Table 2.
Summary of the Most Common Grade 1/2 Treatment-Related Adverse Events During Phases 1 and 2 (>10% Incidence in Total Safety-Evaluable Population) and Any Grade 3/4 Treatment-Related Adverse Events (All Treatment Cycles)
| Phase 1 Dose Escalation, mg/m2 (n = 16) | Phase 2 (n = 27) | Total (n = 43) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 250 (n = 3) | 400 (n = 3) | 550 (n = 7) | 750 (n = 3) | ||||||||||
| G1/2 | G3/4 | G1/2 | G3/4 | G1/2 | G3/4 | G1/2 | G3/4 | G1/2 | G3/4 | G1/2 | G3/4 | Any G | |
| Any TRAE | 3 (100) | 0 | 2 (66.7) | 1 (33.3) | 7 (100) | 0 | 1 (33.3) | 2 (66.7) | 6 (22.2) | 20 (74.1) | 19 (44.2) | 23 (53.5) | 42 (97.7) |
| Weight gain | 0 | 0 | 0 | 0 | 4 (57.1) | 0 | 1 (33.3) | 0 | 9 (33.3) | 7 (25.9) | 14 (32.6) | 7 (16.3) | 21 (48.8) |
| Anemia | 1 (33.3) | 0 | 0 | 0 | 2 (28.6) | 0 | 2 (66.7) | 0 | 11 (40.7) | 1 (3.7) | 16 (37.2) | 1 (2.3) | 17 (39.5) |
| Blood creatinine increased | 2 (66.7) | 0 | 2 (66.7) | 0 | 2 (28.6) | 0 | 2 (66.7) | 0 | 9 (33.3) | 0 | 17 (39.5) | 0 | 17 (39.5) |
| Nausea | 3 (100) | 0 | 1 (33.3) | 0 | 2 (28.6) | 0 | 1 (33.3) | 0 | 8 (29.6) | 0 | 15 (34.9) | 0 | 15 (34.9) |
| Constipation | 1 (33.3) | 0 | 0 | 0 | 4 (57.1) | 0 | 1 (33.3) | 0 | 7 (25.9) | 0 | 13 (30.2) | 0 | 13 (30.2) |
| ALT increased | 0 | 0 | 1 (33.3) | 0 | 3 (42.9) | 0 | 2 (66.7) | 0 | 4 (14.8) | 2 (7.4) | 10 (23.3) | 2 (4.7) | 12 (27.9) |
| AST increased | 2 (66.7) | 0 | 2 (66.7) | 0 | 1 (14.3) | 0 | 2 (66.7) | 0 | 3 (11.1) | 1 (3.7) | 10 (23.3) | 1 (2.3) | 11 (25.6) |
| Neutrophil count decreased | 0 | 0 | 0 | 1 (33.3) | 1 (14.3) | 0 | 0 | 1 (33.3) | 2 (7.4) | 5 (18.5) | 3 (7.0) | 7 (16.3) | 10 (23.3) |
| White blood cell decreased | 0 | 0 | 0 | 0 | 0 | 0 | 2 (66.7) | 0 | 5 (18.5) | 2 (7.4) | 7 (16.3) | 2 (4.7) | 9 (20.9) |
| Vomiting | 0 | 0 | 0 | 0 | 2 (28.6) | 0 | 0 | 0 | 7 (25.9) | 0 | 9 (20.9) | 0 | 9 (20.9) |
| Diarrhea | 0 | 0 | 1 (33.3) | 0 | 2 (28.6) | 0 | 0 | 0 | 5 (18.5) | 0 | 8 (18.6) | 0 | 8 (18.6) |
| Dysgeusia | 0 | 0 | 1 (33.3) | 0 | 2 (28.6) | 0 | 2 (66.7) | 0 | 3 (11.1) | 0 | 8 (18.6) | 0 | 8 (18.6) |
| Fatigue | 1 (33.3) | 0 | 0 | 0 | 0 | 0 | 1 (33.3) | 0 | 5 (18.5) | 1 (3.7) | 7 (16.3) | 1 (2.3) | 8 (18.6) |
| Flatulence | 0 | 0 | 0 | 0 | 2 (28.6) | 0 | 2 (66.7) | 0 | 3 (11.1) | 0 | 7 (16.3) | 0 | 7 (16.3) |
| Urinary incontinence | 0 | 0 | 0 | 0 | 1 (14.3) | 0 | 1 (33.3) | 0 | 5 (18.5) | 0 | 7 (16.3) | 0 | 7 (16.3) |
| Hypernatremia | 1 (33.3) | 0 | 0 | 0 | 0 | 0 | 1 (33.3) | 0 | 4 (14.8) | 0 | 6 (14.0) | 0 | 6 (14.0) |
| Fracture (combined)a | 0 | 0 | 0 | 0 | 1 (14.3) | 0 | 0 | 0 | 3 (11.1) | 2 (7.4) | 4 (9.3) | 2 (4.7) | 6 (14.0) a |
| Headache | 0 | 0 | 0 | 0 | 1 (14.3) | 0 | 1 (33.3) | 0 | 3 (11.1) | 0 | 5 (11.6) | 0 | 5 (11.6) |
| Abdominal pain | 0 | 0 | 0 | 0 | 2 (28.6) | 0 | 0 | 0 | 3 (11.1) | 0 | 5 (11.6) | 0 | 5 (11.6) |
| Pain in extremity | 1 (33.3) | 0 | 0 | 0 | 1 (14.3) | 0 | 0 | 0 | 3 (11.1) | 0 | 5 (11.6) | 0 | 5 (11.6) |
| Increased appetite | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 5 (18.5) | 0 | 5 (11.6) | 0 | 5 (11.6) |
| Platelet count decreased | 0 | 0 | 0 | 0 | 0 | 0 | 1 (33.3) | 1 (33.3) | 2 (7.4) | 0 | 3 (7.0) | 1 (2.3) | 4 (9.3) |
| Neutropenia | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (3.7) | 3 (11.1) | 1 (2.3) | 3 (7.0) | 4 (9.3) |
| Lymphocyte count decreased | 0 | 0 | 0 | 0 | 0 | 0 | 1 (33.3) | 0 | 1 (3.7) | 1 (3.7) | 2 (4.7) | 1 (2.3) | 3 (7.0) |
| Dyspnea | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (33.3) | 1 (3.7) | 0 | 1 (2.3) | 1 (2.3) | 2 (4.7) |
| Syncope | 0 | 0 | 0 | 0 | 0 | 0 | 1 (33.3) | 0 | 0 | 1 (3.7) | 1 (2.3) | 1 (2.3) | 2 (4.7) |
| Neutrophil percentage decreased | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (3.7) | 0 | 1 (2.3) | 1 (2.3) |
| Pancreatitis | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (3.7) | 0 | 1 (2.3) | 1 (2.3) |
| Pulmonary edema | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (33.3) | 0 | 0 | 0 | 1 (2.3) | 1 (2.3) |
| Pneumonia | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (33.3) | 0 | 0 | 0 | 1 (2.3) | 1 (2.3) |
| Respiratory failure | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (33.3) | 0 | 0 | 0 | 1 (2.3) | 1 (2.3) |
| Hypoxia | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (33.3) | 0 | 0 | 0 | 1 (2.3) | 1 (2.3) |
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; TRAE, treatment-related adverse event.
AEs were encoded using Medical Dictionary for Regulatory Activities (version 21.0).
Values for the total population (Phase 1 and Phase 2) are shown in bold for emphasis.
aIncludes preferred terms fibula fracture, femur fracture, fracture, tibia fracture, pathological fracture, and stress fracture. Values correspond to the number (%) of patients, not events. See Supplementary Table S6 for all fracture events (all causality).