within 21 days of dosing, additional pts with indolent and aggressive B-cell NHL are being enrolled to further evaluate safety and efficacy based on Cheson response criteria. Here we report the RP2D and preliminary safety and efficacy results.

Results:
To date, 35 pts (57% male), median age 66 years (range 30–85) have been enrolled: diffuse large B-cell lymphoma (DLBCL, n=18), follicular lymphoma (FL, n=11), transformed FL (n=4), and small lymphocytic lymphoma (n=2). Enrolled patients were heavily pre-treated: 26 pts had received ≥ 3 prior regimens, all pts had received prior rituximab, and 7 pts received prior high-dose therapy followed autologous or allogenic stem cell transplantation. Overall, pts received a median of 4 doses (range 1–25) of DCDT2980S in 7 dose-escalation cohorts, and 2 expansion cohorts at the RP2D. All 3 pts treated with DCDT2980S at 3.2 mg/kg developed Grade 4 neutropenia following the first dose, one of which constituted a DLT. No DLTs were reported in the 6 pts treated at 2.4 mg/kg, which is the RP2D. Across all dose levels, the most common treatment-emergent adverse events (AE) in ≥ 20% of pts were diarrhea (34%), fatigue (34%), nausea (31%), neutropenia (26%), decreased appetite (23%), vomiting (23%), and peripheral edema (20%). Treatment-emergent Grade ≥ 3 AEs were reported in 9 (27%) pts including 5 out of 9 pts who were treated at the RP2D of 2.4 mg/kg. Overall, neutropenia (24%) was the only Grade ≥ 3 AE in ≥ 10% of pts (24%) and was the only Grade ≥ 3 AE reported in > 1 pt (n=2) treated at the RP2D. Eight (26%) pts across all dose levels experienced a serious AE (SAE) of which one Grade 3 dehydration in a pt treated at 3.2 mg/kg was attributed to DCDT2980S. Treatment discontinuation due to AEs occurred in 3 pts: Grade 3 neutropenia (n=1) and Grade 3 peripheral sensory neuropathy (n=2). No deaths were reported within 30 days of the last dose of DCDT2980S. Assessment of Cycle 1 PK after the first dose of DCDT2980S indicated that the exposure of antibody-conjugated MMAE (acMMAE), total antibody, and free MMAE increased with dose. The clearance estimates of both acMMAE and total antibody were similar across doses from 1.0–3.2 mg/kg. The volume of distribution estimates for acMMAE and total antibody approximated plasma volume and did not change with dose and suggest dose-proportional increase of acMMAE and total antibody exposures for doses of 1.0–3.2 mg/kg. Early evidence of anti-tumor activity was observed. At the RP2D of 2.4 mg/kg, 2 of 3 pts with DLBCL had > 75% reduction in tumor sum of perpendicular dimensions (SPD) and negative PET scans; 1 partial response was noted in a pt with FL treated at 1.8 mg/kg. These 3 pts continue on study, each having received at least 8 cycles of study treatment. Two additional pts with DLBCL receiving 0.5 mg/kg and 3.2–2.4 mg/kg had > 50% reduction in tumor SPD and discontinued study treatment after 8 and 6 cycles, respectively, to undergo stem cell transplant.

Conclusions:
In this early experience, DCDT2980S is well tolerated, has a favorable safety profile and has evidence of anti-tumor activity in in a heavily pretreated pts with relapsed/refractory B-cell NHL. Updated clinical data will be presented. These results support additional clinical evaluation of DCDT2980S in B-cell malignancies.

Disclosures:
Advani: Genentech: Research Funding. Off Label Use: anti-CD79b Antibody-Drug Conjugate (ADC) DCDS4501A. Lebovic:Genentech: Speakers Bureau. Brunvand:Genentech: Speakers Bureau. Chen:Genentech: Research Funding. Chang:Genentech: Research Funding. Ho:Genentech: Employment. Kahn:Genentech: Employment. Lu:Genentech: Employment. Su:Genentech: Employment. Chu:Genentech: Employment.