A PHASE I-II TRIAL OF BORTEZOMIB
(BTZ) PLUS ORAL CYCLOPHOSPHAMIDE
(CY) AND PREDNISONE (P) FOR
RELAPSED/REFRACTORY MULTIPLE
MYELOMA (MM)
Donna E Reece, MD1, Giovanni Piza, MD1*,
Suzanne Trudel, MD1, Mariela Pantoja, PhD1*,
Christine Chen, MD1, Joseph R Mikhael, MD1,
Vishal Kukreti, MD1 and A Keith Stewart, MD1.
1Princess Margaret Hospital, University Health
Network, Toronto, ON, Canada, M5G 2M9.
Objectives
· To evaluate the safety of btz when
given in combination with oral CY + P
· To identify the maximum tolerated dose
(MTD) of this combination
· To evaluate the anti-myeloma response
to this regimen
Dose Levels
Dose
Bortezomib
Cyclophosphamide
Prednisone
Level
Dose
Day
Dose (mg/m2)
Dose (mg)
(mg/m2)
1
0.7
1,8,15
150
100
2
0.7
1,8,15
300
100
3
1.0
1,8,15
300
100
4
1.0
1,4,8,11
300
100
5
1.3
1,4,8,11
300
100
6
1.5
1,8,15
300
100
Grade 3-4 Toxicity with Cycle 1
(Phase I portion, n=27)
Dose
N
Grade 3
Grade 4
level
1
6
2 CAP*
2
3
3
3
4
6
1 ANC**
1 pl
1 AST/ALT
5
6
1 nausea
1 ANC
1 ANC
1 PO4
1 PO4
6
3
1 N/V
1 pl
1 ANC
1 pl
* Community acquired pneumonia; protocol amended for levofloxacin during cycle 1
** Protocol amended to exclude G-CSF for 2 weeks prior to study entry
Toxicity of Cycles 2-8 (Total 183)
Episodes of Toxicity
Neutropenia
Grade 3
4
Grade 4
1
Thrombocytopenia
Grade 3
23
Grade 4
3
Diarrhea
Grade 3
1
Nausea
Grade 3
1
Grade 4
1
Neuropathy
Grade 1
18
Grade 2
2*
*At dose level 3 and 5
Total Infections
Pneumonia
6*
Urinary tract infection
1
Sinusitis
1
Febrile neutropenia
1
Shingles
11
HSV
2
* 2 episodes in 2 patients
Response by Dose Level
Dose
N
CR/nCR
PR
MR
SD
Prog
Level
(%)
1
6
0
1(16%)
2(33%)
1(16%)
2(33%)
2
3
0
2(67%)
1(33%)
-
-
3
3
0
0
1(17%)
2(67%)
-
4
6
2(33%)
2(33%)
0
1(17%)
1(17%)
5
6
1(17%)
5(83%)
-
-
-
6
3
3(100%)
-
-
-
-
Expanded
10
2(20%)
6(60%)
1(10%)
-
1(10%)
6
Overall response rate 84% at dose level 6
CR/nCR rate 38 % (5/13 ) and PR rate 46% (6/13 )
Summary and Conclusions
· Btz can be safely added to oral CY + P at a
dose of 1.5 mg/m2 weekly on days 1 8, and
15 of a 28 day schedule
Identified as the MTD
Excellent overall response rate
Excellent tolerance
Minimal neurotoxicity
Clinic visits minimized
· Btz can be safely added to oral CY + P at full
doses twice a week
More thrombocytopenia observed than with the
weekly dose of 1.5 mg/m2
Summary and Conclusions
(continued)
· Shingles occurred in 11 of 37 patients (30%)
after a median of 5 cycles; antiviral
prophylaxis is recommended.
· The PFS and OS compare favorably to other
combination regimens for progressive
myeloma in this preliminary analysis