Table 4.
Pharmacodynamic 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 % |
NA no data available, ND not diseased
aCytogenetic alterations (del 13q14, del 11q22, del 17p and t 12) were assessed by FISH analysis. The thresholds for alterations, defined as the percentage of nuclei carrying the studied alteration, were >5 % for del 13q14, and >10 % for del 11q22, t 12 and del 17p
bDel 13q14, del 11q22 and del 17p not assessed
c26 %
d34 %
eDel 6q probe was used in this patient, and found positive
fDel 11q22, t 12 not assessed
gDay 22 data (day 8 data not available)