June 14, 2011 (London, United Kingdom) — The investigational drug navitoclax (ABT-263, Abbott Laboratories/Genentech) has shown significant activity in patients with heavily pretreated chronic lymphocytic leukemia (CLL). In a phase 2 study, the drug attained an objective response rate of 33% (currently confirmed in 19% of patients); 58% of patients with baseline nodal enlargement showed shrinkage of greater than 50%.
The results show that navitoclax has significant clinical activity in patients with relapsed or refractory CLL, said lead researcher John Seymour, MB BS, head of the Department of Hematology, Peter MacCallum Cancer Centre, Melbourne, Australia.
"I think the most impressive aspects are that navitoclax is a well-tolerated drug, and it has activity despite these patients having adverse prognostic indicators," he told Medscape Medical News.
Dr. Seymour presented the results here at the 16th Congress of the European Hematology Association.
This study looked at the use of navitoclax, a targeted high-affinity inhibitor of the apoptosis regulator protein Bcl-2, specifically in patients with relapsed or refractory CLL. A phase 1 dose-ranging study in a broad group of lymphomas has previously been published (Lancet Oncol. 2010;11:1149-1159). A second phase 1 study of navitoclax specifically in CLL is currently in press in the Journal of Clinical Oncology.
Patients in the study by Dr. Seymour and colleagues were heavily pretreated. All patients had received 1 to 6 previous therapies (median, 2.6), and their disease had relapsed despite extensive treatment. Data on previous treatment were available for 26 patients, and 85% had received fludarabine; 8 patients had disease refractory to that drug. The median age was 70 years (range, 40 to 82 years).
"This is not a patient group in which intensive and toxic treatments like bone-marrow transplantation are applicable," Dr. Seymour noted.
"Initial treatments for CLL are improving dramatically, so chemotherapy and immunotherapy combinations are very good; still, these are difficult to deliver in people over 65 to 70 years. Furthermore, despite these good initial treatments, all of these patients eventually relapse," he said.
Preclinical trials have shown that navitoclax greatly enhances the activity of other chemotherapy agents, so the drug has the potential to be combined with other cytotoxic agents to improve their effectiveness, he explained.
An ongoing study in the United States is looking at combinations that include navitoclax. One study is investigating navitoclax plus a combination of fludarabine, cyclophosphamide, and rituximab; another study is investigating navitoclax plus bendamustine and rituximab in refractory/relapsed CLL. Dr. Seymour's institution is not participating in that study.
Administration Schedule Altered
In the study presented here, patients received a 7-day lead-in of navitoclax 100 mg/day; it was then dosed at 250 mg/day in a 21-day cycle until progressive disease or intolerable toxicity.
Thrombocytopenia was considerably reduced after the schedule of navitoclax was changed. "Originally, the schedule investigated in the phase 1 study was 14 days on the drug, followed by 7 days off. But because marked thrombocytopenia was seen, a lead-in dose of 100 mg/day for 7 days was explored. This reduced the severity of the thrombocytopenia and allowed a higher dose on continuous scheduling," explained Dr. Seymour.
The primary measures of efficacy were objective tumor response rate and progression-free survival. Disease was assessed at the end of cycle 2 and cycle 4, then every 4 cycles to cycle 20, and every 8 subsequent cycles thereafter.
Nine of the 27 patients evaluated to date, in these interim results, showed a partial remission (tumor response rate), equating to an objective response rate of 33%. Among patients with the prognostically adverse cytogenetic abnormalities, 2 of 5 who had a deletion on the short arm of chromosome 17 and 3 of 6 who had a deletion in chromosome 11 also achieved partial remission.
Dr. Seymour reported that the median progression-free survival was 8.7 months. This is based on preliminary data with median time of 5.1 months and 29 patients, so he said it is an imprecise estimation. A number of approved drugs for fludarabine-refractory CLL have a progression-free survival of approximately 6 to 9 months.
Reduction in peripheral blood lymphocyte count was also taken as a measure of effectiveness. Of the 21 patients with counts evaluated at baseline, 19 showed lymphocyte reduction of greater than 50%.
Another manifestation of response was reduction in lymphadenopathy. Twelve of 26 patients with adenopathy (46%) showed lymph node shrinkage of more than 50%; impressively, of patients with a baseline lymph node of greater than 5 cm, 58% had such a reduction.
Toxicity was mainly as expected, Dr. Seymour noted. Grade 3 or 4 platelet count reductions were seen in 39% of patients, 58% of patients experienced nausea, and 48% experienced diarrhea, which was usually mild and easily managed. These gastrointestinal effects were probably related to the drug formulation, according to Dr. Seymour. Relatively low rates of grade 3/4 neutropenia were seen (20%); thrombocytopenia (27%) and some rare events such as tumor lysis syndrome and elevated liver enzymes were reported. Eight patients required dose reductions, and 5 stopped altogether because of adverse effects.
Dr. Seymour explained that the activity seen in this trial was promising enough to lead to a randomized comparison of navitoclax plus rituximab and rituximab alone. "But the activity has been a basis for other combination studies. To date, CLL is a disease for which the single agent has shown modest activity. The way navitoclax works means it has the potential to be used in combination with other drugs in a broad range of lymphomas."
"What I see as most promising relates to the factors that limit dosage (that is, a reduction in platelet count that is due to one of the target proteins — Bcl-w)," explained Dr. Seymour. Navitoclax works by restoring apoptosis in the tumor cells by blocking the function of prosurvival Bcl-2 family proteins. Unfortunately, it also blocks the activity of Bcl-w, which leads to the observed reduction in platelet counts.
"Abbott Laboratories has now developed a Bcl2-selective compound that is predicted to be free of the thrombocytopenia. This compound is now entering phase 1 studies, which will hopefully be free of the dose-limiting toxicity seen here," Dr. Seymour added.
Approached for comment, Peter Hillmen, MD, from the Department of Hematology, St. James University Hospital, Leeds, United Kingdom, said he found the results very encouraging. "Dr. Seymour presented the results of a trial that demonstrated that navitoclax has significant efficacy when used alone in relapsed CLL. It is likely that navitoclax will be most suited to be used in combination with other drugs, such as conventional chemotherapy. The fact that it has efficacy as a single agent indicates that there is a high likelihood that navitoclax will be a useful drug in combination therapeutic regimens."
Abbott Laboratories funded the study and provided the study drug. Dr. Seymour and Dr. Hillmen have disclosed no relevant financial relationships.
16th Congress of the European Hematology Association (EHA). Presented June 11, 2011.
The results show that navitoclax has significant clinical activity in patients with relapsed or refractory CLL, said lead researcher John Seymour, MB BS, head of the Department of Hematology, Peter MacCallum Cancer Centre, Melbourne, Australia.
"I think the most impressive aspects are that navitoclax is a well-tolerated drug, and it has activity despite these patients having adverse prognostic indicators," he told Medscape Medical News.
Dr. Seymour presented the results here at the 16th Congress of the European Hematology Association.
This study looked at the use of navitoclax, a targeted high-affinity inhibitor of the apoptosis regulator protein Bcl-2, specifically in patients with relapsed or refractory CLL. A phase 1 dose-ranging study in a broad group of lymphomas has previously been published (Lancet Oncol. 2010;11:1149-1159). A second phase 1 study of navitoclax specifically in CLL is currently in press in the Journal of Clinical Oncology.
Patients in the study by Dr. Seymour and colleagues were heavily pretreated. All patients had received 1 to 6 previous therapies (median, 2.6), and their disease had relapsed despite extensive treatment. Data on previous treatment were available for 26 patients, and 85% had received fludarabine; 8 patients had disease refractory to that drug. The median age was 70 years (range, 40 to 82 years).
"This is not a patient group in which intensive and toxic treatments like bone-marrow transplantation are applicable," Dr. Seymour noted.
"Initial treatments for CLL are improving dramatically, so chemotherapy and immunotherapy combinations are very good; still, these are difficult to deliver in people over 65 to 70 years. Furthermore, despite these good initial treatments, all of these patients eventually relapse," he said.
Preclinical trials have shown that navitoclax greatly enhances the activity of other chemotherapy agents, so the drug has the potential to be combined with other cytotoxic agents to improve their effectiveness, he explained.
An ongoing study in the United States is looking at combinations that include navitoclax. One study is investigating navitoclax plus a combination of fludarabine, cyclophosphamide, and rituximab; another study is investigating navitoclax plus bendamustine and rituximab in refractory/relapsed CLL. Dr. Seymour's institution is not participating in that study.
Administration Schedule Altered
In the study presented here, patients received a 7-day lead-in of navitoclax 100 mg/day; it was then dosed at 250 mg/day in a 21-day cycle until progressive disease or intolerable toxicity.
Thrombocytopenia was considerably reduced after the schedule of navitoclax was changed. "Originally, the schedule investigated in the phase 1 study was 14 days on the drug, followed by 7 days off. But because marked thrombocytopenia was seen, a lead-in dose of 100 mg/day for 7 days was explored. This reduced the severity of the thrombocytopenia and allowed a higher dose on continuous scheduling," explained Dr. Seymour.
The primary measures of efficacy were objective tumor response rate and progression-free survival. Disease was assessed at the end of cycle 2 and cycle 4, then every 4 cycles to cycle 20, and every 8 subsequent cycles thereafter.
Nine of the 27 patients evaluated to date, in these interim results, showed a partial remission (tumor response rate), equating to an objective response rate of 33%. Among patients with the prognostically adverse cytogenetic abnormalities, 2 of 5 who had a deletion on the short arm of chromosome 17 and 3 of 6 who had a deletion in chromosome 11 also achieved partial remission.
Dr. Seymour reported that the median progression-free survival was 8.7 months. This is based on preliminary data with median time of 5.1 months and 29 patients, so he said it is an imprecise estimation. A number of approved drugs for fludarabine-refractory CLL have a progression-free survival of approximately 6 to 9 months.
Reduction in peripheral blood lymphocyte count was also taken as a measure of effectiveness. Of the 21 patients with counts evaluated at baseline, 19 showed lymphocyte reduction of greater than 50%.
Another manifestation of response was reduction in lymphadenopathy. Twelve of 26 patients with adenopathy (46%) showed lymph node shrinkage of more than 50%; impressively, of patients with a baseline lymph node of greater than 5 cm, 58% had such a reduction.
Toxicity was mainly as expected, Dr. Seymour noted. Grade 3 or 4 platelet count reductions were seen in 39% of patients, 58% of patients experienced nausea, and 48% experienced diarrhea, which was usually mild and easily managed. These gastrointestinal effects were probably related to the drug formulation, according to Dr. Seymour. Relatively low rates of grade 3/4 neutropenia were seen (20%); thrombocytopenia (27%) and some rare events such as tumor lysis syndrome and elevated liver enzymes were reported. Eight patients required dose reductions, and 5 stopped altogether because of adverse effects.
Dr. Seymour explained that the activity seen in this trial was promising enough to lead to a randomized comparison of navitoclax plus rituximab and rituximab alone. "But the activity has been a basis for other combination studies. To date, CLL is a disease for which the single agent has shown modest activity. The way navitoclax works means it has the potential to be used in combination with other drugs in a broad range of lymphomas."
"What I see as most promising relates to the factors that limit dosage (that is, a reduction in platelet count that is due to one of the target proteins — Bcl-w)," explained Dr. Seymour. Navitoclax works by restoring apoptosis in the tumor cells by blocking the function of prosurvival Bcl-2 family proteins. Unfortunately, it also blocks the activity of Bcl-w, which leads to the observed reduction in platelet counts.
"Abbott Laboratories has now developed a Bcl2-selective compound that is predicted to be free of the thrombocytopenia. This compound is now entering phase 1 studies, which will hopefully be free of the dose-limiting toxicity seen here," Dr. Seymour added.
Approached for comment, Peter Hillmen, MD, from the Department of Hematology, St. James University Hospital, Leeds, United Kingdom, said he found the results very encouraging. "Dr. Seymour presented the results of a trial that demonstrated that navitoclax has significant efficacy when used alone in relapsed CLL. It is likely that navitoclax will be most suited to be used in combination with other drugs, such as conventional chemotherapy. The fact that it has efficacy as a single agent indicates that there is a high likelihood that navitoclax will be a useful drug in combination therapeutic regimens."
Abbott Laboratories funded the study and provided the study drug. Dr. Seymour and Dr. Hillmen have disclosed no relevant financial relationships.
16th Congress of the European Hematology Association (EHA). Presented June 11, 2011.
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