Phase I Study of the Anti-CD22 Antibody–Drug Conjugate Pinatuzumab Vedotin with/without Rituximab in Patients with Relapsed/Refractory B-cell Non-Hodgkin Lymphoma

Abstract

Purpose Pinatuzumab vedotin is an antibody–drug conjugate with the potent antimicrotubule agent monomethyl auristatin E (MMAE) conjugated to an anti-CD22 antibody via a protease-cleavable linker. This phase I study determined its recommended phase II dose (RP2D) and evaluated its safety, tolerability, and antitumor activity alone and with rituximab in relapsed/refractory (r/r) non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Experimental Design Patients received escalating doses of pinatuzumab vedotin every 21 days. Clinical activity at the RP2D alone or with rituximab was evaluated in r/r diffuse large B-cell lymphoma (DLBCL) and r/r indolent NHL (iNHL) patients. Results Seventy-five patients received single-agent pinatuzumab vedotin. The RP2D was 2.4 mg/kg, based on dose-limiting toxicities (DLT) of grade 4 neutropenia >7 days in 1 of 3 patients and grade 4 neutropenia <7 days in 2 of 3 patients treated at 3.2 mg/kg (maximum assessed dose). No DLTs occurred at 2.4 mg/kg. At the RP2D, neutropenia was the mostcommon grade ≥3 adverse event. Peripheral neuropathy–related grade ≥2 adverse events most frequently resulted in treatment discontinuation. Rituximab cotreatment did not impact safety, tolerability, or pharmacokinetics of pinatuzumab vedotin. Unconjugated MMAE exposure was much lower than antibody-conjugated MMAE exposure, without accumulation with repeat dosing. At the RP2D, objective responses were observed in DLBCL (9/25) and iNHL (7/14) patients; 2 of 8 patients treated with pinatuzumab vedotin (RP2D) and rituximab had complete responses. CLL patients showed no objective responses. Conclusions The RP2D of pinatuzumab vedotin alone and with rituximab was 2.4 mg/kg, which was well tolerated, with encouraging clinical activity in r/r NHL.

Phase 2 study of the bispecific T-cell engager (BiTE) antibody blinatumomab in relapsed/refractory diffuse large B-cell lymphoma

“…The efficacy of blinatumomab in this study is comparable to that of the novel compounds with the best published results in r/r DLBCL, including the conjugate antibodies pinatuzumab vedotin (ORR, 39%) 20 and 90 Y-ibrutumomab tiuxetan (ORR, 53%), 21 lenalidomide (ORR, 35%), 22 and the anti-PD1 antibody nivolumab (ORR, 36%). 23 Lower response rates have been reported for other new drugs as monotherapy in r/r DLBCL, including inotuzumab ozogamicin (ORR, 15%), 24 the Bruton tyrosine kinase inhibitor ibrutinib (ORR, 22%), 25 and the phosphoinositol-3 kinase inhibitor buparlisib (ORR, 12%).…”

DropArray™, a Wall‐Less 96‐Well Plate for Uptake and Immunofluorescence Microscopy, Confirms CD22 Recycles

“…Various anti‐CD22 antibodies have been mapped to the first four Ig domains, including To15 , IS7 , BL‐3C4 , HD6 , RFB4 , LL2 [humanized as epratuzumab ], G5/44 (a humanized CD22 antibody linked by an acid‐labile linker to the cytotoxic drug calicheamicin to form inotuzumab ozogamicin or CMC‐554) and 10F4 . The latter four have been tested clinically either as naked antibodies or linked to radioisotopes, cytotoxic drugs or toxins for the treatment of B‐cell lymphomas or leukemias . The RFB4 antibody, targeting Ig domain 3 , has no antitumoral activity by itself, but regresses various CD22‐expressing B‐cell xenografts when conjugated to the antimitotic drugs DM1 (a maytansinoid) or MMAE (auristatin E, a synthetic dolastatin‐10 derivative) .…”

The Antitumor Activity of IMGN529, a CD37-Targeting Antibody-Drug Conjugate, Is Potentiated by Rituximab in Non-Hodgkin Lymphoma Models

“…Pinatuzumab vedotin also targets CD22, but the antibody moiety is conjugated, via stable linkage, to MMAE [31] . Recent human trials with this ADC have shown that rituximab can be combined with pinatuzumab vedotin; preliminary efficacy signals suggest an improvement of the combination compared to the ADC alone [32] , [33] . It is unclear whether the mechanisms involved in the CD20 and CD22 combinations are similar or distinct from those described here for our CD37-targeting ADC.…”