A Phase I Study of the Anti-CD79b Antibody-Drug Conjugate (ADC) DCDS4501A Targeting CD79b in Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma (NHL) (2012)

Abstract Abstract 56 Introduction: CD79b, a component of the B-cell receptor (BCR), is expressed by nearly all B-cell malignancies including NHL. DCDS4501A is an ADC consisting of an anti-CD79b monoclonal antibody conjugated to monomethyl auristatin E (MMAE), a microtubule disrupting agent via a protease-cleavable peptide linker. DCDS4501A exhibits potent anti-tumor activity in murine xenograft models of B-cell lymphoma. Methods: A Phase I study of DCDS4501A is being conducted to assess the safety, tolerability, pharmacokinetics (PK), and biologic activity of escalating doses of DCDS4501A in pts with relapsed/refractory B-cell NHL. Pts receive DCDS4501A intravenously every 21 days 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 will be 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, 33 pts have been enrolled (64% male), median age of 65 years (range 20–85): follicular lymphoma (FL, n=14), diffuse large B-cell lymphoma (DLBCL, n=11), MCL (n=4), MZL (n=2), transformed FL (n=1), and small lymphocytic lymphoma (SLL, n=1). Enrolled patients were heavily pre-treated: 29 patients had ≥ 3 prior regimens, all pts had received prior rituximab, and 9 pts received prior high-dose therapy followed by stem cell transplantation. Pts received a median of 3 doses (range 1–12) of DCDS4501A in 6 dose-escalation cohorts with doses ranging from 0.1–2.4 mg/kg. The protocol-specified MTD was not formally reached, however, 2.4 mg/kg DCDS4501A was determined to be the RP2D based on the overall safety and tolerability profile at that dose, which included 1 pt with a DLT of Grade 4 febrile neutropenia and pneumonia. The most common treatment-emergent adverse events (AE) occurring in ≥ 20% of pts were neutropenia (59%), diarrhea (38%), nausea (34%), hyperglycemia (31%), fatigue (31%), constipation (28%), peripheral neuropathy (28%), pyrexia (28%), leukopenia (25%), chills (22%), and cough (22%). Neutropenia (39%) and leukopenia (12%) were the only treatment-emergent Grade ≥ 3 AEs in ≥ 10% of pts. Seven of 12 pts treated at the RP2D of 2.4 mg/kg experienced a Grade 3–4 AE: Grade 3–4 neutropenia in 5 pts, and anemia, leukopenia and fatigue each in 2 pts. Eight (24%) pts across all dose levels experienced a serious AE (SAE). Four SAEs were reported in 2 pts treated at the RP2D of 2.4 mg/kg: 1 pt with atrial fibrillation, neutropenia, and pneumonia and 1 pt with cardiac failure; in both cases the SAE resolved and study treatment resumed. Treatment discontinuation due to AE occurred in 1 pt each for Grade 3 neutropenia and Grade 3 hyponatremia. One pt had a dose reduction for Grade 4 febrile neutropenia and pneumonia. No deaths were reported within 30 days of the last dose of DCDS4501A. Most cases of neutropenia were observed in the absence of growth factor support. Assessment of Cycle 1 PK after the first dose of DCDS4501A indicated that exposure of antibody-conjugated MMAE (acMMAE), total antibody, and free MMAE, increased with dose. The clearance estimates of acMMAE and total antibody were similar across doses from 0.1–2.4 mg/kg; volume of distribution estimates of acMMAE and total antibody approximated plasma volume, which also did not change with dose. These results suggested dose proportional increase of acMMAE and total antibody exposures. Early evidence of anti-tumor activity was observed, including 5 pts with &gt; 50% reduction in target lesion burden at the first on-treatment tumor assessment after 3–4 cycles of treatment: 2 with FL, and 1 each with DLBCL, transformed FL, and MCL; 4 pts continue on treatment with DCDS4501A (range 5–12 cycles). Two of four pts treated at 2.4 mg/kg evaluable for anti-tumor activity to date had &gt; 80% reduction in target lesion burden at the first on-treatment tumor assessment. Conclusions: DCDS4501A, a novel ADC targeting CD79b, has demonstrated an acceptable toxicity profile and encouraging anti-tumor activity in heavily pretreated pts with relapsed/refractory B-cell NHL. Updated clinical data will be presented. These results support additional clinical evaluation of DCDS4501A in B-cell malignancies. Disclosures: Palanca-Wessels: Genentech: Research Funding. Off Label Use: anti-CD79b Antibody-Drug Conjugate (ADC) DCDS4501A. Salles:roche: Consultancy. Morschhauser:Genentech: Honoraria. Advani:Genentech: Research Funding. Press:g: Consultancy. Ho:Genentech: Employment. Kahn:Genentech: Employment. Lu:Genentech: Employment. Su:Genentech: Employment. Chu:Genentech: Employment.