A Phase I Study of the Oral Dual-Acting Pan-PI3K/mTOR Inhibitor Bimiralisib in Patients with Advanced Solid Tumors
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Patients
2.2. Study Design
2.3. Assessments
2.4. Statistics
3. Results
3.1. Patient Demographics and Characteristics
3.2. Dose Escalation, DLTs, and MTD Determination
3.3. Pharmacokinetics of Bimiralisib
3.4. Safety of Bimiralisib
3.5. Efficacy
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Dose Level | Bimiralisib * |
---|---|
−1 ** | 60 mg daily |
1 (starting) | 80 mg daily |
2 | 120 mg daily |
3 | 140 mg daily |
4 | 160 mg daily |
5 | 180 mg daily |
Intermittent Schedules A and B Dose Level | Bimiralisib * |
---|---|
1 (starting) | MTD qd of continuous schedule |
2 | MTD qd + 20 mg |
3 | MTD qd + 40 mg |
4 | MTD qd + 60 mg |
5 | MTD qd + 80 mg |
Characteristic | Continuous (n = 21) | Intermittent A (n = 25) | Intermittent B (n = 24) | Total (n = 70) |
---|---|---|---|---|
Median age, years (range) | 58 (41–78) | 56 (22–81) | 56 (19–83) | 57 (19–83) |
Female, n (%) | 14 (66.7) | 17 (68) | 18 (75) | 49 (70) |
Male, n (%) | 7 (33.3) | 8 (32) | 6 (25) | 21 (30) |
Race, n (%) | ||||
White | 20 (95.2) | 22 (88) | 23 (95.8) | 65 (92.9) |
Black or African American | 1 (4.8) | 2 (8) | 0 (0) | 3 (4.3) |
Asian | 0 (0) | 1 (4) | 1 (4.2) | 2 (2.9) |
ECOG performance status, n (%) | ||||
0 | 9 (42.9) | 9 (36) | 9 (37.5) | 27 (38.6) |
1 | 12 (57.1) | 16 (64) | 15 (62.5) | 43 (61.4) |
Smoking history, n (%) | ||||
Yes | 11 (52.4) | 11 (44) | 12 (50) | 34 (48.6) |
No | 10 (47.6) | 15 (56) | 12 (50) | 36 (51.4) |
Disease primary diagnosis, n (%) | ||||
Lung | 3 | 4 | 0 | 7 |
Breast | 1 | 6 | 4 | 11 |
Prostate/GU | 2 | 0 | 1 | 3 |
Ovarian/Gynecologic | 5 | 5 | 4 | 14 |
Gastroesophageal | 2 | 0 | 0 | 2 |
Colorectal | 2 | 3 | 2 | 7 |
Pancreatic | 1 | 0 | 0 | 1 |
Anal | 1 | 1 | 1 | 3 |
Sarcoma/other | 4 | 2 | 2 | 8 |
Melanoma | 0 | 1 | 0 | 1 |
Lymphoma | 0 | 2 | 0 | 2 |
GBM | 0 | 0 | 1 | 1 |
Disease stage at diagnosis, n (%) | ||||
Stage III | 4 (19) | 4 (16) | 2 (8.4) | 10 (14.3) |
Stage IV | 4 (19) | 7 (28) | 6 (25) | 17 (24.3) |
Disease stage at study entry, n (%) | ||||
Stage III/IV | 3 (14.3) | 7 (28) | 1 (4.2) | 11 (15.7) |
Recurrent | 0 (0) | 4 (16) | 5 (20.8) | 9 (12.9) |
Metastatic | 18 (85.7) | 14 (56) | 18 (75) | 50 (71.4) |
Prior therapy, n (%) | ||||
Prior surgery or non-radiation procedure | 19 (90.5) | 18 (72) | 15 (62.5) | 42 (60) |
Prior radiation | 10 (47.6) | 16 (64) | 17 (70.8) | 43 (61.4) |
Prior antineoplastic therapy | ||||
1 | 1 (4.8) | 4 (16) | 3 (12.5) | 8 (11.4) |
2 | 2 (8.5) | 2 (8) | 4 (16.7) | 8 (11.4) |
≥3 | 18 (85.7) | 19 (76) | 17 (70.8) | 54 (77.2) |
Best response to last prior antineoplastic therapy, n (%) | ||||
Partial response | 0 (0) | 6 (24) | 3 (12.5) | 9 (12.9) |
Stable disease | 9 (42.9) | 6 (24) | 3 (12.5) | 18 (25.7) |
Progressive disease | 12 (57.1) | 11 (44) | 12 (50) | 35 (50.0) |
Unknown | 0 | 2 (8) | 6 (25) | 8 (11.4) |
AE, n (%) | Continuous (n = 21) | Intermittent A (n = 25) | Intermittent B (n = 24) | Total n = 70 |
---|---|---|---|---|
Any TEAE | 21 (100) | 24 (96) | 24 (100) | 69 (98.9) |
Any drug-related AE | 21 (100) | 22 (88) | 21 (88) | 63 (91) |
Common TEAE (≥10% of patients) | ||||
Nausea | 12 (57.1) | 14 (56) | 15 (62.5) | 41 (58.6) |
Fatigue | 13 (61.9) | 12 (48) | 10 (41.7) | 35 (50.0) |
Hyperglycemia | 16 (76.2) | 6 (24) | 9 (37.5) | 31 (44.3) |
Decreased appetite | 11 (52.4) | 9 (36) | 8 (33.3) | 28 (40.0) |
Diarrhea | 10 (47.6) | 11 (44) | 7 (29.2) | 28 (40.0) |
Vomiting | 10 (47.6) | 5 (20) | 7 (29.2) | 22 (31.4) |
Weight decrease | 11 (52.4) | 4 (16) | 3 (12.5) | 18 (25.7) |
Dry Mouth | 10 (47.6) | 3 (12) | 4 (16.7) | 17 (24.3) |
Anxiety | 5 (23.8) | 5 (20) | 6 (25) | 16 (22.9) |
Constipation | 3 (14.3) | 3 (12) | 8 (33.3) | 14 (20.0) |
Rash | 4 (19.1) | 5 (20) | 5 (20.8) | 14 (20.0) |
Back pain | 4 (19.1) | 4 (16) | 5 (20.8) | 13 (18.6) |
Disturbance attention | 11 (52.4) | 1 (4) | 1 (4.2) | 13 (18.6) |
Pruritus | 6 (28.6) | 2 (8) | 5 (20.8) | 13 (18.6) |
AST elevation | 3 (14.3) | 4 (16) | 5 (20.8) | 12 (17.1) |
Asthenia | 6 (28.6) | 2 (8) | 4 (16.7) | 12 (17.1) |
Disease progression | 3 (14.3) | 5 (20) | 3 (12.5) | 11 (15.7) |
Dry skin | 7 (33.3) | 3 (12) | 1 (4.2) | 11 (15.7) |
Headache | 0 (0) | 3 (12) | 7 (29.2) | 10 (14.3) |
Hyperinsulinemia | 7 (33.3) | 1 (4) | 1 (4.2) | 9 (12.9) |
Hypokalemia | 6 (28.6) | 1 (4) | 2 (8.3) | 9 (12.9) |
Abdominal pain | 1 (4.76) | 4 (16) | 3 (12.5) | 8 (11.4) |
Anemia | 0 (0) | 3 (12) | 5 (20) | 8 (11.4) |
Dyspepsia | 1 (4.76) | 3 (12) | 4 (16.7) | 8 (11.4) |
ALT elevation | 1 (4.76) | 3 (12) | 3 (12.5) | 7 (10) |
Cough | 2 (9.5) | 3 (12) | 2 (8.3) | 7 (10) |
Dehydration | 6 (28.6) | 1 (4) | 0 (0) | 7 (10) |
Depression | 5 (23.8) | 0 (0) | 2 (8.3) | 7 (10) |
Dizziness | 3 (14.3) | 1 (4) | 3 (12.5) | 7 (10) |
Dyspnea | 4 (19.1) | 2 (8) | 1 (4.2) | 7 (10) |
Muscular weakness | 3 (14.3) | 0 (0) | 4 (16.7) | 7 (10) |
Peripheral edema | 3 (14.3) | 2 (8) | 2 (8.3) | 7 (10) |
Tachycardia | 4 (19.1) | 2 (8) | 1 (4.2) | 7 (10) |
Dysgeusia | 4 (19.1) | 0 (0) | 2 (8.3) | 6 (8.6) |
Irritability | 0 (0) | 3 (12) | 2 (8.3) | 5 (7.1) |
Upper respiratory tract infection | 1 (4.76) | 3 (12) | 1 (4.2) | 5 (7.1) |
Cachexia | 4 (19.1) | 0 (0) | 0 (0) | 4 (5.7) |
Hyperkalemia | 0 (0) | 3 (12) | 1 (4.2) | 4 (5.7) |
Hyperphosphatasemia | 1 (4.76) | 3 (12) | 0 (0) | 4 (5.7) |
Malaise | 4 (19.1) | 0 (0) | 0 (0) | 4 (5.7) |
Ascites | 0 (0) | 3 (12) | 0 (0) | 3 (4.3) |
Confusional state | 3 (14.3) | 0 (0) | 0 (0) | 3 (4.3) |
Early satiety | 3 (14.3) | 0 (0) | 0 (0) | 3 (4.3) |
Hallucination | 3 (14.3) | 0 (0) | 0 (0) | 3 (4.3) |
Mucosal Inflammation | 0 (0) | 3 (12) | 0 (0) | 3 (4.3) |
Neck pain | 0 (0) | 0 (0) | 3 (12.5) | 3 (4.3) |
Any grade ≥ 3 TEAE | 17 (81) | 14 (56) | 16 (66.7) | 47 (67.1) |
Grade ≥ 3 TEAEs (≥5% of patients) | ||||
Hyperglycemia | 6 (28.6) | 3 (12) | 3 (12.5) | 12 (17.1) |
Fatigue | 7 (33.3) | 0 (0) | 2 (8.3) | 9 (12.9) |
AST elevation | 3 (14.3) | 1 (4) | 1 (4.2) | 4 (5.7) |
ALT elevation | 1 (4.8) | 1 (4) | 2 (8.3) | 4 (5.7) |
Dehydration | 4 (19) | 0 (0) | 0 (0) | 4 (5.7) |
Any serious AE | 9 (43) | 8 (32) | 11 (46) | 28 (40) |
Any drug-related serious AE | 2 (10) | 0 (0) | 2 (8) | 4 (5.7) |
Treatment-related death | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
Any drug-related grade ≥ 3 AE | 11 (52.4) | 5 (20) | 10 (41.7) | 26 (37.1) |
Dosing Schedule | Dose Level | Patients Enrolled | No. of Patients with ≥1 DLT Events | Grade of DLT | TEAE Resulting in Dose Interruption | TEAE Resulting in Dose Reduction |
---|---|---|---|---|---|---|
Continuous Dosing | 80 mg | 11 * | 0 (0%) | NA | 4 (36%) | 0 (0%) |
100 mg | 5 | 1 (20%) | Grade 3 fatigue | 3 (60%) | 1 (20%) | |
120 mg | 5 | 3 (60%) | Grade 3 fatigue | 4 (80%) | 1 (20%) | |
Total per schedule | 21 | 4 (19%) | NA | 11 (52%) | 2 (10%) | |
Intermittent Schedule A | 80 mg | 4 | 0 (0%) | NA | 1 (25%) | 0 (0%) |
100 mg | 3 | 0 (0%) | NA | 1 (33%) | 0 (0%) | |
120 mg | 4 | 0 (0%) | NA | 1 (25%) | 0 (0%) | |
140 mg | 6 | 0 (0%) | NA | 2 (33%) | 0 (0%) | |
160 mg | 3 | 0 (0%) | NA | 1 (33%) | 0 (0%) | |
200 mg | 5 | 0 (0%) | NA | 3 (60%) | 0 (0%) | |
Total per schedule | 21 | 0 (0%) | NA | 9 (36%) | 0 (0%) | |
Intermittent Schedule B | 80 mg | 4 | 0 (0%) | NA | 2 (50%) | 0 (0%) |
100 mg | 7 | 1 (14.3%) | Grade 4 Lipase elevation | 3 (43%) | 0 (0%) | |
120 mg | 3 | 0 (0%) | NA | 0 (0%) | 0 (0%) | |
140 mg | 3 | 0 (0%) | NA | 2 (67%) | 1 (33%) | |
160 mg | 3 | 0 (0%) | NA | 1 (33%) | 0 (0%) | |
200 mg | 4 | 0 (0%) | NA | 1 (25%) | 0 (0%) | |
Total per schedule: | 24 | 1 (4.2%) | NA | 9 (38%) | 1 (4%) |
AE, n (%) | Continuous (n = 21) | Intermittent A (n = 25) | Intermittent B (n = 24) | Total n = 70 |
---|---|---|---|---|
Patients discontinuing study due to AE | 5 (24.0%) | 1 (4.0%) | 3 (12.5%) | 9 (12.9%) |
Fatigue | 3 (14.3%) | 1 (4.2%) | 4 (5.7%) | |
ALT Increased | 2 (8.3%) | 2 (2.8%) | ||
Dehydration | 2 (9.5%) | 2 (2.8%) | ||
AST Increased | 1 (4.2%) | 1 (1.4%) | ||
Ejection Fraction decreased | 1 (4.8%) | 1 (1.4%) | ||
Musculoskeletal chest pain | 1 (4.2%) | 1 (1.4%) | ||
Myalgia | 1 (4.2%) | 1 (1.4%) | ||
Polyuria | 1 (4.2%) | 1 (1.4%) | ||
Pollakiuria | 1 (4.2%) | 1 (1.4%) | ||
Renal Failure | 1 (4.0%) | 1 (1.4%) | ||
Tumor pain | 1 (4.8%) | 1 (1.4%) | ||
Urinary Tract Infection | 1 (4.0%) | 1 (1.4%) |
Dose Level (mg) | Period | Patients (n) | Tmax (h) Median, (Range) | Cmax, (ng/mL) Mean (%CV) | AUC0–8, (h·ng/mL) Geometric Mean (%CV) | AUC0–24, (h·ng/mL) Geometric Mean (%CV) |
---|---|---|---|---|---|---|
Continuous Dosing | ||||||
80 | Day -3 | 11 | 2 (0.5–24) | 407 (47) | 1530 (48) | 4290 (50) |
Day 15 | 7 | 1 (0.5–8) | 766 (60) | 4090 (64) | NA | |
100 | Day 1 | 5 | 1.7 (1–8) | 441 (49) | 1690 (29) | 4660 (24) |
Day 15 | 2 | 2 (2–2) | 1110 (ND) | 5750 (ND) | NA | |
120 | Day 1 | 5 | 2 (1–48) | 876 (79) | 2990 (65) | 7600 (52) |
Day 15 | 1 | 8 | 982 (ND) | 6430 (ND) | NA | |
Intermittent Dose Schedule A | ||||||
80 | Day -3 | 4 | 1.5 (1–2) | 410 (50) | 1580 (53) | 3540 (59) |
Day 8 | 3 | 1 (1–1) | 614 (47) | 2350 (10) | 6740 (n = 1) | |
100 | Day -3 | 4 | 1 (1–1) | 543 (70) | 1970 (59) | 4170 (52) |
Day 8 | 3 | 1 (1–2) | 966 (10) | 3910 (22) | 12,400 (n = 2) | |
120 | Day -3 | 4 | 3 (1–4) | 549 (44) | 2590 (54) | 5590 (62) |
Day 8 | 3 | 1 (1–24) | 872 (79) | 3710 (78) | 8940 (69) | |
140 | Day -3 | 6 | 1 (1–4) | 709 (60) | 2580 (48) | 5810 (42) |
Day 8 | 6 | 1 (0.5–2) | 923 (48) | 3220 (28) | 7590 (30; n = 3) | |
160 | Day -3 | 3 | 1 (1–2) | 539 (25) | 2480 (16) | 5830 (20) |
Day 8 | 3 | 2 (1–2) | 857 (28) | 4080 (41) | 11,100 (64) | |
200 | Day -3 | 4 | 2 (1–2) | 1030 (34) | 3480 (37) | 7050 (37) |
Day 8 | 4 | 2 (1–4) | 963 (61) | 4460 (56) | 15,900 (n = 2) | |
Intermittent Dose Schedule B | ||||||
80 | Day 1 | 4 | 3 (1–6) | 341 (17) | 1680 (40) | 4000 (55) |
Day 8 | 4 | 1.5 (1–8) | 681 (30) | 2600 (34) | 6350 (44; n = 3) | |
100 | Day 1 | 7 | 2 (0.5–8) | 562 (98) | 1920 (67) | 4520 (54) |
Day 8 | 6 | 1.5 (0.5–6) | 714 (69) | 2880 (54) | 6200 (67; n = 4) | |
120 | Day 1 | 3 | 1 (1–2) | 471 (35) | 1530 (5) | 3340 (4) |
Day 8 | 3 | 1 (1–8) | 594 (34) | 2210 (8) | 5850 (24) | |
140 | Day 1 | 3 | 1 (0.5–1) | 1010 (37) | 4150 (63) | 9740 (68) |
Day 8 | 3 | 1 (1–2) | 1560 (30) | 5160 (44) | 12,600 (n = 2) | |
160 | Day 1 | 3 | 12 (1–12) | 317 (63) | 1050 (54) | 3700 (29) |
Day 8 | 3 | 8 (2–22.3) | 325 (83) | 1770 (97) | ND | |
200 | Day 1 | 4 | 1.5 (1–8) | 734 (66) | 3190 (72) | 8010 (68) |
Day 8 | 4 | 1.5 (1–6) | 1200 (46) | 5800 (38) | 14,700 (58; n = 3) |
Best Overall Response (BOR) | Treatment Group/Number of Patients | |||
---|---|---|---|---|
Continuous | Intermittent A | Intermittent B | All Schedules | |
n = 21 | n = 25 | n = 24 | n = 70 | |
Complete response (CR) | 0 | 0 | 0 | 0 |
Partial response | 0 | 1 (4%) | 0 | 1 (1.4%) |
Stable disease | 5 (23.8%) | 12 (48%) | 13 (54.2%) | 30 (43%) |
Non-CR/Non-PD | 0 | 1 (4%) | 3 (12.5%) | 4 (5.7%) |
Progressive disease (PD) | 7 (33.3%) | 6 (24%) | 6 (25%) | 19 (27.1%) |
Missing | 9 (42.9%) | 5 (20%) | 2 (8.3%) | 16 (22.9%) |
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Share and Cite
Janku, F.; Choong, G.M.; Opyrchal, M.; Dowlati, A.; Hierro, C.; Rodon, J.; Wicki, A.; Forster, M.D.; Blagden, S.P.; Yin, J.; et al. A Phase I Study of the Oral Dual-Acting Pan-PI3K/mTOR Inhibitor Bimiralisib in Patients with Advanced Solid Tumors. Cancers 2024, 16, 1137. https://doi.org/10.3390/cancers16061137
Janku F, Choong GM, Opyrchal M, Dowlati A, Hierro C, Rodon J, Wicki A, Forster MD, Blagden SP, Yin J, et al. A Phase I Study of the Oral Dual-Acting Pan-PI3K/mTOR Inhibitor Bimiralisib in Patients with Advanced Solid Tumors. Cancers. 2024; 16(6):1137. https://doi.org/10.3390/cancers16061137
Chicago/Turabian StyleJanku, Filip, Grace M. Choong, Mateusz Opyrchal, Afshin Dowlati, Cinta Hierro, Jordi Rodon, Andreas Wicki, Martin D. Forster, Sarah P. Blagden, Jun Yin, and et al. 2024. "A Phase I Study of the Oral Dual-Acting Pan-PI3K/mTOR Inhibitor Bimiralisib in Patients with Advanced Solid Tumors" Cancers 16, no. 6: 1137. https://doi.org/10.3390/cancers16061137