Introduction
Patients and methods
Patients
Treatment plan
Assessments
Safety
Pharmacokinetics
Anti-leukemic activity
Pharmacodynamics
Results
Patient characteristics
PART I—single dose | PART II—multiple doses | ||||||||
---|---|---|---|---|---|---|---|---|---|
Dose | 50 | 83.5 | 139.5 | 210 | 315 | Overall part I | 2 doses at 210 | 5 doses at 210 | Overall part II |
Patients | (n = 6) | (n = 3) | (n = 3) | (n = 3) | (n = 3) | (n = 18) | (n = 3) | (n = 3) | (n = 6) |
Age
| |||||||||
Mean | 69.2 | 66.0 | 67.0 | 67.0 | 60.0 | 66.4 | 69.0 | 66.7 | 67.8 |
Range | 60–79 | 61–72 | 63–70 | 56–76 | 58–63 | 56–79 | 63–76 | 56–77 | 56–77 |
Gender (number of males, %)
| 2 (33 %) | 2 (67 %) | 2 (67 %) | 2 (67 %) | 3 (100 %) | 11 (61 %) | 2 (67 %) | 2 (67 %) | 4 (67 %) |
Duration of disease (years)
| |||||||||
Mean | 7.6 | 15.0 | 12.7 | 10.4 | 11.0 | 10.7 | 10.7 | 10.8 | 10.7 |
Range | 4–14 | 14–17 | 5–21 | 7–13 | 7–14 | 4–21 | 7–13 | 6–16 | 6–16 |
Performance status
| |||||||||
0 | 3 | 2 | 2 | 3 | 1 | 11 (61 %) | 0 | 2 | 2 (33 %) |
1 | 2 | 1 | 1 | 0 | 2 | 6 (33 %) | 2 | 1 | 3 (50 %) |
2 | 1 | 0 | 0 | 0 | 0 | 1 (6 %) | 1 | 0 | 1 (17 %) |
Rai stage III–IV
| 1 | 1 | 2 | 1 | 1 | 6 (33 %) | 1 | 0 | 1 (17 %) |
Baseline FISH analysis
| |||||||||
Del 13q14 | 4 (67 %) | 3 (100 %) | 1 (33 %) | 0 | 1 (33 %) | 9 (50 %) | 1 (33 %) | 2 (67 %) | 3 (50 %) |
Del 11q22–23 | 1 (17 %) | 1 (33 %) | 1 (33 %) | 0 | 1 (33 %) | 4 (22 %) | 1 (33 %) | 1 (33 %) | 2 (33 %) |
Trisomy 12 | 1 (17 %) | 0 | 0 | 0 | 0 | 1 (6 %) | 2 (67 %) | 1 (33 %) | 3 (50 %) |
Del 17p | 1 (17 %) | 1 (33 %) | 0 | 0 | 0 | 2 (11 %) | 0 | 0 | 0 |
Number of patients with number of prior therapies >1
| 5 | 2 | 2 | 3 | 3 | 15 (83 %) | 2 | 1 | 3 (50 %) |
Range | 1–4 | 1–13 | 1–2 | 2 | 2–6 | 1–13 | 1–7 | 1–4 | 1–7 |
Absolute lymphocyte count (10
9
/L)
| |||||||||
Mean | 40.5 | 30.1 | 67.2 | 70.2 | 31.2 | 46.6 | 132.3 | 16.5 | 74.5 |
Range | 15.7–85.0 | 11.6–53.3 | 38.4–90.5 | 15.7–106.0 | 1.0–68.6 | 1.0–106.0 | 50.0–229.4 | 9.8–29.3 | 9.8–229.4 |
Hemoglobin (g/L)
| |||||||||
Mean | 120.3 | 123.3 | 129.0 | 103.7 | 114.7 | 118.5 | 106.0 | 130.7 | 118.3 |
Range | 110–136 | 114–129 | 107–144 | 103–105 | 99–123 | 99–144 | 9–115 | 116–142 | 99–142 |
Cohort | Dose (mg/kg) | Patient | Rai stage | Binet stage | Relapsed or refractorya
|
---|---|---|---|---|---|
Part I
| |||||
1 | 50 | 1 | 1 | A | Relapsed |
2 | 4 | C | Relapsed | ||
3 | 0 | A | Refractory | ||
4 | 1 | A | Refractory | ||
5 | 2 | A | Refractory | ||
6 | 1 | A | Relapsed | ||
2 | 83.5 | 7 | 0 | A | Relapsed |
8 | 1 | B | Relapsed | ||
9 | 4 | C | Relapsed | ||
3 | 139.5 | 10 | 4 | C | Relapsed |
11 | 4 | C | Refractory | ||
12 | 1 | A | Relapsed | ||
4 | 210 | 13 | 4 | C | Relapsed |
14 | 2 | A | Relapsed | ||
15 | 2 | A | Relapsed | ||
5 | 315 | 16 | 1 | B | Relapsed |
17 | 4 | C | Relapsed | ||
19 | NA | A | Relapsed | ||
Part II
| |||||
6 | 2 × 210 | 20 | 1 | A | Relapsed |
22 | 3 | B | Relapsed | ||
23 | 2 | B | Relapsed | ||
7 | 5 × 210 | 24 | NAb
| NAb
| Relapsed |
25 | 2 | B | Relapsed | ||
26 | 2 | B | Relapsed |
Treatment
Safety and tolerability results
Part I | Part II | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
mg/kg | 50 | 83.5 | 139.5 | 210 | 315 | 2 doses at 210 | 5 doses at 210 | |||
AEs CTCAE grade | 1–2 | 3–4 | 1–2 | 1–2 | 1–2 | 1–2 | 3–4 | 1–2 | 3–4 | 1–2 |
Number possible, probable or definitive drug-related AEs (number of patients) | 11 (4) | 3 (2) | 5 (2) | 1 (1) | 4 (3) | 15 (3) | 3 (2) | 9 (3) | 1 (1) | 21 (3) |
Investigations
| ||||||||||
Alanine aminotransferase increased | 2 (1) | |||||||||
Blood bilirubin increased | 1 (1) | 1 (1) | ||||||||
Blood creatinine increased | 1 (1) | 3 (2) | ||||||||
Platelet count decreased | 1 (1) | 1 (1) | ||||||||
Nervous system disorders
| ||||||||||
Headache | 1 (1) | 1 (1) | 1 (1) | 1 (1) | ||||||
Dizziness | 1 (1) | 1 (1) | ||||||||
Paresthesia | 1 (1) | |||||||||
Presyncope | 1 (1) | |||||||||
Metabolism and nutrition disorders
| ||||||||||
Hyperglycemia | 1 (1) | 1 (1) | ||||||||
Hyperkalemia | 1 (1) | 1 (1) | ||||||||
Hyperuricemia | 1 (1) | |||||||||
Hypoglycemia | 1 (1) | |||||||||
Hypokalemia | 1 (1) | |||||||||
Tumor lysis syndrome | 1 (1) | |||||||||
Gatrointestinal disorders
| ||||||||||
Diarrhea | 2 (1) | 1 (1) | 1 (1) | |||||||
Nausea | 2 (2) | 1 (1) | 5 (2) | |||||||
Gastric disorder | ||||||||||
Vomiting | 1 (1) | 1 (1) | ||||||||
Abdominal pain | 1 (1) | |||||||||
Vascular disorders
| ||||||||||
Hypotension | 1 (1) | 1 (1) | 1 (1) | |||||||
Hypertension | 1 (1) | |||||||||
Hematoma | 1 (1) | |||||||||
Blood and lymphatic disorders
| ||||||||||
Anemia (or hemoglobin decreased) | 1 (1) | 1 (1) | 3 (1) | 3 (2) | 6 (2) | |||||
Thrombocytopenia | 2 (2) | |||||||||
Neutropenia | 1 (1) | |||||||||
Renal and urinary disorders
| ||||||||||
Renal failure acute | 1 (1) | |||||||||
Other non-hematological AEs
| ||||||||||
Other AEs | 2 (2) | 1 (1) | 2 (2) | 1 (1) | 3 (1) |
Pharmacodynamic and anti-leukemic activity results
Part | Cohort | Patient number | Cytogenetic alterationsa
| B cells (cells/mm3) | Sum of bi-dimensional Lymph nodes (cm) | Sum of uni-dimensional liver and spleen nodes (cm) | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Day 1 (pre-dose) | Day 2 | % Variation Day 2 versus Day 1 | Day 8 | % Variation Day 8 versus Day 1 | Day 1 pre-dose | Day 8 | % Variation versus Day 1 | Day 1 pre-dose | Day 8 | % Variation versus Day 1 | ||||
I Single dose | Cohort 1 50 mg/kg | 1 | Del 13q14 | 19,958 | 15,730 | −21 % | 22,839 | 14 % | 2 | 1 | −50 % | ND | ND | – |
2 | Del 13q14 | 84,053 | NA | – | 77,607 | −8 % | 7, 5 | 7, 5 | 0 % | 2 | ND | −100 % | ||
3 | NA | 19,069 | 15,845 | −17 % | 18,734 | −2 % | ND | ND | – | ND | ND | – | ||
4 | Del 13q14 Del 11q22 | 25,274 | 21,856 | −14 % | 22,926 | −9 % | 3 | 3 | 0 % | ND | ND | – | ||
5 | t 12b
| 84,466 | 78,811 | −7 % | 67,663 | −20 % | ND | ND | – | ND | ND | – | ||
6 | Del 13q14 Del 17pc
| 15,903 | 15,141 | −5 % | 8,244 | −48 % | 2 | 2 | 0 % | ND | ND | – | ||
Cohort 2 83.5 mg/kg | 7 | Del 13q14 | 56,506 | 43,464 | −23 % | 62,890 | 11 % | ND | ND | – | ND | ND | – | |
8 | Del 13q14 Del 17pd
| 11,682 | 14,862 | 27 % | 17,326 | 48 % | 3 | 6 | 100 % | ND | ND | – | ||
9 | Del 13q14 Del 11q22 | 23,608 | 22,973 | −3 % | 28,419 | 20 % | 8 | 12 g
| 50 % | 18 | 13 g
| −28 % | ||
Cohort 3 139.5 mg/kg | 10 | No alterations | 92,967 | 67,814 | −27 % | 83,055 | −11 % | 6 | 6 | 0 % | 4 | 1 | −75 % | |
11 | Del 13q14 | 70,717 | NA | – | 82,019 | 16 % | ND | ND | – | 5 | 5 | 0 % | ||
12 | Del 11q22 | 35,073 | 25,140 | −28 % | 33,130 | −6 % | ND | 2 | 100 % | ND | ND | – | ||
Cohort 4 210 mg/kg | 13 | No alterations | 94,500 | 98,464 | 4 % | 103,630 | 10 % | 4, 5 | 5, 5 | 22 % | 1 | 1 | 0 % | |
14 | No alterationse
| 88,556 | 60,840 | −31 % | 87,782 | −1 % | ND | ND | – | 2 | 2 | 0 % | ||
15 | NA | 14,330 | 13,483 | −6 % | 15,163 | 6 % | 2, 5 | 2 | −20 % | ND | ND | – | ||
Cohort 5 315 mg/kg | 16 | No alterations | 18,739 | 22,047 | 18 % | 8,653 | −54 % | 16 | 11 | −31 % | ND | ND | – | |
17 | Del 13q14 Del 11q22 | 62,634 | 61,416 | −2 % | 68,075 | 9 % | 10 | 9 | −10 % | 8 | 7 | −13 % | ||
19 | No alterationsf
| NA | NA | – | NA | – | NA | NA | – | NA | NA | – |
Part | Cohort | Patient number | Cytogenetic alterationsa
| Day 1 pre-dose | Day 2, after the last dose | %variation Day 2 after last dose versus Day 1 | Day 8, after the last dose | % Variation versus Day 8 after last dose versus Day 1 | Day 1 pre-dose | Day 8, after the last dose | % Variation versus Day 1 | Day 1 pre-dose | Day 8, after the last dose | % Variation versus Day 1 |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
II Multiple doses | Cohort 1 2 doses at 210 mg/kg | 20 | Del 13q14 t 12 | 110,267 | 78,062 | −29 % | 94,694 | −14 % | 1, 4 | 2 | 43 % | ND | ND | – |
22 | No alterations | 230,364 | 225,421 | −2 % | 296,661 | 29 % | 15 | 16 g
| 7 % | ND | ND | – | ||
23 | t 12 Del 11q22 | 61,360 | 40,124 | −35 % | 83,364 | 36 % | 31 | 31 | 0 % | 2 | 2 | 0 % | ||
Cohort 2 5 doses at 210 mg/kg | 24 | Del 13q14 | 7,240 | 13,448 | 86 % | 6,440 | −11 % | ND | ND | – | ND | ND | – | |
25 | Del 13q14 Del 11q22 | 31,068 | 75,574 | 143 % | 63,013 | 103 % | 4 | 2 | −50 % | ND | ND | – | ||
26 | t 12 | 9,177 | 5,569 | −39 % | 3,145 | −66 % | 1 | 4, 5 | 350 % | 1 | ND | −100 % |
Pharmacokinetic results
Cohort | Dose (mg/kg) |
t
max (h) |
C
max (ng/mL) | AUC(0→24h) (ng h/mL) |
t
½ (h) |
---|---|---|---|---|---|
(A)
| |||||
Part I | |||||
1 | 50 | ||||
Median | 4.0 | 4,325 | 14,251 | 5.2 | |
Minimum | 3.7 | 2,930 | 9,800 | 1.0 | |
Maximum | 4.3 | 8,139 | 21,213 | 45.4 | |
2 | 83.5 | ||||
Median | 4.1 | 6,888 | 24,614 | 35.0 | |
Minimum | 4.1 | 5,148 | 15,986 | 5.2 | |
Maximum | 4.5 | 10,036 | 32,534 | 79.4 | |
3 | 139.5 | ||||
Median | 4.0 | 12,439 | 39,503 | 25.3 | |
Minimum | 3.9 | 2,449 | 11,549 | 3.8 | |
Maximum | 4.0 | 30,574 | 89,015 | 28.5 | |
4 | 210 | ||||
Median | 4.0 | 38,736 | 123,125 | 16.2 | |
Minimum | 4.0 | 30,431 | 118,235 | 10.2 | |
Maximum | 4.1 | 64,672 | 240,500 | 35.7 | |
5 | 315 | ||||
Median | 4.5 | 35,170 | 240,403 | 61.4 | |
Minimum | 4.2 | 33,855 | 171,809 | 2.6 | |
Maximum | 4.7 | 65,536 | 275,298 | 62.0 | |
Part II | |||||
6 | 2 × 210 | ||||
Day 1 | |||||
Median | 4.1 | 41,851 | 195,556 | 24.6 | |
Minimum | 4.0 | 7,177 | 26,315 | 14.2 | |
Maximum | 4.4 | 68,366 | 228,532 | 25.8 | |
Day 4 | |||||
Median | 4.2 | 28,774 | 126,430 | 98.8 | |
Minimum | 4.0 | 2,213 | 14,858 | 18.8 | |
Maximum | 4.5 | 45,939 | 149,534 | 106.2 | |
7 | 5 × 210 | ||||
Day 1 | |||||
Median | 4.3 | 49,533 | 161,939 | 3.9 | |
Minimum | 4.3 | 41,619 | 117,843 | 3.0 | |
Maximum | 4.6 | 54,892 | 198,014 | 12.0 | |
End of treatment | |||||
Median | 4.1 | 51,456 | 198,646 | 56.2 | |
Minimum | 4.0 | 51,160 | 148,617 | 3.8 | |
Maximum | 4.2 | 67,684 | 231,356 | 65.1 | |
(B)
| |||||
Part I | |||||
1 | 50 | ||||
Median | 4.3 | 52,101 | 312,131 | 72.3 | |
Minimum | 3.67 | 7,666 | 20,438 | 0.5 | |
Maximum | 5.03 | 93,198 | 424,582 | 239.9 | |
2 | 83.5 | ||||
Median | 4.5 | 73,023 | 562,247 | 35.1 | |
Minimum | 4.08 | 71,775 | 360,973 | 34.5 | |
Maximum | 5.08 | 76,814 | 577,760 | 95.2 | |
3 | 139.5 | ||||
Median | 4.0 | 114,001 | 1,023,992 | 66.4 | |
Minimum | 4.00 | 94,144 | 701,177 | 17.6 | |
Maximum | 4.58 | 156,663 | 1,343,691 | 91.2 | |
4 | 210 | ||||
Median | 4.1 | 270,988 | 2,066,170 | 39.8 | |
Minimum | 4.00 | 185,258 | 1,910,548 | 22.2 | |
Maximum | 5.08 | 295,124 | 2,159,142 | 118.2 | |
5 | 315 | ||||
Median | 4.5 | 243,540 | 2,434,242 | 8.1 | |
Minimum | 4.17 | 157,154 | 1,472,810 | 5.7 | |
Maximum | 4.68 | 342,195 | 2,873,273 | 111.7 | |
Part II | |||||
6 | 2 × 210 | ||||
Day 1 | |||||
Median | 4.1 | 275,836 | 2,610,904 | 24.3 | |
Minimum | 4.00 | 152,335 | 853,666 | 12.7 | |
Maximum | 4.42 | 312,929 | 2,747,816 | 26.5 | |
Day 4 | |||||
Median | 4.7 | 223,390 | 2,081,843 | 81.5 | |
Minimum | 4.00 | 95,310 | 738,586 | 64.4 | |
Maximum | 5.50 | 229,030 | 2,538,271 | 134.1 | |
7 | 5 × 210 | ||||
Day 1 | |||||
Median | 5.7 | 265,536 | 1,833,232 | 16.6 | |
Minimum | 5.33 | 159,539 | 1,056,891 | 11.4 | |
Maximum | 6.33 | 344,686 | 2,866,182 | 45.4 | |
End of treatment | |||||
Median | 4.2 | 188,936 | 1,942,209 | 71.3 | |
Minimum | 4.00 | 108,108 | 870,256 | 16.2 | |
Maximum | 5.08 | 265,657 | 2,152,337 | 98.1 |