Phase 1 Dose Escalation Study of the Allosteric AKT Inhibitor BAY 1125976 in Advanced Solid Cancer—Lack of Association between Activating AKT Mutation and AKT Inhibition-Derived Efficacy
Abstract
:1. Introduction
2. Results
2.1. Baseline Patient Demographics
2.2. Dose Escalation and Maximum Tolerated Dose
2.3. Safety
2.4. Pharmacokinetic Evaluation
2.5. Pharmacodynamic Biomarkers
2.6. AKT1E17K Status and Mutational Profiling
2.7. Tumor Response Evaluation
3. Discussion
4. Materials and Methods
4.1. Study Design
4.2. Treatment
4.3. Inclusion Criteria
4.4. Safety, Response, and Pharmacokinetics Assessments
4.5. Biomarker Assessments
4.6. PK/PD analysis
4.7. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Parameter | 10 mg LSF QD | 20 mg LSF QD | 40 mg Tablet QD | 80 mg Tablet QD | 120 mg Tablet QD | 40 mg Tablet BID | 60 mg Tablet BID | 80 mg Tablet BID | 60 mg Expansion | Total | |
---|---|---|---|---|---|---|---|---|---|---|---|
Tablet (BID) | |||||||||||
WT | AKT1E17K | ||||||||||
N | 3 | 3 | 4 | 13 | 6 | 3 | 15 | 4 | 19 | 9 | 79 |
Mean age, years (range) | 53.3 (44–67) | 49.7 (37–64) | 59.0 (47–75) | 61.2 (48–75) | 53.5 (37–69) | 66.3 (50–82) | 55.1 (40–74) | 56.3 (38–70) | 55.3 (31–76) | 57.3 (41–73) | 56.7 (31–82) |
Females, n (%) | 2 (66.7) | 2 (66.7) | 2 (50.0) | 10 (76.9) | 4 (66.7) | 2 (66.7) | 8 (53.3) | 3 (75.0) | 19 (100.0) | 9 (100.0) | 61 (77.2) |
ECOG performance status, n (%) | |||||||||||
0 | 0 | 1 (33.3) | 2 (50.0) | 7 (53.8) | 2 (33.3) | 2 (66.7) | 10 (66.7) | 2 (50.0) | 14 (73.7) | 7 (77.8) | 47 (59.5) |
1 | 3 (100.0) | 2 (66.7) | 2 (50.0) | 5 (38.5) | 4 (66.7) | 1 (33.3) | 5 (33.3) | 1 (25.0) | 5 (26.3) | 2 (22.2) | 30 (38.0) |
2 | 0 | 0 | 0 | 1 (7.7) | 0 | 0 | 0 | 1 (25.0) | 0 | 0 | 2 (2.5) |
Prior systemic anticancer therapy, n (%) | 3 (100.0) | 3 (100.0) | 4 (100.0) | 13 (100.0) | 6 (100.0) | 2 (66.7) | 15 (100.0) | 4 (100.0) | 19 (100.0) | 9 (100.0) | 78 (98.7) |
Prior radiotherapy, n (%) | 3 (100.0) | 3 (100.0) | 2 (50.0) | 8 (61.5) | 5 (83.3) | 2 (66.7) | 12 (80.0) | 1 (25.0) | 18 (94.7) | 6 (66.7) | 60 (75.9) |
Adverse Events | 10 mg LSF QD | 20 mg LSF QD | 40 mg Tablet QD | 80 mg Tablet QD | 120 mg Tablet QD | 40 mg Tablet BID | 60 mg Tablet BID | 80 mg Tablet BID | 60 mg Expansion Tablet (BID) | Total | |
---|---|---|---|---|---|---|---|---|---|---|---|
WT | AKT1E17K | ||||||||||
N | 3 | 3 | 4 | 13 | 6 | 3 | 15 | 4 | 19 | 9 | 79 |
All, n (%) | |||||||||||
Grade 3 | - | - | 1 (25.0) | 5 (38.5) | 4 (66.7) | 2 (66.7) | 6 (40.0) | 4 (100.0) | 12 (61.1) | 8 (88.9) | 42 (53.2) |
Grade 4 | - | - | - | - | 1 (16.7) | - | - | - | - | - | 1 (1.3) |
ALT increased, n (%) | |||||||||||
Grade 3 | - | - | - | 2 (15.4) | 2 (33.3) | 1 (33.3) | 2 (13.3) | 3 (75.0) | 4 (21.0) | 3 (33.3) | 17 (21.5) |
AST increased, n (%) | |||||||||||
Grade 3 | - | - | - | 2 (15.4) | 3 (50.0) | - | 3 (20.0) | 2 (50.0) | 7 (36.8) | 3 (33.3) | 20 (25.3) |
AP increased, n (%) | |||||||||||
Grade 3 | - | - | 1 (25.0) | 3 (23.1) | 2 (33.3) | - | 3 (20.0) | 3 (75.0) | 11 (57.9) | 4 (44.4) | 27 (34.2) |
γ-GT increased, n (%) | |||||||||||
Grade 3 | - | - | - | - | - | - | 1 (6.7) | - | - | - | 1 (1.3) |
Grade 4 | - | - | - | - | 1 (16.7) | - | - | - | - | - | 1 (1.3) |
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Schneeweiss, A.; Hess, D.; Joerger, M.; Varga, A.; Moulder, S.; Tsimberidou, A.M.; Ma, C.; Hurvitz, S.A.; Rentzsch, C.; Rudolph, M.; et al. Phase 1 Dose Escalation Study of the Allosteric AKT Inhibitor BAY 1125976 in Advanced Solid Cancer—Lack of Association between Activating AKT Mutation and AKT Inhibition-Derived Efficacy. Cancers 2019, 11, 1987. https://doi.org/10.3390/cancers11121987
Schneeweiss A, Hess D, Joerger M, Varga A, Moulder S, Tsimberidou AM, Ma C, Hurvitz SA, Rentzsch C, Rudolph M, et al. Phase 1 Dose Escalation Study of the Allosteric AKT Inhibitor BAY 1125976 in Advanced Solid Cancer—Lack of Association between Activating AKT Mutation and AKT Inhibition-Derived Efficacy. Cancers. 2019; 11(12):1987. https://doi.org/10.3390/cancers11121987
Chicago/Turabian StyleSchneeweiss, Andreas, Dagmar Hess, Markus Joerger, Andrea Varga, Stacy Moulder, Apostolia M. Tsimberidou, Cynthia Ma, Sara A. Hurvitz, Christine Rentzsch, Marion Rudolph, and et al. 2019. "Phase 1 Dose Escalation Study of the Allosteric AKT Inhibitor BAY 1125976 in Advanced Solid Cancer—Lack of Association between Activating AKT Mutation and AKT Inhibition-Derived Efficacy" Cancers 11, no. 12: 1987. https://doi.org/10.3390/cancers11121987