Introduction
Methods
Patients and study design
Criteria for evaluation
Results
Patient characteristics
Characteristic | Dose level of F14512 | ||
---|---|---|---|
10 mg/m2/day (n = 5) N (%) | 5 mg/m2/day (n = 6) N (%) | Overall (n = 11) N (%) | |
Age (years) | |||
Median | 63.1 | 62.2 | 63.0 |
Range | [61.4–69.9] | [57.7–68.9] | [57.7–69.9] |
Groups of age, N (%) | |||
< 65 | 3 (60.0) | 4 (66.7) | 7 (63.6) |
≥ 65 | 2 (40.0) | 2 (33.3) | 4 (36.4) |
WHO performance status at baseline, N (%) | |||
0 | 2 (40.0) | 2 (33.3) | 4 (36.4) |
1 | 3 (60.0) | 4 (66.7) | 7 (63.6) |
Body weight (kg) | |||
Median | 65.0 | 63.7 | 65.0 |
Range | [49.7–83.0] | [50.0–86.9] | [49.7–86.9] |
BSA (m2) | |||
Median | 1.7 | 1.7 | 1.7 |
Range | [1.5–1.8] | [1.5–2.0] | [1.5–2.0] |
Primary tumor site | |||
Epithelial ovarian cancer | 4 (80.0) | 4 (66.7) | 8 (72.7) |
Peritoneal carcinoma | 1 (20.0) | 2 (33.3) | 3 (27.3) |
Histology, N (%) | |||
Serous Carcinoma | 4 (80.0) | 4 (66.7) | 8 (72.7) |
Endometroid carcinoma | 1 (20.0) | 1 (16.7) | 2 (18.2) |
Unknown | – | 1 (16.7) | 1 (9.1) |
Histopathological grade, N (%) | |||
G2 moderately differentiated | 2 (40.0) | – | 2 (18.2) |
G2 poorly differentiated | 2 (40.0) | 4 (66.7) | 6 (54.5) |
Unknown | 1 (20.0) | 2 (33.3) | 3 (27.3) |
Figo stage, N (%) | |||
III B | 1 (20.0) | 1 (16.7) | 2 (18.2) |
III C | – | 3 (50.0) | 3 (27.3) |
III | 2 (40.0) | – | 2 (18.2) |
IV | – | 2 (33.3) | 2 (18.2) |
IC | 1 (20.0) | – | 1 (9.1) |
Unknown | 1 (20.0) | – | 1 (9.1) |
Time from first diagnosis to study entry (months) | |||
Median | 28.1 | 16.2 | 18.6 |
[Range] | [11.2–44.8] | [9.7–25.4] | [9.7–44.8] |
Progression free interval (months) | |||
Median | 0.4 | 0.4 | 0.4 |
[Range] | [0.0–7.7] | [0.0–0.7] | [0.0–7.7] |
Unknown | 1 | 1 | 2 |
Number of organs involved, N (%) | |||
1 organ | 1 (20.0) | 2 (33.3) | 3 (27.3) |
2 organs | 1 (20.0) | 3 (50.0) | 4 (36.4) |
≥ 3 organs | 3 (60.0) | 1 (16.7) | 4 (36.4) |
Type of organs involved at baseline, N (%) | |||
Liver | 3 (60.0) | 5 (83.3) | 8 (72.7) |
Lymph nodes | 3 (60.0) | 2 (33.3) | 5 (45.5) |
Peritoneum | 1 (20.0) | 2 (33.3) | 3 (27.3) |
Colon | 1 (20.0) | 1 (16.7) | 2 (18.2) |
Pleural effusion | 2 (40.0) | – | 2 (18.2) |
Other | 2 (40.0) | 1 (16.7) | 3 (27.3) |
Determination of MTD and DLTs
Dose of F14512 (mg/m2/day) | Treated/evaluable patients (N) | Patients with DLT (N) | Total cycles N (%) | Cycles administered median [range] | Type of DLTs (N) |
---|---|---|---|---|---|
10 | 5/4 | 3 | 13 (100.0) | 1.0 [1.0–9.0] | Grade 3 Febrile neutropenia (2) Grade 3 Nausea (1) Grade 3 Asthenia (1) Grade 3 Decreased appetite (1) Grade 4 Neutropenia lasting at least 7 days (1) |
5 | 6/6 | 2 | 16 (83.3) | 1.5 [1.0–9.0] | Grade 3 Febrile neutropenia (2) |
Safety
Dose level of F14512 | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|
System Organ Class | Preferred Term | 10 mg/m2/day n = 5 | 5 mg/m2/day n = 6 | Overall n = 11 | ||||||
Grade 3 N (%) | Grade 4 N (%) | Overall N (%) | Grade 3 N (%) | Grade 4 N (%) | Overall N (%) | Grade 3 N (%) | Grade 4 N (%) | Overall N (%) | ||
Any related TESS | 2 (40.0) | 1 (20.0) | 5 (100.0) | 4 (66.7) | 0 (0.0) | 6 (100.0) | 6 (54.5) | 1 (9.1) | 11 (100.0) | |
Blood and lymphatic system disorders | 2 (40.0) | 1 (20.0) | 3 (60.0) | 2 (33.3) | – | 2 (33.3) | 4 (36.4) | 1 (9.1) | 5 (45.5) | |
Febrile neutropenia | 2 (40.0) | – | 2 (40.0) | 2 (33.3) | – | 2 (33.3) | 4 (36.4) | – | 4 (36.4) | |
Neutropenia | – | 1 (20.0) | 1 (20.0) | – | – | – | – | 1 (9.1) | 1 (9.1) | |
Gastrointestinal disorders | 1 (20.0) | – | 3 (60.0) | 1 (16.7) | – | 3 (50.0) | 2 (18.2) | – | 6 (54.5) | |
Constipation | – | – | 1 (20.0) | – | – | 1 (16.7) | – | – | 2 (18.2) | |
Diarrhea | – | – | 1 (20.0) | – | – | 1 (16.7) | – | – | 2 (18.2) | |
Dyspepsia | – | – | 1 (20.0) | – | – | – | – | – | 1 (9.1) | |
Nausea | 1 (20.0) | – | 3 (60.0) | 1 (16.7) | – | 3 (50.0) | 2 (18.2) | – | 6 (54.5) | |
Stomatitis | – | – | 1 (20.0) | – | – | – | – | – | 1 (9.1) | |
Vomiting | – | – | 2 (40.0) | – | – | 2 (33.3) | – | – | 4 (36.4) | |
General disorders and administration site conditions | 1 (20.0) | – | 5 (100.0) | 1 (16.7) | – | 4 (66.7) | 2 (18.2) | – | 9 (81.8) | |
Asthenia | 1 (20.0) | – | 5 (100.0) | 1 (16.7) | – | 4 (66.7) | 2 (18.2) | – | 9 (81.8) | |
Pyrexia | – | – | – | – | – | 1 (16.7) | – | – | 1 (9.1) | |
Infections and infestations | – | – | – | – | – | 1 (16.7) | – | – | 1 (9.1) | |
Gingivitis | – | – | – | – | – | 1 (16.7) | – | – | 1 (9.1) | |
Neutropenic infection | – | – | – | – | – | 1 (16.7) | – | – | 1 (9.1) | |
Musculoskeletal and connective tissue disorders | – | – | 1 (20.0) | – | – | 1 (16.7) | – | – | 2 (18.2) | |
Muscle spasms | – | – | 1 (20.0) | – | – | 1 (16.7) | – | – | 2 (18.2) | |
Myalgia | – | – | 1 (20.0) | – | – | – | – | – | 1 (9.1) | |
Nervous system disorders | – | – | – | – | – | 1 (16.7) | – | – | 1 (9.1) | |
Dysgeusia | – | – | – | – | – | 1 (16.7) | – | – | 1 (9.1) | |
Psychiatric disorders | – | – | – | – | – | 1 (16.7) | – | – | 1 (9.1) | |
Confusional state | – | – | – | – | – | 1 (16.7) | – | – | 1 (9.1) | |
Skin and subcutaneous tissue disorders | – | – | 1 (20.0) | – | – | 3 (50.0) | – | – | 4 (36.4) | |
Alopecia | – | – | 1 (20.0) | – | – | 1 (16.7) | – | – | 2 (18.2) | |
Night sweats | – | – | – | – | – | 1 (16.7) | – | – | 1 (9.1) | |
Onycholysis | – | – | – | – | – | 1 (16.7) | – | – | 1 (9.1) |
Efficacy
Pharmacokinetics and pharmacodynamics
PK parameter | F14512 (n = 11) Mean [range] | F16490 (n = 11) Mean [range] | ||
---|---|---|---|---|
D1 | D3 | D1 | D3 | |
AUCinf/dose level | 152 [67.7–308] | 156 [65.9–270] | 84.6 [41.3–136] | 88.0 [46.0–141] |
Cltot (L/h) | 13.2 [6.17–22.4] | 12.9 [5.92–23.1] | – | – |
Metabolic ratio | – | – | 0.580 [0.440–0.709] | 0.584 [0.495–0.698] |