Clinical Trials in AMD3100

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Clinical Trials in AMD3100

• Leslie Andritsos, M.D.
• Grand Rounds 5/27/2005

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AMD3100

• Chemokine receptor antagonist
• Reversibly blocks SDF-1/CXCR4 interaction, HIV
  gp120/CXCR4
• Anti-HIV properties, stem cell mobilizer

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CD26
MMP-9, MMP-2
G-CSFR
C-kit
CD34
NE CG
VLA-4
CXCR4
Stromal Cell
VCAM-1
SDF-1
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CD26
MMP-9, MMP-2
G-CSFR
CD34
C-kit
NE CG
VLA-4
CXCR4
AMD3100
Stromal Cell
VCAM-1
SDF-1
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AMD3100 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)

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Phase 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
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Results

• 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
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Phase 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
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Phase 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
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Phase 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

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Fig 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
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A 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

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Inclusion 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

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AMD3100 Mobilization
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G-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)
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Transplantation 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

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Patient and Donor Characteristics
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Comparison of Stem Cell Products
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Toxicities
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Recipient Engraftment
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Recipient Chimerism
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GVHD and Infection
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Conclusions

• 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

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Compassionate 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

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Patient Characteristics
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Mobilization 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

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Cumulative Apheresis Products Pre- and
Post-AMD3100
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Comparison of PB Peak CD34 cells/µl with each
mobilization regimen
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Engraftment 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

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Results

• 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

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Conclusions

• 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

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The 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

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G-CSF dose 10 µg/kg AMD3100 dose 160 µg/kg
1st 8 pts, 240 µg/kg remainder of pts
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Engraftment

• 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

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Toxicity

• 6 SAEs
• None related to study drug
• Grade I toxicities with AMD3100
• diarrhea
• injection site erythema
• nausea

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Conclusions

• AG superior to G alone more CD34 cells with
  fewer aphereses
• No greater than grade 1 toxicity
• Similar to superior engraftment kinetics

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Overall 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

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Current 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