FDA has granted Priority Review for Venetoclax, an inhibitor of the Bcl-2 protein, in chronic lymphocytic leukemia
The FDA ( Food and Drug Administration ) has accepted the New Drug Application ( NDA ) and granted Priority Review for Venetoclax for the treatment of people with chronic lymphocytic leukemia ( CLL ) who have received at least one prior therapy, including those with 17p deletion.
Venetoclax is a small molecule inhibitor of the Bcl-2 protein, and was granted Breakthrough Therapy Designation by the FDA in April 2015 for the treatment of people with previously treated ( relapsed or refractory ) chronic lymphocytic leukemia with 17p deletion.
The NDA for Venetoclax is based in part on data from the pivotal phase II M13-982 study.
A Marketing Authorization Application ( MAA ) has also been validated by the European Medicines Agency ( EMA ).
The NDA for Venetoclax is based in part on data from the pivotal phase II M13-982 study. M13-982 is an open-label, single arm, multicenter study evaluating the efficacy and safety of Venetoclax in patients with relapsed, refractory or previously untreated chronic lymphocytic leukemia ( CLL ) with 17p deletion.
The study included 107 patients with relapsed or refractory disease, and all but one had 17p deletion.
Additionally, about 50 patients with relapsed, refractory or previously untreated disease have been enrolled in the safety expansion cohort.
The primary endpoint of the study is overall response rate ( ORR ) as determined by an independent review committee ( IRC ), and secondary endpoints include complete response ( CR ), partial response ( PR ), duration of response ( DOR ), progression-free survival ( PFS ) and overall survival ( OS ).
The level of minimal residual disease ( MRD ) in peripheral blood and/or bone marrow was assessed in a subset of patients.
The study met its primary endpoint, with an ORR of 79.4% among the 107 patients with relapsed or refractory disease receiving Venetoclax, as assessed by IRC.
In addition, 7.5% of patients achieved a complete response with or without complete recovery of blood counts in the bone marrow ( CR/CRi ).
Forty-five patients had an assessment for MRD in the blood. Of these, 18 patients achieved MRD-negativity, meaning no cancer could be detected using a specific test. Ten of these 18 patients also had bone marrow assessments and six were MRD-negative.
At one year, 84.7% of all responses and 94.4% of MRD-negative responses were maintained. The one-year progression-free survival and overall survival rates were 72% and 86.7%, respectively.
The most common serious adverse events were fever ( 7% ), low red blood cell count as a result of immune response ( 7% ), pneumonia ( 6% ) and low white blood cell count with fever ( 5% ).
The most common grade 3-4 adverse events were low white blood cell count ( 40% ), low red blood cell count ( 18% ) and low platelet count ( 15% ).
Grade 3 or higher infection occurred in 20% of patients.
Laboratory tumor lysis syndrome was reported in five patients; none had clinical consequences.
Venetoclax is an investigational small molecule designed to selectively bind and inhibit the BCL-2 protein, which plays an important role in a process called apoptosis ( programmed cell death ). It is believed that blocking BCL-2 may restore the signaling system that tells cells, including cancer cells, to self-destruct.
The BCL-2 protein is linked to the development of resistance in certain blood cancers and is expressed in chronic lymphocytic leukemia ( CLL ) and non-Hodgkin’s lymphoma ( NHL ).
Although signs of chronic lymphocytic leukemia may disappear for a period of time after initial treatment, the disease is considered incurable and many people will require additional treatment due to the return of cancerous cells.
In certain cases of chronic lymphocytic leukemia, a part of chromosome 17 is lost and along with it an important gene that controls apoptosis called p53. The 17p deletion is found in 3 to 10% of previously untreated cases and approximately 30 to 50% of relapsed or refractory cases. ( Xagena )
Source: Genentech, 2016
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