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Phase I interim safety and efficacy of venetoclax (ABT-199/GDC-0199) monotherapy for relapsed/refractory (R/R) multiple myeloma (MM)

Dr. Shaji Kumar
Mayo Clinic
Rochester, MN, USA

06.04.15

Background: The anti-apoptotic protein BCL-2 has been implicated in mediating the survival of MM cells. Venetoclax (VEN) is a potent, selective, orally bioavailable small-molecule BCL-2 inhibitor. VEN induces cell death in MM cell lines and primary samples in vitro, especially in t(11;14)-positive (pos) cells, which express a high ratio of BCL2 to MCL1(VEN resistance factor). The current Ph 1 study evaluates safety and efficacy of VEN in pts with R/R MM.

Methods: Primary objectives are to evaluate safety, PK, and RPTD; other objectives include preliminary efficacy and impact of chromosomal abnormalities. In dose-escalation cohorts, VEN was given PO daily at 300, 600, 900, or 1200 mg after a 2-week dose ramp-up. Pts were monitored for tumor lysis syndrome (TLS).

Results: As of 12/19/2014, there were 28 pts with median age 65 (12/16 F/M); 9 ISS stage I, 11 stage II, 6 stage III. Median (range) prior therapies: 6 (1–13). 23 had prior bortezomib (15 refractory), 26 lenalidomide (12 refractory), and 13 auto-HSCT. 10 pts were t(11;14)-pos. AEs in ≥20% pts: diarrhea (32%), nausea (32%), neutropenia (21%), fatigue (21%). Grade 3/4 AEs (≥10%): thrombocytopenia (18%), anemia (14%), neutropenia (14%). 7 pts had SAEs, with 1 (epigastric pain) possibly related to VEN. 17 pts have discontinued (D/C): 14 due to PD, 2 for AEs (worsening shortness of breath, hypokalemia), and 1 withdrew consent; 11 still receiving therapy. 2 deaths occurred (both PD). 2 DLTs were seen at 600 mg (cohort was expanded): epigastric pain, nausea with abdominal pain. No pt had TLS. Preliminary PK (n=11; 300 and 600 mg): mean Cmax and AUC24 were ~dose-proportional with high intra-dose variability. 21 of 28 pts were evaluable for preliminary efficacy. Best response by t(11;14) status shown in Table.

Conclusions: VEN monotherapy was well tolerated in heavily-pretreated R/R MM. Responses (including CR) and longer ToS were observed in t(11;14)-pos pts. RPTD was achieved; study is now enrolling in the safety expansion cohort at 1200 mg (with 2-week ramp-up). Clinical trial information: NCT01794520


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Mayo Clinic
Rochester, MN, USA


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