|
Lurbinectedin without primary G-CSF prophylaxis |
Lurbinectedin with primary G-CSF prophylaxis |
||
RD |
All dose levels |
RD |
All dose levels |
|
Gender |
|
|
|
|
Male |
4 (50%) |
5 (33%) |
6 (67%) |
7 (64%) |
Female |
4 (50%) |
10 (67%) |
3 (33%) |
4 (36%) |
Median age, years (range) |
52 (38-65) |
52 (38-65) |
61 (40-77) |
61 (40-77) |
ECOG performance status |
|
|
|
|
0 |
5 (63%) |
11 (73%) |
2 (22%) |
4 (36%) |
1 |
3 (38%) |
4 (27%) |
7 (78%) |
7 (64%) |
Median BSA, m2 (range) |
1.7 (1.6-1.8) |
1.6 (1.3-1.8) |
1.6 (1.5-1.8) |
1.6 (1.5-1.9) |
Primary tumors |
|
|
|
|
Biliopancreatic |
1 (13%) |
3 (20%) |
1 (11%) |
2 (18%) |
Breast |
1 (13%) |
1 (7%) |
1 (11%) |
2 (18%) |
Endometrial |
1 (13%) |
2 (13%) |
1 (11%) |
1 (9%) |
Left upper jaw |
1 (13%) |
1 (7%) |
. |
. |
Parotid gland |
1 (13%) |
2 (13%) |
. |
. |
Rib |
1 (13%) |
1 (7%) |
. |
. |
Urinary bladder |
1 (13%) |
1 (7%) |
. |
. |
Left adrenal gland |
1 (13%) |
1 (7%) |
. |
|
Esophageal |
. |
2 (13%) |
. |
. |
Sigmoid colon |
. |
1 (7%) |
. |
. |
Ureter |
. |
. |
1 (11%) |
1 (9%)) |
Unknown primary site |
. |
. |
1 (11%) |
1 (9%) |
Lung |
. |
. |
1 (11%) |
1 (9%) |
Oropharynx |
. |
. |
1 (11%) |
1 (9%) |
Right inguinal subcutaneous sweat gland |
. |
. |
1 (11%) |
1 (9%) |
Retroperitoneum |
. |
. |
1 (11%) |
1 (9%) |
Histology type |
|
|
|
|
Adenocarcinoma |
7 (88%) |
9 (60%) |
4 (44%) |
6 (55%) |
Carcinoma |
. |
3 (20%) |
2 (22%) |
2 (18%) |
Sarcoma |
1 (13%) |
3 (20%) |
1 (11%) |
1 (9%) |
Other |
. |
. |
2 (22%) a |
2 (18%) |
Sites of disease |
|
|
|
|
Lung |
5 (63%) |
10 (67%) |
5 (56%) |
5 (46%) |
Liver |
2 (25%) |
5 (33%) |
4 (44%) |
6 (55%) |
Bone |
1 (13%) |
1 (7%) |
1 (11%) |
1 (9%) |
Lymph node |
6 (75%) |
10 (67%) |
4 (44%) |
4 (36%) |
Pleura |
3 (38%) |
4 (27%) |
1 (11%) |
1 (9%) |
Soft tissue/skin |
1 (13%) |
2 (13%) |
1 (11%) |
1 (9%) |
Peritoneum |
. |
. |
2 (22%) |
2 (18%) |
Other |
3 (38%) |
6 (40%) b |
2 (22%) |
2 (18%) c |
Prior treatment for advanced disease |
|
|
|
|
Median (range) |
1 (1-2) |
2 (1-3) |
2 (1-3) |
2 (1-3) |
Prior anticancer agents |
|
|
|
|
Cisplatin |
4 (50%) |
8 (53%) |
3 (33%) |
4 (36%) |
Carboplatin |
2 (25%) |
2 (13%) |
4 (44%) |
4 (36%) |
Doxorubicin |
4 (50%) |
6 (40%) |
2 (22%) |
2 (18%) |
Paclitaxel |
2 (25%) |
6 (40%) |
3 (33%) |
4 (36%) |
Fluorouracil |
2 (25%) |
6 (40%) |
2 (22%) |
2 (18%) |
Irinotecan |
2 (25%) |
3 (20%) |
1 (11%) |
1 (9%) |
Gemcitabine |
1 (13%) |
4 (27%) |
1 (11%) |
3 (27%) |
Gimeracil |
1 (13%) |
3 (20%) |
3 (33%) |
4 (36%) |
Oteracil |
1 (13%) |
3 (20%) |
3 (33%) |
4 (36%) |
Tegafur |
1 (13%) |
3 (20%) |
3 (33%) |
4 (36%) |
Investigational drug |
1 (13%) |
3 (20%) |
2 (22%) |
3 (27%) |
a Clear cell carcinoma (n=1 patient) and phyllodes tumor (n=1).
b Ascites (n=2), pleural effusion, left upper jaw, bladder and kidney (n=1 patient each).
c Psoas major muscle and muscle (n=1 each).
BSA, body surface area; ECOG, Eastern Cooperative Oncology Group; G-CSF, granulocyte colony-stimulating factor; RD, recommended
dose.
Table 1 : Baseline characteristics of patients.
Dose level |
Dose |
No. of patients with DLTs / No. of evaluable patients a |
Description of DLTs |
Lurbinectedin without primary G-CSF prophylaxis |
|||
DL1 |
1.5 |
0 / 3 |
. |
DL2 (RD) |
2.5 |
0 / 8 |
. |
DL3 |
3.2 |
2 / 4 |
Grade 3 neutropenia ≥ 7 days (n=1) |
Grade 4 neutropenia ≥ 3 days (n=1) b |
|||
Lurbinectedin with primary G-CSF prophylaxis |
|||
DL1 (RD) |
3.2 |
2 / 9 |
Grade 4 thrombocytopenia (n=2) b |
DL2 (MTD) |
3.5 |
1 / 2 |
Grade 4 ventricular arrhythmia c, grade 4 neutropenia and grade 4 thrombocytopenia (n=1) |
a A total of 26 patients were evaluable for DLTs: 15 without primary G-CSF prophylaxis and 11 with G-CSF.
b This toxicity resulted in lurbinectedin dose reduction.
c This toxicity resulted in treatment discontinuation.
Table 2: Distribution of patients and dose-limiting toxicities over the dose levels studied, without or with primary G-CSF prophylaxis
Lurbinectedin without primary G-CSF prophylaxis |
|||||||||
|
RD |
|
All dose levels |
||||||
NCI-CTCAE grade |
1-2 |
3 |
4 |
Total |
|
1-2 |
3 |
4 |
Total |
Hematological laboratory abnormalities (regardless of relationship) |
|||||||||
Anemia |
7 (88%) |
. |
. |
7 (88%) |
|
13 (87%) |
. |
. |
13 (87%) |
Lymphopenia |
2 (25%) |
5 (63%) |
. |
7 (88%) |
|
6 (40%) |
6 (40%) |
. |
12 (80%) |
Neutropenia |
4 (50%) |
1 (13%) |
. |
5 (63%) |
|
5 (33%) |
2 (13%) |
2 (13%) |
9 (60%) |
Leukopenia |
4 (50%) |
1 (13%) |
. |
5 (63%) |
|
4 (27%) |
4 (27%) |
. |
8 (53%) |
Thrombocytopenia |
2 (25%) |
. |
. |
2 (25%) |
|
4 (27%) |
1 (7%) |
. |
5 (33%) |
Biochemical laboratory abnormalities (regardless of relationship) |
|||||||||
ALT increased |
7 (88%) |
. |
. |
7 (88%) |
|
9 (60%) |
1 (7%) |
. |
10 (67%) |
AP increased |
5 (63%) |
. |
. |
5 (63%) |
|
9 (60%) |
. |
. |
9 (60%) |
AST increased |
6 (75%) |
. |
. |
6 (75%) |
|
12 (80%) |
. |
. |
12 (80%) |
Bilirubin increased |
. |
. |
. |
. |
|
. |
1 (7%) |
. |
1 (7%) |
Treatment-related AEs |
|||||||||
Nausea |
6 (75%) |
. |
. |
6 (75%) |
|
11 (73%) |
. |
. |
11 (73%) |
Constipation |
2 (25%) |
. |
. |
2 (25%) |
|
4 (27%) |
. |
. |
4 (27%) |
Decreased appetite |
3 (38%) |
. |
. |
3 (38%) |
|
7 (47%) |
. |
. |
7 (47%) |
Lurbinectedin with primary G-CSF prophylaxis |
|||||||||
|
RD |
|
All dose levels |
||||||
NCI-CTCAE grade |
1-2 |
3 |
4 |
Total |
|
1-2 |
3 |
4 |
Total |
Hematological laboratory abnormalities (regardless of relationship) |
|||||||||
Anemia |
7 (78%) |
2 (22%) |
. |
9 (100%) |
|
8 (73%) |
3 (27%) |
. |
11 (100%) |
Lymphopenia |
5 (56%) |
4 (44%) |
. |
9 (100%) |
|
6 (54%) |
5 (46%) |
. |
11 (100%) |
Neutropenia |
1 (11%) |
1 (11%) |
1 (11%) |
3 (33%) |
|
1 (9%) |
1 (9%) |
2 (18%) |
4 (36%) |
Leukopenia |
2 (22%) |
2 (22%) |
. |
4 (44%) |
|
3 (27%) |
2 (18%) |
1 (9%) |
6 (55%) |
Thrombocytopenia |
5 (56%) |
. |
2 (22%) |
7 (78%) |
|
6 (55%) |
. |
3 (27%) |
9 (82%) |
Biochemical laboratory abnormalities (regardless of relationship) |
|||||||||
ALT increased |
5 (56%) |
2 (22%) |
. |
7 (78%) |
|
5 (46%) |
2 (18%) |
1 (9%) |
8 (73%) |
AP increased |
8 (89%) |
1 (11%) |
. |
9 (100.0%) |
|
9 (82%) |
1 (9%) |
. |
10 (91%) |
AST increased |
4 (44%) |
1 (11%) |
. |
5 (56%) |
|
5 (46%) |
1 (9%) |
1 (9%) |
7 (64%) |
Treatment-related AEs |
|||||||||
Nausea |
6 (67%) |
|
. |
6 (67%) |
|
7 (64%) |
. |
. |
7 (64%) |
Constipation |
3 (33%) |
. |
. |
3 (33%) |
|
3 (27%) |
. |
. |
3 (27%) |
Decreased appetite |
6 (67%) |
. |
. |
6 (67%) |
|
7 (64%) |
. |
. |
7 (64%) |
Ventricular arrhythmia |
. |
. |
. |
. |
|
. |
. |
1 (9%) |
1 (9%) |
Drug-induced liver injury |
. |
. |
. |
. |
|
. |
1 (9%) |
. |
1 (9%) |
Data shown are number of patients (n) and percentages (%).
Hematological and biochemical abnormalities are shown regardless of relationship to treatment.
AEs, adverse events; ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; JCOG, Japan Clinical Oncology
Group; NCI-CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events (Japanese translation version by
JCOG); G-CSF, granulocyte colony-stimulating factor; RD, recommended dose.
Table 3: Treatment-related adverse events (>10% of patients or grade ≥3) and laboratory abnormalities (regardless of relationship) at the recommended
dose and all dose levels, reported for lurbinectedin without or with primary G-CSF prophylaxis
|
Lurbinectedin |
Lurbinectedin |
||||||||
Dose level |
Dose level |
|||||||||
DL1 |
DL2 (RD) |
DL3 (MTD) |
DL1 (RD) |
DL2 (MTD) |
||||||
n |
% |
n |
% |
n |
% |
n |
% |
n |
% |
|
CR |
. |
. |
. |
. |
. |
. |
. |
. |
. |
. |
PR |
. |
. |
1 |
12.5 |
. |
. |
. |
. |
. |
. |
SD ≥4 months |
. |
. |
. |
. |
1 |
25.0 |
3 |
33.3 |
. |
. |
SD <4 months |
1 |
33.3 |
3 |
37.5 |
1 |
25.0 |
6 |
66.7 |
2 |
100.0 |
PD |
2 |
66.7 |
4 |
50.0 |
2 |
50.0 |
. |
. |
. |
. |
ORR (%) |
. |
12.5 |
. |
. |
. |
|||||
CBR (%) a |
. |
12.5 |
25.0 |
33.3 |
. |
|||||
Data shown are number of patients (n) and percentages (%).
a Patients with CR or PR or SD ≥4 months.
CBR, clinical benefit rate; CI, confidential interval; CR, complete response; DL, dose level; G-CSF, granulocyte colony-stimulating factor;
MTD, maximum tolerated dose; ORR, overall response rate; PD, progressive disease; PR, partial response; RD, recommended dose; SD, stable
disease.
Table 4: Antitumor activity according to the Response Evaluation Criteria In Solid Tumors (RECIST) v.1.1 (Japan Clinical Oncology Group
translation version) in patients evaluable for efficacy at each dose level treated with lurbinectedin without or with primary G-CSF prophylaxis
Dose level |
n |
Cmax |
AUC |
CLt |
t1/2 |
Vss |
Albumin |
AAG |
CRP |
1.5 |
3 |
78.6 |
273.8 |
8.0 |
37.7 |
219.4 (92.3) |
3.8 |
109.7 |
13.8 (10.2) |
2.5 (RD) |
8 |
129.4 |
498.9 |
9.9 |
51.2 (15.8) |
364.4 (148.7) |
4.0 |
109.8 |
12.2 (10.1) |
3.2 (MTD in LRB without G-CSF) and RD in LBR with G-CSF) |
13a |
120.1 |
477.6 |
15.0 |
42.4 (12.2) |
467.8 (216.5) |
3.9 |
72.2 |
11.0 (22.3) |
3.5 |
2 |
111.0 |
569.0 |
11.1 |
84.8 (43.2) |
821.8 (283.4) |
2.2 |
49.7 |
16.6 |
Values are expressed as mean (standard deviation).
a Total of patients from LRB without G-CSF (n=4) plus LRB with G-CSF (n=9).
AAG, alpha-1-acid glycoprotein; AUC, area under the plasma concentration-time curve from time zero to infinite; CL, total body clearance;
Cmax, maximum plasma concentration; CRP, C-reactive protein; G-CSF, granulocyte colony-stimulating factor; LRB, lurbinectedin; n, number
of patients; t1/2, half-life; Vss, volume of distribution at steady-state.
Table 5: Non-compartmental pharmacokinetic parameters of lurbinectedin by dose level
Clinical trial |
Statistics |
CLt |
t1/2 |
Vss |
Vz |
PM1183-A-013-15 |
n |
26 |
26 |
26 |
26 |
Mean |
12.30 |
47.42 |
433.85 |
788.37 |
|
SDev |
6.25 |
19.25 |
229.37 |
410.71 |
|
Min |
3.87 |
18.18 |
141.41 |
279.22 |
|
Median |
10.28 |
43.47 |
362.12 |
699.74 |
|
Max |
28.85 |
115.38 |
1022.12 |
1598.77 |
|
CV% |
50.85 |
40.59 |
52.87 |
52.10 |
|
PM1183-A-001-08 |
n |
15 |
15 |
15 |
15 |
Mean |
11.79 |
61.68 |
443.09 |
803.68 |
|
SDev |
6.54 |
37.09 |
185.86 |
333.55 |
|
Min |
2.41 |
21.59 |
209.76 |
371.59 |
|
Median |
11.3 |
53.98 |
436.66 |
762.68 |
|
Max |
21.67 |
154.36 |
862.48 |
1515.77 |
|
CV% |
55.52 |
60.13 |
41.95 |
41.5 |
CLt, total body clearance; CV, coefficient of variation (%); Max, maximum value; Min, minimum value; n, the number of patients; RD, recommended
dose; SDev, standard deviation; t1/2, terminal half-life; Vss, volume of distribution at steady-state; Vz, volume of distribution based on
the terminal phase.
Table 6: Summary of total plasma lurbinectedin dose-independent pharmacokinetic parameters in present study (PM1183-A-013-15) and
First-in-Human trial (PM1183-A-001-08)
Figure 1: Lurbinectedin swimmer plot of progression-free survival in all individual patients treated with and without primary G-CSF prophylaxis by dose level G-CSF, granulocyte colony-stimulating factor; MTD, maximum tolerated dose; PFS, progression-free survival; PR, partial response; RECIST, Response Evaluation Criteria In Solid Tumors v.1.1 (Japan Clinical Oncology Group translation version); RD, recommended dose.
Figure 2: Lurbinectedin total plasma concentration-time profiles by dose level h, hour; LLOQ, lower limit of quantification; PM01183, lurbinectedin.
Figure 3: Relationship of lurbinectedin CLt with AAG and CRP by dose level AAG, alpha-1-acid glycoprotein; CLt, total body clearance; CPR, C-reactive protein; PM01183, lurbinectedin; RSQ, coefficient of determination
Tables at a glance
Figures at a glance