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Phase I Trial of plerixafor and bortezomib as a chemosensitization strategy in Relapsed or
Relapsed and Refractory Multiple Myeloma
Irene M.Ghobrial, Abdelkareem Azab, Jacob Laubach, Ranjit Banwait, Meghan Bagshaw, Stacey Chuma, Janet Kunsma, Nikhil Munshi,
Robert Schlossman, Phong Quang, Brittany Morgan, Amy Sam,Tiffany Poon, Diane Warren, Kenneth C. Anderson, Paul G. Richardson.
1Dana-Farber Cancer Inst., Boston, MA.
INTRODUCTION
PATIENTS AND METHODS
RESULTS
ASSESSMENT
· MM is characterized by the presence of multiple lytic lesions and widespread involvement of the BM at diagnosis in
.Response was assessed by the International Myeloma Workshop recommendations.
Baseline characteristics:
most patients indicating continuous spread of MM cells in and out of the BM.
Definition of DLT:
·Sixteen patients have been enrolled to date. Level 5B is currently enrolling. One additional
· The mechanisms by which the MM cells migrate (home) from the peripheral blood to the BM and re-circulate
All adverse events should be graded according to the CTEP Common Toxicity Criteria
(egress) into the circulation are not well understood.
patient was enrolled on level 5.
(CTCAE v3.0).
· Studies have shown that adhesion of MM cells to the bone marrow microenvironment induces resistance to
·No DLTs have been observed.
therapy.
·DLT was defined as:
·The median age is 59 (43-75).
·The influence of SDF-1/CXCR4 axis on detachment/mobilization of cells from their tissue niches was studied in
·Grade 3 or greater non-hematologic toxicity, considered by the investigator to be
models of mobilization of normal stem cells.
related to plerixafor or bortezomib, with the exception of nausea, vomiting or diarrhea
·The median lines of prior therapy is 2 (1-4). All of the patients received prior bortezomib,
·Plerixafor (Mozobil, AMD3100, Genzyme Inc) is a selective reversible CXCR4 inhibitor that is currently FDA
unless receiving maximal medical therapy. Grade 4 hematologic toxicity defined as:
except for 2.
approved for stem cell mobilization.
thrombocytopenia with platelets <10,000 on more than one occasion within first cycle
·Five patients were assessed by light chain, and three patients were assessed by urine
·Plerixafor has been tested in several clinical trials which demonstrate that it improves the number of CD34+ cells despite transfusion. Grade 4 neutropenia must occur for more than 5 days and/or
protein.
mobilized even in patients who failed to mobilize with G-CSF alone. Peak mobilization of stem cells occurred in
result in neutropenic fever with elevated temperature (defined as > 101 degrees F).
healthy volunteers 6 h after i.v. injection of plerixafor.
Lymphopenia, a recognized side effect of bortezomib, is not considered a DLT.
·The median number of cycles on therapy was 5 (1-8).
· We previously showed that plerixafor inhibits adhesion and induces mobilization of MM tumor cells in vivo in a
Inability to receive Day 1 dose for Cycle 2 due to toxicity. A toxicity that would prohibit
xenograft mouse model of MM.
a patient from receiving Cycle 2 day 1 would include a patient experiencing one of the
RESPONSE
·The kinetics of mobilization of MM cells differed from those of CD34+ stem cells.
two following events.
· Plerixafor induced de-adhesion and chemosensitization to therapeutic agents used in MM including bortezomib,
melphalan and dexamethasone.
TREATMENT PLAN
Response
N= 15 evaluable
·In vivo, the combination of plerixafor and bortezomib showed a significantly better tumor response compared to
bortezomib alone or plerixafor alone.
CR
1 (7%)
Dose Level
Assigned therapy. A cycle = 21 days
·Based on these in vivo and in vitro studies, we initiated the first phase I study as a proof of concept of
MR
1 (7%)
chemosensitization in MM.
Level 1
Plerixafor sq 160 µg/kg daily from day 1 to 6 and bortezomib IV push 1 mg/m2 Days 3, 6,
10, and 13.
ORR (PR + MR+CR)
2 (13%)
OBJECTIVES
Level 2
Plerixafor sq 160 µg/kg daily from day 1 to 6 and bortezomib IV push 1.3 mg/m2 Days 3, 6,
Stable Disease
11 (73%)
10, and 13.
Level 3
Plerixafor sq 240 µg/kg daily from day 1 to 6 and bortezomib IV push 1 mg/m2 Days 3, 6,
Progression
2(13)
10, and 13.
·This study aimes to assess the safety and activity of plerixafor and bortezomib
in patients with relapsed and relapsed/refractory MM.
Level 4
Plerixafor sq 240 µg/kg daily from day 1 to 6 and bortezomib IV push 1.3 mg/m2 Days 3, 6,
10 and 13.
·To determine in vivo kinetics of mobilization of MM tumor cells, CD34+ stem
Level 5
Plerixafor sq 320 µg/kg daily from day 1 to 6 and bortezomib IV push 1.3 mg/m2 Days 3, 6,
cells and other microenvironmental cells present in the bone marrow.
10 and 13.
ADVERSE EVENTS
Level 5B
Plerixafor sq 320 µg/kg days 1, 2, 3, 6,10 and 13. Bortezomib IV push 1.3 mg/m2 Days 3,
Overall, the combination is very well tolerated. Grade 3 possibly related toxicities include
6, 10 and 13.
lymphopenia (25%), hypophosphatemia (12%), anemia (6%), and hyponatremia (6%), blurred vision
Level 6
Plerixafor sq 400 µg/kg days 1, 2, 3, 6,10 and 13. Bortezomib IV push 1.3 mg/m2 Days 3,
(6%), and nausea (6%). No grade 2 or higher neuropathy has been noted in these patients. No
PATIENTS AND METHODS
6, 10 and 13.
other Grade 3 or 4 toxicities were observed.
Level 7
Plerixafor sq 480 µg/kg daily days 1, 2, 3, 6,10 and 13. Bortezomib IV push 1.3 mg/m2
Days 3, 6, 10 and 13.
PATIENT POPULATION
Eligibility criteria included
CONCLUSION
1) patients with relapsed or relapsed/refractory MM with any prior
lines of therapy
including bortezomib,
Day
Sampling Time
Plerixafor
Bortezomib
PD
PK1
PK1
samples
2) measurable disease,
Day 1
Before plerixafor dose
X
X
·The combination of plerixafor and bortezomib is very well tolerated with minimal neuropathy or
3) Not receiving chemotherapy > 3 weeks, or biological/novel
Day 1
2 hours post (+/- 30 minutes)
X
X
Day 1
4 hours post (+/- 30 minutes)
X
X
other toxicities.
therapy for MM > 2 weeks.
Day 1
24 hours post (+/- 30 minutes)
X
X
4) Laboratory values obtained <14 days prior to registration:
Day 2
Before plerixafor dose (same as day 1 dose at
X
X
·The responses observed are encouraging in this relapsed/refractory population.
·ANC >1000/mL
24 hours post)
Day 3
Before plerixafor and bortezomib doses
X
X
X
·The ability to demonstrate transient de-adhesion of MM cells and accessory cells in vivo indicates
·PLT >75,000/mL
Day 3
2 hours post plerixafor dose (+/- 30 minutes)
X
X
X
that these cells can be separated from their protective stromal environment which may make them
Day 3
4 hours post plerixafor dose (+/- 30 minutes)
X
X
X
·Total bilirubin <2.0 mg/dL
Day 3
24 hours post plerixafor dose (+/- 30 minutes)
X
X
X
more sensitive to chemotherapy.
Day 4
Before plerixafor dose (same as day 1 dose at
X
X
·AST < 3 x upper limit of normal (ULN)
24 hours post)
Day 6
Before plerixafor and bortezomib doses
X
X
X
·Creatinine < 3.5 x ULN
Day 6
2 hours post plerixafor dose (+/- 30 minutes)
X
X
X
REFERENCES
Day 6
4 hours post plerixafor dose (+/- 30 minutes)
X
X
X
Day 10
Before bortezomib dose
X
X
Day 10
2 hours post (+/- 30 minutes)
X
X
1-CXCR4 inhibitor AMD3100 disrupts the interaction of multiple myeloma cells with the bone marrow microenvironment and
Day 10
4 hours post (+/- 30 minutes)
X
X
enhances their sensitivity to therapy. Azab AK, Runnels JM, Pitsillides C, Moreau AS, Azab F, Leleu X, Jia X, Wright R, Ospina B,
Day 13
Before bortezomib dose
X
X
Carlson AL, Alt C, Burwick N, Roccaro AM, Ngo HT, Farag M, Melhem MR, Sacco A, Munshi NC, Hideshima T, Rollins BJ,
Day 13
2 hours post (+/- 30 minutes)
X
X
Day 13
4 hours post (+/- 30 minutes)
X
X
Anderson KC, Kung AL, Lin CP, Ghobrial IM. Blood. 2009 Apr 30;113(18):4341-51. Epub 2009 Jan 12.
·This study was supported by R01CA133799-01, and by Genzyme.