PHASE 1 STUDY OF VENETOCLAX MONOTHERAPY FOR RELAPSED/REFRACTORY MULTIPLE MYELOMA
(Abstract release date: 05/19/16)
EHA Library. Kumar S. 06/12/16; 135308; S814
Prof. Shaji Kumar
Contributions
Contributions
Abstract
Abstract: S814
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:15 - 08:30
Location: Hall C14
Background
The anti-apoptotic protein BCL-2 has been implicated in the survival of multiple myeloma (MM) cells. Venetoclax (VEN) is an oral, highly selective BCL-2 inhibitor, which induces cell death in MM cell lines and primary samples, particularly those with t(11;14), and a high BCL-2 and low BCL-XL profile.
Aims
The objectives of the study are to evaluate safety, PK, recommended phase two dose, and preliminary efficacy of VEN monotherapy in relapsed/refractory (R/R) MM.
Methods
After 2-week dose-ramp-up, VEN was given daily at 300, 600, 900, or 1200 mg in dose escalation cohorts and 1200 mg in the safety expansion cohort.
Results
As of 9/17/15, 48 patients were enrolled: 30 in the dose escalation and 18 in the safety expansion. Median age was 65 and 28 patients had ISS stage II/III. Median (range) number of prior therapies was 5 (1–15), and 45 patients had prior bortezomib (32 refractory), 46 lenalidomide (37 refractory), and 40 had SCT. 18 patients had t(11;14)-positive MM. Adverse events (AEs) in ≥30% of patients were diarrhea (40%), nausea (40%), and thrombocytopenia (31%). Grade 3/4 AEs in ≥10% were thrombocytopenia (29%), anemia and neutropenia (17% each). SAEs in ≥2 patients were sepsis (n=3), cough, malignant neoplasm progression, and pyrexia (2 each).Median (range) time on VEN was 1.9 (0.2–13.8) months. 33 (69%) patients discontinued (DC): 26 related to disease progression, 4 due to AEs (worsening shortness of breath, hypokalemia, nausea, lung disorder), 2 withdrew consent, 1 due to death (brain hemorrhage following injury). 5 deaths occurred (3 disease progression, 1 brain hemorrhage, 1 lung disorder). 2 DLTs were seen at 600 mg (cohort was expanded): epigastric pain,and nausea with abdominal pain. Steady state mean Cmax and AUC24 were ~dose proportional at all doses except 900 mg (n=21).43 of 48 patients were evaluable for efficacy (Table).
In the patients with complete responses, these were maintained for 9.7 (600 mg) and 9.0 months (900 mg, ongoing). Very good partial responses were reported for 3 patients, all in the 1200 mg dose cohort.
Conclusion
Venetoclax monotherapy has a tolerable safety profile in R/R MM. Preliminary efficacy, including complete responses, and very good partial responses, support venetoclax single agent activity in this population, primarily in patients with MM harboring the t(11;14) chromosomal translocation.
Session topic: Experimental approaches for plasma cell disorders
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:15 - 08:30
Location: Hall C14
Background
The anti-apoptotic protein BCL-2 has been implicated in the survival of multiple myeloma (MM) cells. Venetoclax (VEN) is an oral, highly selective BCL-2 inhibitor, which induces cell death in MM cell lines and primary samples, particularly those with t(11;14), and a high BCL-2 and low BCL-XL profile.
Aims
The objectives of the study are to evaluate safety, PK, recommended phase two dose, and preliminary efficacy of VEN monotherapy in relapsed/refractory (R/R) MM.
Methods
After 2-week dose-ramp-up, VEN was given daily at 300, 600, 900, or 1200 mg in dose escalation cohorts and 1200 mg in the safety expansion cohort.
Results
As of 9/17/15, 48 patients were enrolled: 30 in the dose escalation and 18 in the safety expansion. Median age was 65 and 28 patients had ISS stage II/III. Median (range) number of prior therapies was 5 (1–15), and 45 patients had prior bortezomib (32 refractory), 46 lenalidomide (37 refractory), and 40 had SCT. 18 patients had t(11;14)-positive MM. Adverse events (AEs) in ≥30% of patients were diarrhea (40%), nausea (40%), and thrombocytopenia (31%). Grade 3/4 AEs in ≥10% were thrombocytopenia (29%), anemia and neutropenia (17% each). SAEs in ≥2 patients were sepsis (n=3), cough, malignant neoplasm progression, and pyrexia (2 each).Median (range) time on VEN was 1.9 (0.2–13.8) months. 33 (69%) patients discontinued (DC): 26 related to disease progression, 4 due to AEs (worsening shortness of breath, hypokalemia, nausea, lung disorder), 2 withdrew consent, 1 due to death (brain hemorrhage following injury). 5 deaths occurred (3 disease progression, 1 brain hemorrhage, 1 lung disorder). 2 DLTs were seen at 600 mg (cohort was expanded): epigastric pain,and nausea with abdominal pain. Steady state mean Cmax and AUC24 were ~dose proportional at all doses except 900 mg (n=21).43 of 48 patients were evaluable for efficacy (Table).
| Best response, n (%) | With t(11;14) (n=17) | Without t(11;14)(n= 26) | All (n= 43) |
| ORR | 4 (24) | 1 (4) | 5 (12) |
| CR | 2 (12) | 0 | 2 (5) |
| VGPR | 2 (12) | 1 (4)* | 3 (7) |
| MR | 1 (6) | 0 | 1 (2) |
| SD | 5 (29) | 12 (46) | 17 (40) |
| PD | 6 (35) | 12 (46) | 18 (42) |
| DC before assessment | 1 (6) | 1 (4) | 2 (5) |
| *Patient has translocation of chromosome 14 with unknown partner | |||
Conclusion
Venetoclax monotherapy has a tolerable safety profile in R/R MM. Preliminary efficacy, including complete responses, and very good partial responses, support venetoclax single agent activity in this population, primarily in patients with MM harboring the t(11;14) chromosomal translocation.
Session topic: Experimental approaches for plasma cell disorders
Abstract: S814
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:15 - 08:30
Location: Hall C14
Background
The anti-apoptotic protein BCL-2 has been implicated in the survival of multiple myeloma (MM) cells. Venetoclax (VEN) is an oral, highly selective BCL-2 inhibitor, which induces cell death in MM cell lines and primary samples, particularly those with t(11;14), and a high BCL-2 and low BCL-XL profile.
Aims
The objectives of the study are to evaluate safety, PK, recommended phase two dose, and preliminary efficacy of VEN monotherapy in relapsed/refractory (R/R) MM.
Methods
After 2-week dose-ramp-up, VEN was given daily at 300, 600, 900, or 1200 mg in dose escalation cohorts and 1200 mg in the safety expansion cohort.
Results
As of 9/17/15, 48 patients were enrolled: 30 in the dose escalation and 18 in the safety expansion. Median age was 65 and 28 patients had ISS stage II/III. Median (range) number of prior therapies was 5 (1–15), and 45 patients had prior bortezomib (32 refractory), 46 lenalidomide (37 refractory), and 40 had SCT. 18 patients had t(11;14)-positive MM. Adverse events (AEs) in ≥30% of patients were diarrhea (40%), nausea (40%), and thrombocytopenia (31%). Grade 3/4 AEs in ≥10% were thrombocytopenia (29%), anemia and neutropenia (17% each). SAEs in ≥2 patients were sepsis (n=3), cough, malignant neoplasm progression, and pyrexia (2 each).Median (range) time on VEN was 1.9 (0.2–13.8) months. 33 (69%) patients discontinued (DC): 26 related to disease progression, 4 due to AEs (worsening shortness of breath, hypokalemia, nausea, lung disorder), 2 withdrew consent, 1 due to death (brain hemorrhage following injury). 5 deaths occurred (3 disease progression, 1 brain hemorrhage, 1 lung disorder). 2 DLTs were seen at 600 mg (cohort was expanded): epigastric pain,and nausea with abdominal pain. Steady state mean Cmax and AUC24 were ~dose proportional at all doses except 900 mg (n=21).43 of 48 patients were evaluable for efficacy (Table).
In the patients with complete responses, these were maintained for 9.7 (600 mg) and 9.0 months (900 mg, ongoing). Very good partial responses were reported for 3 patients, all in the 1200 mg dose cohort.
Conclusion
Venetoclax monotherapy has a tolerable safety profile in R/R MM. Preliminary efficacy, including complete responses, and very good partial responses, support venetoclax single agent activity in this population, primarily in patients with MM harboring the t(11;14) chromosomal translocation.
Session topic: Experimental approaches for plasma cell disorders
Type: Oral Presentation
Presentation during EHA21: On Sunday, June 12, 2016 from 08:15 - 08:30
Location: Hall C14
Background
The anti-apoptotic protein BCL-2 has been implicated in the survival of multiple myeloma (MM) cells. Venetoclax (VEN) is an oral, highly selective BCL-2 inhibitor, which induces cell death in MM cell lines and primary samples, particularly those with t(11;14), and a high BCL-2 and low BCL-XL profile.
Aims
The objectives of the study are to evaluate safety, PK, recommended phase two dose, and preliminary efficacy of VEN monotherapy in relapsed/refractory (R/R) MM.
Methods
After 2-week dose-ramp-up, VEN was given daily at 300, 600, 900, or 1200 mg in dose escalation cohorts and 1200 mg in the safety expansion cohort.
Results
As of 9/17/15, 48 patients were enrolled: 30 in the dose escalation and 18 in the safety expansion. Median age was 65 and 28 patients had ISS stage II/III. Median (range) number of prior therapies was 5 (1–15), and 45 patients had prior bortezomib (32 refractory), 46 lenalidomide (37 refractory), and 40 had SCT. 18 patients had t(11;14)-positive MM. Adverse events (AEs) in ≥30% of patients were diarrhea (40%), nausea (40%), and thrombocytopenia (31%). Grade 3/4 AEs in ≥10% were thrombocytopenia (29%), anemia and neutropenia (17% each). SAEs in ≥2 patients were sepsis (n=3), cough, malignant neoplasm progression, and pyrexia (2 each).Median (range) time on VEN was 1.9 (0.2–13.8) months. 33 (69%) patients discontinued (DC): 26 related to disease progression, 4 due to AEs (worsening shortness of breath, hypokalemia, nausea, lung disorder), 2 withdrew consent, 1 due to death (brain hemorrhage following injury). 5 deaths occurred (3 disease progression, 1 brain hemorrhage, 1 lung disorder). 2 DLTs were seen at 600 mg (cohort was expanded): epigastric pain,and nausea with abdominal pain. Steady state mean Cmax and AUC24 were ~dose proportional at all doses except 900 mg (n=21).43 of 48 patients were evaluable for efficacy (Table).
| Best response, n (%) | With t(11;14) (n=17) | Without t(11;14)(n= 26) | All (n= 43) |
| ORR | 4 (24) | 1 (4) | 5 (12) |
| CR | 2 (12) | 0 | 2 (5) |
| VGPR | 2 (12) | 1 (4)* | 3 (7) |
| MR | 1 (6) | 0 | 1 (2) |
| SD | 5 (29) | 12 (46) | 17 (40) |
| PD | 6 (35) | 12 (46) | 18 (42) |
| DC before assessment | 1 (6) | 1 (4) | 2 (5) |
| *Patient has translocation of chromosome 14 with unknown partner | |||
Conclusion
Venetoclax monotherapy has a tolerable safety profile in R/R MM. Preliminary efficacy, including complete responses, and very good partial responses, support venetoclax single agent activity in this population, primarily in patients with MM harboring the t(11;14) chromosomal translocation.
Session topic: Experimental approaches for plasma cell disorders
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