Title: Clinical Trials in AMD3100
1Clinical Trials in AMD3100
- Leslie Andritsos, M.D.
- Grand Rounds 5/27/2005
2AMD3100
- Chemokine receptor antagonist
- Reversibly blocks SDF-1/CXCR4 interaction, HIV
gp120/CXCR4 - Anti-HIV properties, stem cell mobilizer
3CD26
MMP-9, MMP-2
G-CSFR
C-kit
CD34
NE CG
VLA-4
CXCR4
Stromal Cell
VCAM-1
SDF-1
4CD26
MMP-9, MMP-2
G-CSFR
CD34
C-kit
NE CG
VLA-4
CXCR4
AMD3100
Stromal Cell
VCAM-1
SDF-1
5AMD3100 and Stem Cell Mobilization
- During PK studies patients noted to have
increased WBC, peaked 6 hours after injection - Further studies showed significant proportion was
CD34 - Stimulated interest in using AMD3100 for SCM
- Animal studies for SCM followed (Broxmeyer 2001)
6Phase I Study Liles, et al.
- 26 healthy volunteers, 13 male, 13 female
- Normal peripheral blood counts
- Group 1 (n10) AMD3100 80 mcg/kg subq x 1
- Group 2 (n13) 40-240 mcg sq x 1
- Group 3 (n3) AMD3100 80 mcg sq daily x 3
consecutive days
Blood 2003 1028, 2728-2730
7Results
- Single 80 mcg injection caused 4-fold increase in
circulating CD34 cells, peak 6 hours - Dose escalation study showed dose-dependent
effect, peak 10-fold increase in PB CD34 cells
at 9 hours after 240 mcg injection - Daily 80 mcg injection caused increase in PB
CD34 cells of similar magnitude each day - Adverse effects injection site reaction,
nausea, abdominal distension, not dose dependent - Effects were temporary
Blood 2003 1028, 2728-2730
8Phase I Study Devine, et al.
- 7 patients with MM, 6 with NHL
- Last dose of chemo between 4 8 weeks of study
entry - Normal peripheral blood cell counts
- 4 with prior RT
- Median age 53 (39-67)
- Median prior chemo regimens 1
- Median prior cycles 6
JCO 2004 221095
9Phase I Study Devine, et al.
- 160 mcg/kg in 6
- 240 mcg/kg in 7
- WBC, PB CD34 cell counts analyzed at 4 and 6
hours
JCO 2004 221095
10Phase I Study Devine, et al.
- Results
- All patients mobilized successfully
- Rise in PB WBC and CD34 cells at 4 and 6 hours
- PB CD34 counts higher in 240 mcg group
- No greater than grade I toxicity
11Fig 1. Total WBC count and peripheral blood CD34
cell count observed in patients receiving AMD3100
at 160 microg/kg or 240 microg/kg at baseline
and 4, 6, and 24 hours (WBC count only at 24
hours) after the dose
Devine, S. M. et al. J Clin Oncol 221095-1102
2004
12A Pilot Study Evaluating the Safety and Efficacy
of AMD3100 for the Mobilization and
Transplantation of HLA-matched Sibling Donor
Hematopoietic Stem Cells in Patients with
Advanced Hematological Malignancies
- AMD3100 will rapidly mobilize CD34 cells in
healthy donors - AMD3100 will cause less morbidity than G-CSF and
require fewer treatment days - Allografts mobilized with AMD3100 will be
functionally similar to those mobilized with
G-CSF - Risk of acute GVHD will not be greater with
AMD3100 mobilized allografts
13Inclusion Criteria
- Ages 18 65
- Patient with advanced hematologic malignancy
- Patient has a 6/6 HLA antigen matched sibling
willing to donate PBSC - Patient meets criteria for allo SCT
14AMD3100 Mobilization
15G-CSF Mobilization
Day 2
Day 3
Day 4
Day 5
Day 6
Day 1
G-CSF 10?g/kg
G-CSF 10?g/kg
G-CSF 10?g/kg
G-CSF 10?g/kg
G-CSF 10?g/kg
G-CSF 10?g/kg
Leukapheresis (if needed)
Commence leukapheresis (20 liters)
16Transplantation Regimen
- Conditioning Regimen
- Cyclophosphamide 60mg/kg IV days 3 and 2
- Single dose TBI (550cGy) day 1
- AMD3100 mobilized PBSC allograft transplanted day
0 - GVHD Prophylaxis
- Cyclosporine 3mg/kg actual body weight beginning
day 1 - Growth Factor Post Transplant
- G-CSF 5mcg/kg s.c. beginning day 1, until ANC gt
1500/ul for 3 consecutive days
17Patient and Donor Characteristics
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20Comparison of Stem Cell Products
21Toxicities
22Recipient Engraftment
23Recipient Chimerism
24GVHD and Infection
25Conclusions
- AMD3100 results in modest but sufficient increase
in CD34 counts within 4 hours - 5 of 6 donors collected gt 2.0 x 106 CD34
cells/kg after 1 or 2 LP procedures - No significant acute toxicity
- Similar engraftment kinetics to allografts
mobilized with G-CSF - Optimal dose of AMD3100, interval between dosing
apheresis remains to be determined - Accrual is ongoing
26Compassionate use study in patients who have
failed prior mobilization
- Inclusion criteria
- Age gt 18
- Advanced hematologic malignancy
- Failed prior attempt at mobilization
- Candidate for high dose chemotherapy with stem
cell support
27Patient Characteristics
28Mobilization Schema
- G-CSF 10 mcg/kg daily x 4 days
- Evening of day 4 pts received AMD3100 240 mcg/kg
- Day 5 pts received G-CSF, apheresis commenced
- Apheresis continued until pt collected sufficient
CD34 cells/kg for auto transplant
29Cumulative Apheresis Products Pre- and
Post-AMD3100
30Comparison of PB Peak CD34 cells/µl with each
mobilization regimen
31Engraftment data patients 1-5
- ANC gt 1500 x 3 consecutive days by day 17
- Median time to ANC engraftment 11 days
- Plt gt 20K x 3 consecutive in all pts by 18 days
- Median time to platelet engraftment 14 days
- Follow-up range 23-180 days
- All pts with sustained engraftment at follow-up
32Results
- All 6 patients collected sufficient CD34 cells
for transplantation - Median of apheresis procedures and AMD doses
3, max 4 - 2/6 required combination of products
- 5/6 pts had higher peak fold increase in PB CD34
absolute count with AMD3100 - First 5 patients have demonstrated sustained
engraftment
33Conclusions
- AMD3100 plus G-CSF is an effective salvage
regimen for pts failing mobilization due to prior
chemo - No significant increased toxicity compared with
G-CSF alone - Engraftment kinetics similar to cytokine or
chemomobilization
34The use of AMD3100 plus G-CSF for autologous
hematopoietic progenitor cell mobilization is
superior to G-CSF alone. Flomenberg et al.,
Blood 2005 early release
- Primary objective AG mobilization better than
G alone? - Secondary
- fewer apheresis days with AG
- neutrophil engraftment by day 21
35G-CSF dose 10 µg/kg AMD3100 dose 160 µg/kg
1st 8 pts, 240 µg/kg remainder of pts
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40Engraftment
- 24 pts transplanted
- 19 received only AG product
- 18/19 engrafted neutrophils between days 10-13
- 1 delayed day 34 (sepsis)
- 5 pts received both G and AG products
- Platelet engraftment median 16 d
41Toxicity
- 6 SAEs
- None related to study drug
- Grade I toxicities with AMD3100
- diarrhea
- injection site erythema
- nausea
42Conclusions
- AG superior to G alone more CD34 cells with
fewer aphereses - No greater than grade 1 toxicity
- Similar to superior engraftment kinetics
43Overall Conclusions
- AMD3100 is safe
- Effectively mobilizes CD34 cells in healthy
donors, patients who have received prior
chemotherapy, and patients who have failed prior
attempts at mobilization - Similar engraftment kinetics
- Fewer apheresis days
- No bone pain
44Current Studies at Wash U
- Compassionate use study in patients who have
failed prior mobilization - Pilot study evaluating safety/efficacy of AMD3100
in healthy donors for HLA-matched siblings - Phase II study in Hodgkins lymphoma
- Phase III studies in myeloma and non-Hodgkins
lymphoma