CLINICAL NEWS
Phase I Study Shows Venetoclax Active in Patients With Relapsed / Refractory Myeloma
The B-cell lymphoma / leukemia-2 ( BCL-2 ) inhibitor venetoclax may be a new option for patients with heavily treated multiple myeloma ( MM ), according to results from an open-label , phase I trial presented at the 2016 ASH Annual Meeting , in which treatment with the drug led to an overall response rate ( ORR ) of 21 percent . Shaji Kumar , MD , from the Division of Hematology at the Mayo Clinic in Rochester , Minnesota , and co-authors also found that patients with t ( 11 ; 14 ) had higher response rates and longer durations of response , compared with patients without the translocation .
Together with the “ acceptable and well tolerated ” safety profile , Dr . Kumar reported that “ the results are encouraging enough that additional studies are planned , especially alternative combinations .”
The researchers enrolled 66 patients with relapsed / refractory MM ( median age = 63 years ; range = 31-79 years ): 30 patients were in the dose-escalation phase and 36 were in the safetyexpansion phase . Most patients ( n = 39 ; 62 %) had International Staging System II / III disease . Patients were heavily pretreated , having received a median of five prior therapies ( range = 1-15 therapies ), mostly bortezomib ( n = 62 ; 94 %), lenalidomide ( n = 6 ; 94 %), and autologous hematopoietic cell transplantation ( n = 50 ; 76 %).
After a two-week lead-in period with weekly dose escalation , venetoclax was administered daily at 300 , 600 , 900 , or 1,200 mg in the dose-escalation phase and at 1,200 mg in the safetyexpansion phase , all in 21-day cycles . If patients progressed while receiving venetoclax monotherapy , they could receive venetoclax plus dexamethasone and continue the study .
Fifty-one patients ( 77 %) discontinued the study for the following reasons : disease progression ( n = 39 ), adverse events ( AEs ) or toxicity ( n = 5 ), consent withdrawal ( n = 2 ), lost to follow-up ( n = 1 ), or reasons not specified ( n = 4 ).
The most common all-grade AEs were nausea ( 48 %), diarrhea ( 36 %), neutropenia ( 32 %), thrombocytopenia ( 32 %), fatigue ( 27 %), anemia ( 23 %), back pain ( 21 %), and vomiting ( 21 %). Grade 3 / 4 AEs included thrombocytopenia ( 26 %), neutropenia ( 20 %), lymphopenia ( 15 %), anemia ( 14 %), and leukopenia ( 12 %). Serious AEs included pneumonia ( 8 %), sepsis ( 5 %), pain , pyrexia , cough , and hypotension ( 3 % each ). No events of tumor lysis syndrome were observed .
Eight patients died during the study : six due to disease progression , one due to a lung disorder , and one due to a brain hemorrhage following injury . None of the deaths was considered treatment-related .
After a median of 2.5 months ( range = 0.2-23 months ), the ORR was 21 percent ( n = 14 ), including two complete responses ( CRs ), two stringent CRs , and six very good partial responses ( VGPRs ). The median duration of response and time to progression was 9.7 months ( range = 1-22 months ) and 2.6 months ( range = 1-23 months ), respectively . Notably , responses were more common and deeper in the 30 patients with t ( 11 ; 14 ) MM , Dr . Kumar and researchers observed . The ORR in that cohort increased to 40 percent ( n = 12 ), including eight patients who achieved a VGPR or better . “ Venetoclax activity in t ( 11 ; 14 ) myeloma was independent of refractory status to prior therapies ,” Dr . Kumar said , adding that “ patients who achieved at least minimal response in the t ( 11 ; 14 ) group had a median of four prior therapies and were mostly refractory to bortezomib , lenalidomide , or both ( 71 %).”
Venetoclax was even more effective in a smaller subgroup of nine patients with t ( 11 ; 14 ) and a high BCL-2 : BCL2L1 ratio , compared with patients with a low BCL-2 : BCL2L1 ratio ( ORR = 88 % vs . 20 %; p value not provided ). “ I think we have a drug that can change the outcome for a lot of patients with myeloma ,” Dr . Kumar said . “ It may be the first drug that is actually going to be a biomarker-driven drug in this disease .”
The study is limited by the small study population and the potential effect of adding dexamethasone to venetoclax monotherapy for patients who progressed . Also , though there appeared to be improved response rates in the t ( 11 ; 14 ) population , the study did not report p values , so the significance of the comparisons is unknown .
REFERENCE
Kumar S , Vij R , Kaufman JL , et al . Venetoclax monotherapy for relapsed / refractory multiple myeloma : safety and efficacy results from a phase I study . Abstract # 488 . Presented at the 2016 ASH Annual Meeting , December 4 , 2016 ; San Diego , California .
BLU-285 Shows Tolerable Safety , Early Clinical Activity in Patients With Advanced Systemic Mastocytosis
BLU-285 , an oral inhibitor of KIT D816V , is well tolerated and could alleviate symptom burden for patients with advanced systemic mastocytosis ( SM ), according to data from an ongoing phase I trial presented at the 2016 ASH Annual Meeting .
KIT D816V is a key driver of SM and is present in approximately 95 percent of cases . Available therapies do not effectively target this mutation , according to Mark Drummond , MBChB , PhD , from the Beatson West of Scotland Cancer Centre at the National Health Services Greater Glasgow and Clyde in the United Kingdom , and co-authors .
“ Advanced SM is a rare and severe disease that shortens life expectancy with a wide range of debilitating symptoms and organ damage ,” said study presenter Daniel DeAngelo , MD , PhD , of the Dana- Farber Cancer Institute in Boston , Massachusetts , noting the need for treatments that address the underlying cause of the disease . “ The objective decreases in mast cell burden and improvements in symptoms seen in these early data are encouraging .” Adult patients with aggressive SM , SM with associated hematologic non-mast cell disorder , or mast cell leukemia were eligible for study inclusion and received BLU-285 once daily on a four-week cycle following a “ 3 + 3 ” dose-escalation design . The authors assessed pharmacokinetics and biomarkers , D816V mutant allele fraction in blood and bone marrow ( BM ), and co-occurring mutations , as well as liver and spleen size .
At the data cut-off point ( November 11 , 2016 ), 12 patients ( median age = 61.5 years ; range = 39-82 years ) had been treated with BLU-285 at three dose levels ( 30 mg , 60 mg , or 100 mg once daily ). Most patients ( n = 11 / 12 ) had the KIT D816V mutation . All patients had mast cell-related organ damage , which was defined as one of the following : BM dysfunction with ≥1 cytopenia ; hepatomegaly with impaired liver function , ascites , and / or portal hypertension ; osteolytic skeletal lesions ; splenomegaly with hypersplenism ; or malabsorption with weight loss . Patients had a median of 1.5 of these symptoms ( range = 1-3 symptoms ).
Ten patients remained on the clinical trial at the data cut-off point , with treatment duration ranging from 1 month to 8.1 months . BLU-285 appeared to be well tolerated at all doses ; no patients discontinued treatment due to adverse events ( AEs ), and no grade ≥4 AEs were reported . Most AEs were grade 1 or 2 and included fatigue , dizziness , headache , rash , shingles , anemia , and thrombocytopenia ( n = 1 for each ). Grade 3 alkaline phosphatase elevation was observed in three patients , and all cases were asymptomatic and transient , according to the authors .
“ These elevations occurred in the three patients with the highest BM mast cell burden at baseline , suggesting this may be consistent with a pharmacodynamic effect of BLU-285 on mast cells in the bone ,” they added . “ One of the three cases of alkaline phosphatase elevation was considered possibly treatment-related and defined as a dose-limiting toxicity at the 60 mg dose level .” However , all three patients continued treatment with BLU-285 without a dose reduction .
A maximum-tolerated dose has not yet been established . This phase I trial continues to enroll patients , with a target enrollment of 60 , including 25 in the dose-escalation phase and 35 in the doseexpansion phase .
Objective decreases in mast cell burden were also observed in six of eight evaluable patients , including a decline in peripheral blood and BM KIT D816V DNA levels ( n = 6 ), five of whom experienced this reduction within the first two treatment cycles . Serum tryptase
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