A Phase I Study of DCDT2980S, an Antibody-Drug Conjugate (ADC) Targeting CD22, in Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma (NHL)

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.

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.

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.

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.

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.