Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma

Abstract

Purpose B-cell leukemia/lymphoma-2 (BCL-2) overexpression is common in many non-Hodgkin lymphoma (NHL) subtypes. A phase I trial in patients with NHL was conducted to determine safety, pharmacokinetics, and efficacy of venetoclax, a selective, potent, orally bioavailable BCL-2 inhibitor. Patients and Methods A total of 106 patients with relapsed or refractory NHL received venetoclax once daily until progressive disease or unacceptable toxicity at target doses from 200 to 1,200 mg in dose-escalation and safety expansion cohorts. Treatment commenced with a 3-week dose ramp-up period for most patients in dose-escalation cohorts and for all patients in safety expansion. Results NHL subtypes included mantle cell lymphoma (MCL; n = 28), follicular lymphoma (FL; n = 29), diffuse large B-cell lymphoma (DLBCL; n = 34), DLBCL arising from chronic lymphocytic leukemia (Richter transformation; n = 7), Waldenström macroglobulinemia (n = 4), and marginal zone lymphoma (n = 3). Venetoclax was generally well tolerated. Clinical tumor lysis syndrome was not observed, whereas laboratory tumor lysis syndrome was documented in three patients. Treatment-emergent adverse events were reported in 103 patients (97%), a majority of which were grade 1 to 2 in severity. Grade 3 to 4 events were reported in 59 patients (56%), and the most common were hematologic, including anemia (15%), neutropenia (11%), and thrombocytopenia (9%). Overall response rate was 44% (MCL, 75%; FL, 38%; DLBCL, 18%). Estimated median progression-free survival was 6 months (MCL, 14 months; FL, 11 months; DLBCL, 1 month). Conclusion Selective targeting of BCL-2 with venetoclax was well tolerated, and single-agent activity varied among NHL subtypes. We determined 1,200 mg to be the recommended single-agent dose for future studies in FL and DLBCL, with 800 mg being sufficient to consistently achieve durable response in MCL. Additional investigations including combination therapy to augment response rates and durability are ongoing.

Fig 1.

Venetoclax induces response in several non-Hodgkin lymphoma histologies. (A) Waterfall plot depicting the best percentage change in the sum of the product of the diameters of target lymph nodes in patients with evaluable disease. Objective response by target dose level in patients with (B) mantle cell lymphoma (MCL), (C) diffuse large B-cell lymphoma (DLBCL), and (D) follicular lymphoma (FL). CR, complete response; MZL, marginal zone lymphoma; PD, progressive disease; PR, partial response; RT, Richter transformation; SD, stable disease; WM, Waldenström macroglobulinemia.

Fig 2.

Durability of antitumor activity of venetoclax. Dashed lines indicate the 50% mark in each panel. (A) Progression-free survival (PFS) of patients with mantle cell lymphoma (MCL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL). Of note, three patients with previously chemotherapy-refractory disease, including DLBCL, primary mediastinal large B-cell lymphoma, and MCL, who proceeded to allogeneic stem-cell transplantation after achieving remission with venetoclax were censored when they left the study but remained disease free during the protocol-defined 2-year follow-up period after venetoclax therapy. (B) Overall survival (OS) of patients with MCL, FL, and DLBCL. Duration of response in (C) evaluable patients with MCL and (D) patients with FL who achieved a complete (CR) or partial response (PR).

Fig 3.

Patient status during study by histology, including mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), DLBCL with Richter transformation (RT), Waldenström macroglobulinemia (WM), and marginal zone lymphoma (MZL). Right arrows indicate patients who continue to receive active treatment.

Fig A1.

Mean venetoclax plasma concentration. Time profiles in (A, B) dose-escalation and (C, D) safety expansion cohorts according to (A, C) linear and (B, D) log-linear scales. Error bars represent standard deviations.