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Lipegfilgras+m A new long-‐ac,ng recombinant human G-‐CSF
Joseph Gligorov MD, PhD ESO Advanced Breast Cancer Task Force
APHP-‐HUEP-‐Tenon, Paris Ins+tut Universitaire de Cancérologie
Université Pierre & Marie Curie, Sorbonne Universités
Conflict of interest
• Amgen® • Genomic Health®
• Eisai® • Roche-‐Genentech® • Nanostring ® • Novar,s ®
Clinical trials support, advisory boards, speaker
• Molecular structure : « glycoPEGyla+on technology »
• Long-‐ac+ng human recombinant G-‐CSF (r-‐metHuG-‐CSF)
Lipegfilgrastim
GlycoPEGyla+on
Explanation § Two enzymes - one-pot reaction § Two substrates
• Activated sugar • Activated sugar linked to PEG
§ The PEGylation site is threonine 134 (THR134)
Filgrastim (E. coli derived)
Lipegfilgrastim (glycoPEGylated XM21)
ENZYME 1 ENZYME 2
XM21
S 1
THR134
XM21
THR134
XM21
S 1
S 2
THR134 S 1 A1
A1 S 2 A2
A2
S 1 A1 S 2 A2 PEG
Clinical development Phase I studies
XM22-01-CH PK/PD single dose, bodyweight adjusted dosing N=53 25/50/100 µg/kg lipegfilgrastim vs pegfilgrastim
XM22-05-CH PK/PD single dose, fixed dose N=36 6 mg lipegfilgrastim vs pegfilgrastim
XM22-06 PK at three different injection sites (upper arm, abdomen, thigh)
N=20 6 mg lipegfilgrastim vs pegfilgrastim
Phase II studie
XM22-02 Dose finding with three different doses of Lonquex® compared to 6mg pegfilgrastim in breast cancer patients
N=208 3/4.5/6 mg lipegfilgrastim vs 6mg pegfilgrastim
phase III studies
XM22-03 Efficacy and safety of 6mg Lonquex® compared to 6 mg pegfilgrastim in breast cancer patients
N=202 6 mg lipegfilgrastim vs 6mg pegfilgrastim
XM22-04 Efficacy and safety of 6 mg Lonquex® compared to placebo in non small cell lung cancer patients
N=373 6 mg lipegfilgrastim vs placebo
Phase I studies Healthy volunteers
1. lipegfilgras,m 25, 50, 100 µg/kg vs pegfilgras,m 100 µg/kg: XM22-‐01
2. lipegfilgras,m, 6 mg vs pegfilgras,m 6 mg: XM22-‐05
3. lipegfilgras,m, 6 mg, 3 sites d’injec,on: XM22-‐06
1 ANC : absolute neutrophil count
XM22-‐01
XM22-‐05
Objec+ves PK/PD single dose 25, 50, 100 μg/kg of lipegfilgras+m or 100 μg/kg pegfilgras+m bodyweight adjusted dosing (n = 53)
PK/PD single 6 mg fixed dose lipegfilgras+m or pegfilgras+m (n = 36)
Methods Phase I randomised, single-‐blind study in healthy volunteers
Phase I randomised, single-‐blind study in healthy volunteers
Primary endpoint
ANC1 AOBEC (area over baseline effect curve)
ANC AOBEC
Secondary endpoints
§ PD: CD34+ AOBEC, CD 34+ max , ANC max,
§ PK: AUC, Cmax, Tmax, T ½ terminal § Safety
§ PD: CD34+ AOBEC, CD 34+ max , ANC max,
§ PK: AUC, Cmax, Tmax, T ½ terminal § Safety
Phase I studies
0 24 48 72 96 120 144 168 192 216 240 0
XM22-01-CH body weight depending dosing
Bioavailability AUC of lipegfilgrastim 56-57% > AUC of pegfilgrastim
(Median ± SD)
XM22-05-CH fixed dose
100000
200000
300000
400000
500000
600000
Time* [h]
Con
cent
ratio
n [p
g/m
l]
0 0 24 48 72 96 120 144 168 192
100000
200000
300000
400000
500000
600000
Time* [h] C
once
ntra
tion
[pg/
ml]
216 240
50 µg/kg lipegfilgrastim (n=15) 100 µg/kg pegfilgrastim (n=15)
25 µg/kg lipegfilgrastim (n=8) 100 µg/kg lipegfilgrastim (n=15)
6 mg pegfilgrastim, n = 15
6 mg lipegfilgrastim, n = 18
Bioavailability AUC of lipegfilgrastim 63-64% > AUC of pegfilgrastim
(Median ± SD)
Seiberling M, et al. Research report. XM22-01-CH. Mannheim, Germany: BioGenerix, 2009. Seiberling M, et al. Research report. XM22-05-CH. Mannheim, Germany: BioGenerix, 2009
0
10
20
30
40
50
60
0
10
20
30
40
50
60
XM22-01-CH body weight depending dosing
XM22-05-CH fixed dose
96 168 192 216 264 288 360 384 408
Time*[h]
AN
C [n
eut /
nl]
336 312 240 144 120 72 48 24 0 96 168 192 216 264 288 360 384 408
Time*[h] A
NC
[neu
t /nl
] 336 312 240 144 120 72 48 24 0
50 µg/kg lipegfilgrastim (n=15) 100 µg/kg pegfilgrastim (n=15)
25 µg/kg lipegfilgrastim (n=8) 100 µg/kg lipegfilgrastim (n=15)
6 mg pegfilgrastim, n = 15
6 mg lipegfilgrastim, n = 18
With equivalent doses, ANC AUC with lipegfilgrastim > 32% ANC AUC with pegfilgrastim
(Median ± SD)
ANC AUC with lipegfilgrastim > 30% ANC AUC with pegfilgrastim
(Median ± SD)
Seiberling M, et al. Research report. XM22-01-CH. Mannheim, Germany: BioGenerix, 2009. Seiberling M, et al. Research report. XM22-05-CH. Mannheim, Germany: BioGenerix, 2009
0 48 96 168 192 216 240 264 288 432 456 480 504
20
0
60
80
100
120 140
Time (h)
CD
34 +
[cel
l cou
nt/u
l)
40
24 72 120 144 312 336 360 384 408
100 µg/kg lipegfilgrastim (n=15)
100 µg/kg pegfilgrastim (n=15)
25 µg/kg lipegfilgrastim (n=8)
50 µg/kg lipegfilgrastim (n=15)
0 48 96 168 192 216 240 264 288 432 456 480 504
20
0
60
80
100
120 140
Time (h)
40
24 72 120 144 312 336 360 384 408
CD
34 +
[cel
l cou
nt/u
l) With equivalent doses: CD34+ 83% and CD34+ max
98% higher with lipegfilgrastim vs pegfilgrastim (Median)
6 mg pegfilgrastim, (n=18)
6 mg lipegfilgrastim, (n=18)
Seiberling M, et al. Research report. XM22-01-CH. Mannheim, Germany: BioGenerix, 2009. Seiberling M, et al. Research report. XM22-05-CH. Mannheim, Germany: BioGenerix, 2009
CD34+ 9% and CD34+ max 16% higher with lipegfilgrastim vs pegfilgrastim (ns)
(Median)
XM22-01-CH body weight depending dosing
XM22-05-CH fixed dose
11
XM22-‐01 n=53
XM-‐05 n= 36
Lipegfilgras+m n=38
Pegfilgras+m n=15
lipegfilgras+m n=18
Pegfilgras+m n=18
Any AE 35 (92,5%) 14 (93,3%) 15 (83,3%) 17 (94,4%)
Gastrointes+nal 7 (18,4%) 1 (6,7%) 3 (16,7%) 3 (16,7%)
Arthralgia 30 (79%) 13 (86,7%) 1 (5,6%) 0 (0%)
Back pain 4 (10,5%) 0 (0%) -‐ -‐
Headaches 21 (55,2%) 7 (46,7%) 10 (55,6%) 9 (50%)
Bone pain 1 (2,6%) 2 (13,3%) 12 (66,7%) 15 (83,3%)
• AEs were mostly mild to moderate in severity • No serious AEs • No clinicaly significant change in biologic and vital signs, ECG and sonographic examina,on of the spleen • No injec,on site was observed
Seiberling M, et al. Research report. XM22-01-CH. Mannheim, Germany: BioGenerix, 2009. Seiberling M, et al. Research report. XM22-05-CH. Mannheim, Germany: BioGenerix, 2009
Safety in studies XM22-‐01, XM22-‐05
*AE = adverse events
Phase II study
Breast cancer lipegfilgras,m 3mg, 4.5 mg , 6 mg vs pegfilgras,m 6mg
§ Primary objective:
§ To identify the optimal fixed dose of lipegfilgrastim in breast cancer patients treated with chemotherapy compared to 6mg pegfilgrastim
§ Methods:
§ Multinational, multicentre, randomised, double-blind, controlled study with 4 treatment arms (6 european countries; 37 centres)
§ Patients were stratified according to geographical localisation, indication of chemotherapy (adjuvant/metastatic) and body weight
Kaufmann M, et al. Research report XM22-02. Mannheim, Germany: BioGenerix, 2011.
Phase II study
§ Main inclusion criteria: § Stage II,III,IV Breast Cancer Cancer treated with 4 cycles of AT (doxorubicine 60 mg/m2- docetaxel 75 mg/m2) every 3 weeks § No previous chemo § ANC ≥ 1,5 x 109/L, thrombocytes ≥ 100 x 109/L § ECOG* ≤ 2 § Normal heart, kidney and liver function
§ Main exclusion criteria: § Previous G-CSF exposure § Anti infectious treatment (antibiotics) ≤ 72 hours before chemo initiation § Radiotherapy ≤ 4 weeks before study inclusion § Previous bone marrow transplantation
*ECOG= Eastern Cooperative Oncology Group
Phase II study
Doxorubicin 60 mg/m2 + Docetaxel 75 mg/m2
( n=208)
lipegfilgrastim 3.0 mg (n=53)
lipegfilgrastim 4.5 mg (n=51)
lipegfilgrastim 6.0 mg (n=50)
pegfilgrastim 6.0 mg (n=54)
Primary breast cancer patients (N=229)
Randomization Next chemo cycle if ANC ≥1.5 x 109/L and platelet
count ≥100 x 109/L
One chemotherapy cycle
= 21 days
rGCS-‐F therapy
Chemotherapy
Run-‐in Cycle 1 Cycle 2 Cycle 3 Cycle 4 Follow-‐up D1 D22 D43 D64
D85 End of study D180
Ab test D360
Ab test D2 D23 D44 D65
Ab=antibody test; D=day; chemo=chemotherapy.
Haematological and biochemical parameters measured on Day 15 of each cycle
Multinational, multicenter, randomized, double blind
Data on file Buchner, A. et all JCO, 29:2011 (Suppl; abstr 9080)
Phase II study
§ Primary Endpoint: Dura,on of Severe Neutropenia (DSN) in the first cycle of chemotherapy in the respec,ve arms
§ Secondary Endpoint
§ Incidence of Febrile Neutropenia in cycles 1, 2, 3, and 4 and across all cycles. Febrile
§ DSN in cycles 2, 3, and 4. § The following secondary efficacy endpoints were evaluated in cycles
1, 2, 3, and 4: § Depth of ANC nadir. § Time to ANC recovery ( ANC ≥2.0 x 109/L). § Incidence of grade 4 neutropenia (ANC < 0.5 x 109/L). § Safety
Data on file Buchner, A. et all JCO, 29:2011 (Suppl; abstr 9080)
Severe Neutropenia =grade 4 neutropenia (ANC < 0.5 x 109/L). Very Severe Neutropenia (ANC < 0.1 x 109/L)
Febrile Neutropenia was defined as axillary body temperature of > 38.5°C for more than 1 h and ANC <0.5 x 109/L, both measured on the same day L)
Phase II study
No significant difference between groups
4 groupes aux caractéristiques démographiques et médicales comparables (en ITT et en PP)
Pegfilgrastim N=54
lipegfilgrastim 3 mg, N=53
lipegfilgrastim 4,5 mg, N=51
lipegfilgrastim 6 mg, N=50
Total N=208
Age (years) Median ± SD ≤ 64 years, %
49,5 ±11,1
92,6%
53,1 ±9,2
86,8%
52,8 ± 10,1
88,2%
51,4 ± 9,8
90%
51,7 ±10,1
89,4%
Weight ≤ 60 kg
60 à 75 kg > 75 kg
25,9% 33,3% 40,7%
22,6% 45,3% 32,1%
25,5% 39,2% 35,3%
26,0% 38,0% 36,0%
25,0% 38,9% 36,1%
CT indication Adjuvant
Métastatic
79,6% 20,4%
81,1% 18,9%
86,3% 13,7%
82,0% 18,0%
82,2% 17,8%
Disease stage High-risk stage II
Stage III Stage IV
40,7% 42,6% 16,7%
39,6% 43,4% 17,0%
37,3% 51,0% 11,8%
36,0% 48,0% 16,0%
38,5% 46,2% 15,4%
ECOG status 0 1 2
61,1% 38,9%
0%
64,1% 34,0% 1,9%
51,0% 43,1% 5,9%
56,0% 42,0% 2,0%
58,2% 39,4% 2,4%
Patients caracteristics
Duration of Severe Neutropenia in cycle 1 (ITT population)
pegfilgrastim 6mg
Lonquex® 3mg
Lonquex® 4.5mg
Lonquex® 6mg
N valid, Mean ± standard deviation (median) Minimum to maximum
54
0.9±1.0 (1.0)
0.0 to 3.0
53
1.1±1.1 (1.0)
0.0 to 4.0
51
0.8±1.0 (1.0)
0.0 to 4.0
50
0.8±1.1 (0.0)
0.0 to 3.0
No statistically significant difference between treatment arms Same results in PP population and within sub-groups analysis..
Phase II study
§ Conclusion :
§ Non-inferiority of lipegfilgrastim 6 mg vs pegfilgrastim 6 mg was demonstrated on DSN in cycle 1
§ Significantly more patients without severe neutropenia in the lipegfilgrastim group vs pegfilgrastim group, in cycles 2, 3 and 4
§ Time to ANC recovery (ANC ≥ 2 x 10 9/L) significantly shorter with lipegfilgrastim than pegfilgrastim 6 mg, in each cycle
§ Safety profile similar to pegfilgrastim 6 mg
Phase II study
Phase III study XM22-‐03
Lipegfilgras,m 6mg vs pegfilgras,m 6 mg
Breast cancer
Bondarenko I, et al. BMC Cancer. 2013: 2013;13(1): 386.
§ Primary Objective : § Demonstration of non-inferiority of Lonquex® versus
pegfilgrastim in patients treated for breast cancer (doxorubicine-docétaxel)
Non inferiority hypothesis demonstrated if : Δ DSN (lipegfilgrastim –pegfilgrastim) < 1 day
§ Design: § Multinational, multicenter, randomized, double-blind, phase III
study
Phase III study, XM22-‐03
Doxorubicin 60 mg/m2 + Docetaxel 75 mg/m2
(Pooled n=202)
Lipegfilgrastim 6 mg (n=101)
pegfilgrastim 6.0 mg (n=101)
Ab=antibody test; D=day; CTX=chemotherapy; ANC=absolute neutrophil count.
Primary breast cancer
patients (n=218)
Randomization Next CTX
cycle if ANC ≥1.5 x 109/L and platelet
count ≥100 x 109/L
One chemotherapy cycle = 21 days
Multinational, multicenter, randomized, double-blind, phase III study
rGCS-‐F therapy
Chemotherapy
Run-‐in Cycle 1 Cycle 2 Cycle 3 Cycle 4 Follow-‐up D1 D22 D43 D64
D85 End of study
D180 Ab test
D360 Ab test D2 D23 D44 D65
Bondarenko, I. et all JCO, 30, 2012 (Suppl; abstr 19587) Bondarenko et al,Jcancer Research and Clin Oncology , 2012, Submitted
Phase III study, XM22-‐03
§ Primary Endpoint: Duration of Severe Neutropenia (DSN) in the first cycle of chemotherapy.
§ Secondary Endpoints: § Efficacy parameters
§ Incidence of Febrile Neutropenia in cycles 1-4 § Duration of Severe Neutropenia in cycle 2-4 § Depth of ANC nadir in each cycle § Time to ANC recovery (ANC ≥ 2.0 109/L) § Incidence of severe neutropenia
§ Safety parameters
Bondarenko, I. et all JCO, 30, 2012 (Suppl; abstr 19587)
• Severe Neutropenia/Grade 4 (NCI) :ANC < 0.5X109/L • Febrile neutropenia (FN): Severe Neutropenia + Axyllary temperature > 38.5° C for at least one hour +/-(documented neutropenic sepsis and /or documented of serious or life threatening infection)
Phase III study, XM22-‐03
Patients caracteristics : similar in both groups
Pegfilgras+m 6 mg
N=101 Lipegfilgras+m 6 mg
N=101
Age Median ± SD (years)
≤ 64, n (%) 65 à 74, n (%)
51.1 ± 9.4 94 (93.1) 7 (6.9)
49.9 ± 10.1 94 (93.1) 7 (6.9)
Body weight Median ± SD (kg)
≤ 60, n (%) >60 à ≤75, n (%)
>75, n (%)
73.2 ± 14.6 16 (15.8) 49 (48.5) 36 (35.6)
73.9 ± 17.1 22 (21.8) 40 (39.6) 39 (38.6)
Indica+on for CT, n (%) Adjuvant
Métasta,c
74 (73.3) 27 (26.7)
75 (74.3) 26 (25.7)
ECOG status 0 1 2
47 (46.5) 54 (53.5) 0 (-‐)
45 (44.6) 56 (55.4) 0 (-‐)
Stage High-‐risk stage II
III IV
36 (35,6) 45 (44,6) 20 (19,8)
39 (38,6) 48 (47,5) 14 (13,9)
Bondarenko I, et al. BMC Cancer. 2013: 2013;13(1): 386.
Phase III study, XM22-‐03
Tumor and treatment caracteristics similar in both arms
Variable Pegfilgras+m 6 mg N=101 (%)
Lipegfilgras+m 6 mg N=101 (%)
Months since diagnosis Mean ± SD
Median Varia,ons
6,1 ± 26,6
1 0 à 185
5,3 ±16,7
2 0 à 130
Surgery 59 (59,4) 50 (49,5)
Time since surgery (months) Mean ± SD
9,1 ± 34,1
6,7 ± 15,5
Type of surgery Conserva,ve Mastectomy
Axillary dissec,on
7 (6,9) 55 (54,5) 46 (45,5)
4 (4)
46 (45,5) 44 (43,6)
Bondarenko I, et al. BMC Cancer. 2013: 2013;13(1): 386.
Phase III study, XM22-‐03
Primary endpoint : DSN in cycle 1
Non-inferiority of Lipegfilgrastim 6 mg vs Pegfilgrastim 6 mg demonstrated (Δ DSN < 1 jour)
Results confirmed in sub-groups analysis by country, indication for CT and body weight
Lipegfilgrastim 6mg
Pegfilgrastim 6 mg
Δ Lipegfilgrastim- pegfilgrastim (IC95) p
PP population
DSN median ± SD LS Mean (95% CI)
0,7 ± 0,9 jours 0
0,8 ±0,9 jours 1
- 0,218 jours (-0,498 à 0,062) 0,1260
Bondarenko I, et al. BMC Cancer. 2013: 2013;13(1): 386.
Phase III study, XM22-‐03
Secondary endpoints (PP population)
Pegfilgras+m 6mg
Lipegfilgras+m 6mg p
DSN Cycle 2 Cycle 3 Cycle 4
0,3 ± 0,6 0,2 ± 0,4 0,2 ± 0,5
0,1 ± 0,5 0,1 ± 0,3 0,2 ± 0,6
0,1287 0,6227 0,922
Incidence of FN Cycle 1
Cycles 1 to 4
3,2% 3,2%
0,0% 0,0%
NS
Incidence of SN Cycle 1 Cycle 2
Cycles 1 à 4
51,1% 21,5% 58,5%
43,6% 8,5% 50,0%
0,341 0,013* 0,269
Bondarenko I, et al. BMC Cancer. 2013: 2013;13(1): 386.
Phase III study, XM22-‐03
Neutropenia in cycles 1-4 (PP population)
Nadir comparable in cycle 1 in both treatment groups ANC values to nadir significantly higher in cycles 2 and 3 in the lipegfilgrastim group
Pegfilgrastim 6 mg (N=94) [NCx109/L]
Lipegfilgrastim 6 mg (N=94) [NCx109/L]
p
Nadir (109/L) Cycle 1 Cycle 2 Cycle 3 Cycle 4
1,0 ± 1,3 2,0 ± 1,6 2,0 1,5 2,3 1,8
1,2 ± 1,3 2,6 ± 2,1 2,5 ± 1,6 2,7 ± 1,7
0,254 0,019 0,035 0,112
ANC recovery* Cycle 1 Cycle 2 Cycle 3 Cycle 4
1,6 ± 1,2 0,8 ± 1,0 0,8 ± 1,0 0,7 ± 0,9
1,3 ± 1,0 0,5 ± 0,7 0,4 ± 0,7 0,4 ± 0,7
0,062 0,076 0,021 0,076
*Time to ANC recovery ≥1,5x109 /L after nadir (days)
Bondarenko I, et al. BMC Cancer. 2013: 2013;13(1): 386.
Phase III study, XM22-‐03
Time to ANC recovery (≥ 2x 109/L after ANC < 2x 109/L ) in cycles 1-4 (PP
population)
Cycle pegfilgras+m 6mg N=94
Lipegfilgras+m 6mg
N=94
p
1 7.4±3.6 5.9±3.4 0.003* 2 5.3±4.6 3.6±4.1 0.008* 3 5.1±4.3 3.9±4.8 0.033* 4 4.3±4.7 3.3±4.1 0.223
Course of ANC in cycle 1
Bondarenko I, et al. BMC Cancer. 2013: 2013;13(1): 386.
Phase III study, XM22-‐03
30
Quality of life • Global decreasing of the score during the treatment phase • No sta,s,cal difference among the 2 arms according to QLQ-‐C30 nor
QLQ-‐BR23 scales
Mean variations of EORTC QLQ-BR23 scoring scales between inclusion and end of the study
Phase III study, XM22-‐03
Safety
Safety profile similar in both treatment groups
a : 1 neutropenia and 1 paroxysmal tachycardia b : epistaxis c : FN stage 3 and enterocolitis
Phase III study, XM22-‐03
pegfilgras+m 6mg N=101
lipegfilgras+m 6mg N01=1
Category of TEAE N (%) N (%) Any TEAE 99 (98.0) 100 (99.0)
Drug related TEAE=TEADR 26 (25.7) 28 (27.7)
Serious TEAE 7 (6.9) 3 (3.0)
Serious TEADR 1 (1.0) 1 (1.0)
Severe TEAE 35 (34.7) 26 (25.7)
Severe TEADR 2 (2.0) a 1 (1.0) b
Discon,nued due to TEAE 2 (2.0) 3 (3.0)
Discon,nued due to TEADR 1 (1.0) 0 (0)
Death 0 (0) 1 (1.0) c
Comparable safety profile
Phase III study, XM22-‐03
Most frequent side effects occurring in ≥ 3 % pa+ents (ITT popula+on)
Side effects Pegfilgras+m 6 mg (N=101)
Lonquex® 6 mg (N=101)
N (%) N (%)
Bone pain 10 (9.9) 13 (12.9)
Myalgia 5(5.0) 7 (6.9)
Erythema 3(3.0) 6 (5.9)
Arthralgia 0 (-‐) 3 (3.0)
Nausea 3 (3.0) 2 (2.0)
Conclusions :
§ Non inferiority of lipegfilgrastim 6 mg vs pegfilgrastim 6 mg demonstrated on
DSN in cycle 1
§ Secondary endpoints : significant differences in favor of lipegfilgrastim on following
endpoints :
§ Lower incidence of severe neutropenia in cycle 2
§ Lower depth of neutropenia in cycles 2 and 3
§ Time to ANC recovery ≥ 2 x109/L shorter in cycles 1, 2 and 3
§ Comparable safety profiles
Phase III study, XM22-‐03
Conclusion
Lipegfilgras+m:
• Molecular structure : « glycoPEGyla,on technology »
• Long-‐ac,ng human recombinant G-‐CSF (r-‐metHuG-‐
CSF)
• Efficacy and safety profile comparable to pegfilgras,m
THANKS