June 17, 2013
AbbVie Presents Preliminary Results from Phase I Study of Investigational Oncology Compound ABT-199/GDC-0199 in Patients with High-Risk Chronic Lymphocytic Leukemia (CLL) at European Hematology Association Annual Meeting
Analysis Evaluates Response Rates in Patients with 17p Deletion, Fludarabine-Refractory CLL
Data in Patients with Mantle Cell Lymphoma (MCL) Also Presented

NORTH CHICAGO, Ill., June 17, 2013 /PRNewswire/ -- AbbVie (NYSE: 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 18th 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."

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.

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.

About ABT-199/GDC-0199
ABT-199/GDC-0199 is a selective inhibitor of B-cell lymphoma-2 (BCL-2) proteins. The B-cell lymphoma 2 gene prevents apoptosis (death) of some cells including lymphocytes, and can be highly expressed in cancers in the lymph nodes, spleen, and other organs of the immune system. As a BH3-mimetic, ABT-199/GDC-0199 is designed to block the function of the BCL-2 protein by restoring the communication system that tells cancer cells to self-destruct. ABT-199/GDC-0199 is being developed in collaboration with Genentech in the United States and Roche outside the United States. Together, the companies are pioneering BCL-2 research with ABT-199/GDC-0199, which is currently in Phase 1/1b clinical trials for the treatment of CLL and several other cancers.

Enrollment is currently active in ABT-199/GDC-0199 clinical trials in CLL, NHL and multiple myeloma. AbbVie and Genentech expect to move the compound into later-stage clinical trials in the near future. 

About Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia is the second most common leukemia in adults, affecting approximately 124,000 people in the European Union. It is a slow-progressing cancer of the blood and bone marrow in which the bone marrow makes too many lymphocytes, a type of white blood cell that helps the body fight infection. The cause of CLL is unknown, though researchers believe it may be linked to a genetic mutation.

About Non-Hodgkin's Lymphoma
Non-Hodgkin's lymphoma includes a diverse group of blood cancers that originates in lymphocytes, a type of white blood cell that is part of the body's immune system. NHL is the most common hematological cancer and the fifth leading cause of cancer death. In the EU, NHL affects approximately 90,000 to 138,000 people. 

Mantle cell lymphoma is an aggressive, rapidly progressive subtype of NHL. The median life expectancy for a patient with MCL following first relapse is one to two years.

About AbbVie Oncology
The fight against cancer is one of the greatest battles in medicine and the varied nature of the disease requires a diverse approach that looks at multiple disease targets in a variety of tumor types. AbbVie's oncology research is focused on the discovery and development of targeted therapies that work against the processes cancers need to survive. By investing in new technologies and approaches, we are breaking ground in some of the most widespread and difficult-to-treat cancers, including multiple myeloma and chronic lymphocytic leukemia. Our oncology pipeline includes multiple new molecules in clinical trials being studied in more than 15 different cancers and tumor types.

About AbbVie
AbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott. The company's mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world's most complex and serious diseases. In 2013, AbbVie employs approximately 21,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visit Follow @abbvie on Twitter or view careers on our Facebook or LinkedIn page.


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