AbbVie Issues Prelim. Results from Phase I Study of ABT-199/GDC-0199 for High-Risk CLL

AbbVie ABBV today announced preliminary results from a Phase I study of ABT-199/GDC-0199, an investigational BCL-2 (B-cell lymphoma 2) selective inhibitor, in patients with high-risk relapsed/refractory chronic lymphocytic leukemia (CLL), and in patients with relapsed/refractory non-Hodgkin's lymphoma (NHL). High-risk CLL patients are those with deletions of chromosome 17p or whose disease is refractory to fludarabine therapy. These data were presented at the 18^th Congress of the European Hematology Association (EHA) in Stockholm, Sweden. This Phase I, open-label, multicenter, international trial was designed to assess the safety, determine the maximum tolerated dose and recommended Phase II dose, and evaluate the pharmacokinetics of ABT-199/GDC-0199 in patients with relapsed/refractory CLL and NHL. Secondary objectives included preliminary efficacy, including objective response rate, duration of response, time to progression, progression-free survival and overall survival.  "New treatment options are critically needed for patients with hard-to-treat cancers including high risk CLL and MCL," said Gary Gordon, M.D., divisional vice president, oncology clinical development, AbbVie. "The preliminary data presented at EHA further support the ongoing clinical trial program for ABT-199/GDC-0199 via the BCL-2 pathway." CLL Arm As of April 2013, 56 patients have enrolled in the CLL arm of the Phase I trial, and 40 patients are currently active. Study participants were given a single oral dose of ABT-199/GDC-0199, followed by six days without medication, before continuous once-daily dosing. Due to concerns over tumor lysis syndrome (TLS), the initial dose was reduced and daily dosing was modified. Single-agent activity was observed in the trial and warrants further single-agent and combination trials evaluating ABT-199/GDC-0199 in patients with CLL. Dose and schedule evaluation will continue. Of the 56 patients enrolled, 34 were considered high-risk CLL patients – those with deletions of chromosome 17p or whose disease is refractory to fludarabine therapy. In the post-hoc analysis to determine if high-risk CLL patients could have similar response rates to the overall study population, 17 (30%) patients had 17p deletion and 18 (32%) had fludarabine-refractory CLL. "High-risk CLL patients are a challenging subgroup to treat, as they tend to have disappointing results with conventional chemotherapy regimens," said Professor Andrew Roberts, Hematologist at the Royal Melbourne Hospital and head of Clinical Translation at the Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.  "While still early in the development process, preliminary response rates observed in these patients appear similar to those observed in other CLL patients being treated with ABT-199/GDC-0199.  These data justify further investigation of this compound in patients with 17p deletion and fludarabine-refractory CLL." During the study, 16 patients discontinued treatment; nine due to progressed disease and seven for other reasons (two due to TLS, three for other illnesses, one for thromboembolic event and one consent withdrawal). The most common hematological adverse events (AEs) during the study were neutropenia (39%), thrombocytopenia (18%) and anemia (13%). The most common non-hematological AEs were diarrhea (41%), nausea (38%), fatigue (29%), upper respiratory tract infection (27%) and cough (23%). In the first study group, TLS occurred in all three of the enrolled patients; once the modified dosing schedule was utilized, three of the 53 patients experienced TLS, one of which was a fatal AE that occurred within dose escalation to 1200mg. Preliminary efficacy results demonstrated that 13 of 16 evaluable patients (81%) with 17p deletion achieved a response to ABT-199/GDC-0199. Specifically, 2 patients (12%) achieved a complete response (CR) or complete response with incomplete bone marrow recovery and 11 patients (69%) achieved a partial response (PR). Among the patients with F-refractory CLL, 14 of 18 evaluable patients (78%) achieved a response; 3 (17%) achieved a complete response or complete response with incomplete bone marrow recovery and 11 (61%) achieved a partial response.  These results are similar to the preliminary efficacy observed in the overall CLL study population (84 percent response rate). Further clinical studies to evaluate the efficacy and safety of ABT-199/GDC-0199 in CLL, and specifically in patients with high-risk CLL, are necessary. NHL Arm As of April 2013, 32 patients have enrolled in the NHL arm of the trial, and 12 are currently active. Patients were given a single oral dose (50-400mg) followed by six days without medication before being dosed with continuous once-daily dosing. Due to concerns over TLS, a dose-escalation protocol was implemented. Patients who were treated with up to 900mg have been evaluated to date. Single-agent activity was observed in the trial and warrants further clinical investigation. Dose escalation will continue to determine maximum-tolerated dose and optimal dosing regimen. The most common hematological AEs during the study were neutropenia, thrombocytopenia (16% each), and anemia (13%). The most common non-hematological AEs were nausea (41%), diarrhea (28%), dyspepsia, vomiting, fatigue, pyrexia, upper respiratory tract infection and cough (19% each). Grade 3/4 thrombocytopenia, neutropenia and anemia occurred in four patients (13% each). Grade 3/4 thrombocytopenia was not dose dependent. TLS was seen after the initial dose in one patient with bulky mantle cell lymphoma (MCL) (>10 cm). With a median follow-up of five months (range 0.5-15), 17 patients discontinued: 13 due to progression of disease, two due to AEs and two proceeded to bone marrow transplant in ongoing response. Of the patients enrolled in this arm of the trial, eight (26%) had MCL, an aggressive, rapidly progressive subtype of NHL that does not respond well to current therapies. Preliminary efficacy results showed that all eight patients (100%) with MCL achieved a partial response. Further clinical studies to evaluate the efficacy and safety of ABT-199/GDC-0199 in MCL are necessary.