A Phase I MMRC Clinical Trial testing the Combination of Bortezomib and Tipifarnib
in Relapsed/Refractory Multiple Myeloma.
Sagar Lonial MD1, Dixil Francis1, Chatchada Karanes MD2, Suzanne Trudel MD3, Akari Dollard4, Marc Buacharern2, Renee Smith1, Faraz Zaman3,
Engin Gul3, Amrita Krishnan MD2, Donna Reece MD3, Donald Harvey1, Jonathan Kaufman MD1
1Winship Cancer Institute, Emory University, 2City of Hope Cancer Center, 3University Health Network, Toronto, ON, Canada, 4Multiple Myeloma Research Consortium (MMRC)
Abstract:
Introduction:
Methods:
Results:
Results:
Background:
Preclinical work from our group and others has
Despite numerous advances in oncology, multiple myeloma remains
Cohort Dose
demonstrated that the combination of a farnesyl transferase inhibitor (FTI)
an incurable disease for most patients.
Recent advances have
Patients with relapsed or refractory multiple myeloma after
To date 22 patients have been enrolled in this study, of which 20
level
No. of pts
DLT
Responses
and the proteaso
a
me inhibitor
o bortezo
z mib resul
u ts
t in enh
n anced plasma cell
included the
th
early use of autologo
g us
u
stem cell trans
n pla
p nt for
fo most
2 or more pri
pr or lines of th
t er
h apy
er
were
r
el
e igi
ig ble
b
for
fo inclusion
o
into
are ev lb
alua l
ble for response.
100
6
0
3 PD, 2 SD, 1 MR
apoptosis and is associated with AKT activation (David, Blood 2005).
patients, though this approach is palliative, and nearly all patients
the study.
More recently, further preclinical data suggests that the mechanism
will relapse. Targeted agents represent a unique mechanism by
Dose escalation was determined using the EWOC method
Characteristic
No (N=18)
Range
%
200
5
1
2 PD, 2 SD, 1 PR
responsible for this profound synergy is due to inhibition of HDAC6 with a
which biologically based therapies can be applied and tested. Our
of phase I design .
Sex
resultant inhibition of both the proteasome and aggresome pathway
Female
11
61.1
group
has
previously
reported
that
the
combination
of
the
300
7
1
2 PD, 4SD, 1UNEVALAUBLE
(David ASH 2007). Based upon these observations, with the MMRC we
Male
7
38.9
farnesyltransferase inhibitor lonafarnib and the proteasome inhibitor
initiated a phase I trial combining the FTI tipifarnib with bortezomib to
bortezomib results in synergistic myeloma cell death when using
400
2
0
UNAVAILABLE
Age (n=16), years
62
42-76
clinically evaluate the efficacy of this combination.
myeloma cell lines or primary tumor cells from patients (David et al,
Creatinine
1.2
0.7-2.7
Methods: Patients with relapsed or refractory myeloma were treated with
Blood 2005). More recently, we have explored the preclinical use of
Hgb, g/dl
10.2
7.5- 11.8
bortezomib at 1.0 mg/m2 given on days 1,4,8, and 11 in conjunction with
tipifarnib, an oral FTI, in combination with bortezomib and have
Overall, 18 patients are evaluable for response, and 10 of
Albumin, g/dl
3.6
2.1- 4.4
escalating doses of tipifarnib (100-400mg/BID) given on days 2-15 every
demonstrated that not only is the combination synergistic, the
18 had stable disease or better, and 3 of the responders had
Isotype
21 days. Dose escalation was accomplished using an adaptive phase I
combination of these agents appears to result in significant reduction
Ig A
2
11.1
bortezomib resistant disease at the time of study entry.
Ig G
13
72.2
design (Escalation With Overdose Control (EWOC)) Eligibility criteria
in HDAC6 expression with resultant blockad
a e of aggresome
Ig D
2
11.1
One patient with refractory
py PCL achieved a 90% reduction
design (Escalation With Overdose Control (EWOC)). Eligibility criteria
e
IgM
1
5.6
included a serum creatinine of <2.0, normal liver function, ANC>1000, and
formation. In analysis similar to what is reported for the combination
in circulating plasma cells on study, and was graded as SD.
Prior lines of therapy
4.5
platelets >25. If dose escalation is able to proceed to 400mg of tipifarnib
of an HDAC inhibitor (vorinostat, LBH 589, romidepsin) with a
with 1.0mg/m2, the tipifarnib dose escalation will restart with bortezomib
proteasome inhibitor, the combination of tipifarnib and bortezomib
Toxicity
given at 1.3mg/m2. Results: Sixteen patients have been enrolled to date
results in significant blockade of both proteasomal and aggresomal
Conclusion:
into respective tipifarnib dose levels 100 mg(n=6),200mg (n=5) and
based protein catabolism, and is the reason for the observed
Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Total (%)
300mg (n=5). Median age for the enrolled patients is 59 (range 43-76)
pronounced synergy when the 2 drugs are combined in vitro. Based
Altered Mental
Status
n=1
5.9
and median time from myeloma diagnosis was 4.7 years. 15/16 patients
upon this observation, we have initiated , through the MMRC, a
Elevated
The combination of bortezomib and tipifarnib is active in a refractory
Creatinine
n=2
11.8
had received prior high dose therapy. The average number of prior
phase I clinical trial testing the combination of tipifarnib and
patient population, and able to induce response among bortezomib
Pneumonia
n=1
5.9
therapies was 4.5, and of the16 patients, 8 were refractory to prior
bortezomib in patients with relapsed and refractory myeloma.
resistant patients
Diarrhea
n=2
n=2
23.5
bortezomib (relapsed on therapy or within 6 months) 4 were bortezomib
Fatigue
n=1
n=1
11.8
Novel phase I design allows for safe and rapid dose escalation
naïve, and 4 were previously exposed to bortezomib but not know to be
Nausea/ Vomiting
n=1
5.9
Toxicities are predominately GI and hematologic
refracto
r
ry. Amo
Am ng
n these pati
a ents with
t
advanced mye
my l
e oma
om
and re
r fr
e a
fr c
a tory
to
Brui
u sin
i g
n=1
59
5.9
disease, stabilization of disease or better was seen among 7/16 patients
Constipation
n=1
5.9
Further dose escalation with full dose bortezomib is planned to
with 2 of the 7 achieving an MR. Of note, among the patients achieving
Chills
n=1
5.9
evaluate the ability to deliver higher doses of both agents.
clinical benefit, 1 patient had a stable M-protein, but experienced an 80%
Edema
n=1
5.9
Correlative studies are in progress to evaluate the effect of the
reduction in circulating plasma cells while on therapy, and another has
Muscle Cramps
n=1
5.9
combination on HDAC6 and aggresome formation.
had a 75% reduction in the free light chain assay. The most common drug
Bone Pain
n=1
5.9
related side effects were was Gr2 diarrhea (23.5%). Hematologic toxicities
Total (%)
52.9
23.5
23.5
0
0
100.0
Disclosures: Consultant for Millennium; SL. JK, Speakers Bureau for
were difficult to ascertain as patients had advanced myeloma and many
Millennium: JK, AK, DR, Consultant, Research Support and Speakers
were entered onto study with platelet counts between 25 and 50.
Bureau for Ortho Biotech: DR, ST
Additional grade 3 toxicities included renal insufficiency (related to PD),
pneumonia and altered mental status which were all considered not
related to study drug but to progression of disease. There were no Grade
Aggresome inhibition with the combination
3 -5 drug rel
re ate
a d
te
toxi
tox cities
e . There were
r
no card
ca i
rd ac
a events or DVT, and 1
patient experienced grade 2 peripheral neuropathy who did not have pre
This work is supported by a translational research grant from the
existing PN at baseline. Conclusions: The combination of bortezomib
Leukemia and Lymphoma Society (SL)
and tipifarnib is supported by preclinical rationale and has produced stable
disease or better among a group of patients with refractory and advanced
myeloma. To date the optimal dose of both tipifarnib and bortezomib have
All the possible dose sequences that could be realized for the first
yet to be defined, and additional patients will be enrolled to define the
four patients. It assumes no simultaneous treatment of patients.
MTD for tipifarnib with 1.0mg/m2 of bortezomib, followed by escalation of
The values of alpha used to calculate the next dose is 0.25 for all
tipifarnib with 1.3mg/m2 of bortezomib.
patients in stage 1. Alpha is the probability that the dose is above
the MTD.

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