A Phase I MMRC Clinical Trial testing the Combination of Bortezomib and
Tipifarnib in Relapsed/Refractory Multiple Myeloma.
Sagar Lonial MD1, Dixil Francis MPH1, Chatchada Karanes MD2, Suzanne Trudel MD3, Akari Dollard MA4,Fermin Arceo2
Faraz Zaman MBBS3, Engin Gul3, Amrita Krishnan MD2, Donna Reece MD3, R. Donald Harvey PharmD,1, 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:
Table showing all adverse events ( related and unrelated) and the corresponding
Background:
Preclinical
work
from
our
group
and
others
has
Despite numerous advances in oncology, multiple myeloma remains
Patients with relapsed or refractory multiple myeloma after
grade of the adverse event per CTC version 3.0 guidelines
Cohort Dose level
demonstrated that the combination of a farnesyl transferase inhibitor (FTI)
an incurable disease for most patients.
Recent advances have
2 or more prior lines of therapy were eligible for inclusion into
Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Tipifarnib
Bortezomib
No. of pts
DLT
Responses
and the proteasome inhibitor bortezomib results in enhanced plasma cell
included the early use of autologous stem cell transplant for most
the study.
Thrombocytopenia
n=3
n=2
n=5
100
1.0
6
0
3 PD, 2 SD, 1 MR
Anemia
n=2
n=3
n=1
apoptosis and is associated with AKT activation (David, Blood 2005).
patients, though this approach is palliative, and nearly all patients
Dose escalation was determined using the EWOC method
Neutropenia
n=3
n=1
Sequence of bortezomib followed by a FTI synergistically inhibited cell
will relapse. Targeted agents represent a unique mechanism by
of phase I design .
200
1.0
5
1
2 PD, 2 SD, 1 PR
Nausea/ Vomiting
n=2
n=7
n=2
growth
compared
to
concurrent
treatment.
More recently, further
which biologically based therapies can be applied and tested. Our
Diarrhea
n=2
n=5
n=1
preclinical data suggests that the mechanism responsible for this profound
group
has
previously reported
that
the
combination
of
the
Bone/ Joint Pain
n=4
n=4
n=1
300
1.0
7
1
2 PD, 4SD, 1UNEVALAUBLE
synergy is due to inhibition of HDAC6 with a resultant inhibition of both the
Muscle Pain/ Abdominal pain
farnesyltransferase inhibitor lonafarnib and the proteasome inhibitor
n=2
n=3
n=2
Eleveated Creatinine
n=1
n=1
n=2
400
1.0
2
0
1 PD, 1 SD
proteasome and aggresome pathway (David ASH 2007). Based upon
bortezomib results in synergistic myeloma cell death when using
Shortness of Breath
n=3
n=1
n=1
these observations, with the MMRC, we initiated a phase I trial combining
300
1.3
8
1
1 PD, 5 SD,1 PR (unconfirmed)
myeloma cell lines or primary tumor cells from patients (David et al,
Altered Mental Status
n=3
n=1
1UNEVALAUBLE
the FTI tipifarnib with bortezomib to clinically evaluate the efficacy of this
Blood 2005). More recently, we have explored the preclinical use of
Hypokalemia
n=3
n=1
combination.
tipifarnib, an oral FTI, in combination with bortezomib and have
Febrile Neutropenia
n=1
n=1
Overall, 26 patients are evaluable for response, and 17 of
Methods: Patients with relapsed or refractory myeloma were treated with
Urinary Tract Infection
n=1
n=1
demonstrated that not only is the combination synergistic, the
26 had stable disease or better, and 3 of the responders had
Dehydration
n=2
bortezomib at 1.0 mg/m2 or 1.3mg/m2 given on days 1,4,8, and 11 in
combination of these agents appears to result in significant reduction
bortezomib resistant disease at the time of study entry.
Pneumonia
n=2
conjunction with escalating doses of tipifarnib (100-400mg PO BID) given
in HDAC6 expression with resultant blockade of aggresome
One patient with refractory PCL achieved a 90% reduction
Pulmonary embolism
n=1
on days 2-15 every 21 days, respectively. Dose escalation was
formation. In analysis similar to what is reported for the combination
Lymphompenia
n=1
in circulating plasma cells on study, and was graded as SD.
accomplished using an adaptive phase I design (Escalation With
of an HDAC inhibitor (vorinostat, LBH 589, romidepsin) with a
Infection
n=1
Overdose Control (EWOC)). Eligibility criteria included a serum creatinine
Fatigue
n=3
n=5
proteasome inhibitor, the combination of tipifarnib and bortezomib
Neuropathy (Motor and Sensory)
n=5
n=3
of <2.5, normal liver function, ANC>500, and platelets >25.
Results:
results in significant blockade of both proteasomal and aggresomal
Constipation
n=3
n=1
Conclusion:
Twenty-eight patients have been enrolled to date: bortezomib 1.0 mg/m2
based protein catabolism, and is the reason for the observed
Rash
n=2
n=1
with tipifarnib 100 mg (n=6), 200mg (n=5), 300mg (n=7), 400mg (n=2) and
pronounced synergy when the 2 drugs are combined in vitro. Based
Anorexia
n=1
n=2
bortezomib 1.3mg/m2 with tipifarnib 300mg (n=8), 400mg to be enrolled.
upon this observation, we have initiated , through the MMRC, a
Shingles
n=1
n=1
The combination of bortezomib and tipifarnib is active in a refractory
Hypotension
Median age is 63 (range 42-77). 20/28 patients had received prior high
n=1
phase I clinical trial testing the combination of tipifarnib and
Coughn=2
n=1
patient population, and able to induce response among bortezomib
dose therapy. The average number of prior therapies was 4.5, and, of the
bortezomib in patients with relapsed and refractory myeloma.
Edema
n=1
n=1
resistant patients
28 patients, 10 were refractory to bortezomib (relapsed on therapy or
To date 28 patients have been enrolled in this study, of which 26
Muscle Cramps
n=4
Novel phase I design allows for safe and rapid dose escalation
Proteinuria
n=4
within 6 months) 12 were bortezomib naïve, and 6 were previously
are evaluable for response.
Chills
n=2
exposed to bortezomib but not refractory.
Among these patients with
Toxicities are predominately GI and hematologic
Dizziness
n=2
Patient Characteristics
advanced myeloma and refractory disease, 50% had stabilization of
Diaphoresis
n=2
Further dose escalation with full dose bortezomib is planned to
disease or better. Maximum number of cycles received was 10. Of note,
Characteristic
No (N=28)
Range
%
Dyspepsia
n=2
evaluate the ability to deliver higher doses of both agents.
among the patients achieving clinical benefit, 1 had a stable M-protein, but
Hypocalcemia/ Hypercalcemia
n=2
Sex
ALT/AST
n=2
Correlative studies are in progress to evaluate the effect of the
experienced an 80% reduction in circulating plasma cells while on therapy,
Female
11
39
Headache
n=2
combination on HDAC6 and aggresome formation.
and another has had a 75% reduction in the free light chain assay. The
Male
17
61
Upper Respiratory Infection
n=2
most
common
drug-related
toxicities
were
GI
(19.0%)
with
Bruising/ Petechiae
n=2
Disclosures: Consultant for Millennium; SL. JK, Speakers Bureau for
nausea/vomiting occurring most frequently. Hematologic toxicities were
Age, years
64
42-77
Syncope
n=1
Millennium: JK, AK, DR, Consultant, Research Support and Speakers
difficult to ascertain as patients had advanced myeloma and many entered
Insominia
n=1
Creatinine
1.1
0.7-3.1
Hyperphosphatemia
n=1
Bureau for Ortho Biotech: DR, ST
with platelet counts of 25-50. Additional grade 3 toxicities included renal
Hyperglycemia
Hgb, g/dl
10.8
7.5- 14.3
n=1
insufficiency (related to PD), pneumonia and altered mental status which
Albuminemia
n=1
Albumin, g/dl
3.8
2.1- 4.5
Hyponatremia
n=1
were all considered due to disease progression. There were no Grade 3-
Aggresome inhibition with the combination
Weakness
n=1
5 non-hematologic drug related toxicities. There were no cardiac events or
Isotype
Ig A
4
12
DVT, and 1 patient experienced grade 2 peripheral neuropathy who did
Ig G
21
76
not have pre existing PN at baseline. Conclusions: The combination of
Ig D
2
8
IgM
1
4
bortezomib and tipifarnib is supported by preclinical rationale and has
Prior lines of therapy (mean)
4.5
2-9
This work is supported by a translational research grant from the
produced stable disease or better among a group of patients with
Leukemia and Lymphoma Society (SL)
refractory and advanced myeloma.
To date the optimal doses of both
tipifarnib and bortezomib have yet to be defined, and additional patients
will be enrolled to define the MTD by escalation of tipifarnib to 400 with
1.3mg/m2 of bortezomib. Correlative studies evaluating the effect of the
combination on HDAC6 and plasma cell apoptosis will be presented.

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