Tanespimycin + Bortezomib Demonstrates Safety, Activity, and Effective Inhibition in
Relapsed/Refractory Myeloma Patients: Updated Results of a Phase 1/2 Study
Paul G. Richardson, MD,1 Asher A. Chanan-Khan, MD,2 Sagar Lonial, MD,3 Amrita Y. Krishnan, MD, FACP,4 Michael P. Carroll, MD,5 Maher Albitar, MD,6 Marianne Messina, MS,7 David Berman, MD, PhD,8 Kenneth C. Anderson, MD1
1Dana-Farber Cancer Institute, Boston, MA, USA; 2Roswell Park Cancer Institute, Buffalo, NY, USA; 3Emory University, Winship Cancer Institute, Atlanta, GA, USA; 4City of Hope, Duarte, CA, USA; 5Sutter Regional Cancer Institute, Sacramento, CA, USA;
6Quest Diagnostics Nichols Institute, San Juan Capistrano, CA, USA; 7Bristol-Myers Squibb Research and Development, Wallingford, CT, USA; 8Bristol-Myers Squibb, Princeton, NJ, USA
Background
Methods (cont)
Results (cont)
Results (cont)
Conclusions
n
Tanespimycin disrupts heat shock protein 90 (Hsp90), a key molecular chaperone for
Assessments
Efficacy
Pharmacodynamics
signal transduction proteins critical to myeloma growth, survival, and drug resistance.
n
Tanespimycin + bortezomib in combination is wel tolerated
n TumorresponsewasassessedusingthemodifiedEuropeanGroupforBloodand
n Amongthe67evaluablepatients,2patients(3%)hadcompleteresponses(CR),8
n
Tanespimycin effectively targets Hsp90, as evidenced by increased Hsp70 expression
n
Hsp90 inhibitors suppress IGF-1R and IL-6R signaling, resulting in simultaneous
MarrowTransplantation(EBMT)criteria.
patients(12%)hadpartialresponses(PRs),and8patients(12%)hadaminimalresponse
(Figure 2).
with a low frequency of peripheral neuropathy and
interruption of oncogenic signal transduction pathways that are pivotal to tumor
(MR)foranoveral responserate(ORR;MR)of27%(Table 2).
n AEswereevaluatedusingNCICTCAEv3.0.
neutropenia, which compares favorably with historical data
progression and survival.
­ From baseline to day 1 hour 4
1
n ORRs(MR)were48%inthe21bortezomib-naivepatients,22%inthe23
n Peripheralbloodmononuclearcel s(PBMCs)werecol ectedandlysateswereanalyzed
· 1.8-foldincreaseat275mg/m2 tanespimycin
on bortezomib monotherapy.
n
Increased Hsp70 expression is a pharmacodynamic marker for Hsp90 inhibition.2
for Hsp70 expression and 20S proteasome activity on days 1 and 11 at 0, 4, and 24
bortezomib-pretreated patients, and 13% in the 23 bortezomib-refractory patients.
· 1.4-foldincreaseat340mg/m2 tanespimycin
n
Several reports have now shown that overexpression of Hsp70 may protect against
hours postdose and normalized to baseline pretreatment levels in each patient.
Table 2. Efficacy in Evaluable Patients by Modified EBMT Criteria (n=67)*
­ From baseline to day 11 hour 0
n
Tanespimycin + bortezomib effectively inhibits Hsp90 as
nervous system injury.3-5
n
Hsp70 levels were measured by Western blot, and 20S proteasome activity was
Response
n (%)
95% CI
· 2.0-foldincreaseat275mg/m2 tanespimycin
reflected by increased Hsp70 expression and targets the
n
Addition of tanespimycin blocks this response and has synergistic antitumor activity and
measured as a composite of chymotrypsin, trypsin, and caspase activity.
enhanced proteasome inhibition in primary cel s.
· 2.2-foldincreaseat340mg/m2 tanespimycin
6
ORR (CR + PR + MR)
proteasome as reflected by decreased 20S proteasome
All

18(27)
17­39
Figure 2. Hsp70 Expression by Dose Level for Al Patients
activity.
n
Tanespimycin + bortezomib has demonstrated durable responses in patients with
Bortezomib-naive (n=21)

10(48)
26­70
relapsed/refractory MM with low rates of neutropenia and peripheral neuropathy
Bortezomib-pretreated (n=23)
5 (22)
8­44
4
relative to historical data on bortezomib monotherapy (neutropenia 19­20%; peripheral
Bortezomib-refractory (n=23)
3 (13)
3­34
n
Tanespimycin + bortezomib induced durable responses in
Day 1 Hour 0
neuropathy 31­39%).
CR+PR
10 (15)
7­26
7­10
Results
CR
2 (3)
3.5
Day 1 Hour 4
heavily pretreated patients with relapsed or refractory MM,
PR

8(12)
n
In preclinical studies, tanespimycin protected against bortezomib-induced peripheral
Day 11 Hour 0
including those who were refractory to bortezomib.
neuropathy (BIPN).11
n
MR

8(12)
Seventy-two patients were enrol ed with 42 patients treated at the highest doses
3
(340 mg/m2 tanespimycin, 1.3 mg/m2 bortezomib).
Baseline
Day 11 Hour 4
CI,confidenceinterval;CR,completeresponse;EBMT,theEuropeanGroupforBloodandMarrowTransplantation;MR,
minimal response; PR, partial response.
2.5
n
The median age was 60 years, and 72% had IgG subtype (Table 1).
*Evaluablepatientcohortexcludes3patientswhoreceivedthelowestdosesoftanespimycin+bortezomiband2patients
Over
with no M protein at baseline.
Deviation
Future Directions
n
Aim
Median time since MM diagnosis was 50 months and the median number of prior
2
regimenswas5(range,1­15)includingstemcel transplant(69%),thalidomide(89%),
n
n
To evaluate pharmacodynamic data including Hsp70 expression levels and proteasome
ORRwas64%inbortezomib-naivepatientswhohad3priorregimens.
bortezomib (69%), lenalidomide (17%), and other Hsp90 inhibitors (13%).
n
Tanespimycin + bortezomib is currently in phase 3 of
Increase
1.5
n
activityandtoevaluateupdatedsafetyandefficacyprofilesoftanespimycin+bortezomib
n
Themediandurationofresponsewas12months(n=18patients),including3bortezomib-
Atotalof78%ofpatientshadahistoryofperipheralneuropathypriortostudyentry.
in patients with relapsed/refractory MM
development in patients with multiple myeloma.
refractory patients each with durable PRs through months 12, 22, and 27, respectively.
Standard+ 1
Table 1. Patient Demographics and Baseline Characteristics
Fold
n
Of these 3 bortezomib-refractory patients with long-term responses, 2 patients had
Demographic/Characteristic
N=72
progressed while being treated with prior bortezomib (bortezomib/dexamethasone and
Mean
0.5
Methods
bortezomib/thalidomide/dexamethasone).
Disclosures
Median age, years (range)

60(39­80)
0
Key eligibility criteria
Gender, n (%)
Safety
150
220
275
340
n Dr.RichardsonisonthespeakersbureauforMil enniumPharmaceuticalsandCelgeneCorporationandreceives
research funding from Mil ennium Pharmaceuticals.
n
Men
40 (56)
Dose (mg/m2)
n
Age18years,evidenceofrelapsed/refractoryMM,andaKarnofskyperformancestatus
ThemostcommonAEs(al grades)areshowninTable 3.
(KPS)of70%
n Dr.Chanan-Khanisonaspeakersbureauandreceiveshonoraria(organizationswerenotdisclosed).
Ethnicity, n (%)
n
Thrombocytopenia occurred in 40% of patients (25% Grade 3/4). In cycle 1, mean platelet
White
54 (75)
n Dr.LonialisaconsultantforCelgeneCorporation,Mil enniumPharmaceuticals,Bristol-MyersSquibbandNovartis
n Patientsmusthavereceived2priorregimensofanti-cancertherapy,whichcould
countsdecreasedfrom180,000/µLonday1to154,000/µLonday11.
n Tanespimycineffectivelytargetsproteasomeactivityasreflectedbydecreasesfrom
and receives research funding from Mil ennium Pharmaceuticals and Gloucester Pharmaceuticals.
Black

13(18)
100% at baseline to 40%, 56%, 65%, and 52% at day 11 hour 1 with tanespimycin doses
include bone marrow transplant.
Other
5 (7)
n Drs.KrishnanandCarrol havenorelevantconflictsofinteresttodisclose.
n
Neutropenia was observed in only 4% of patients (3% Grade 3).
of 150 (n=2), 220 (n=3), 275 (n=5), and 340 mg/m2 (n=23), respectively.
­ Patientshadtobe3weekspastlastdoseofpriortherapyand4weekspostbone
n Dr. Albitar is a consultant (organization was not disclosed).
KPS, median (range)*
90 (70­100)
n Incycle1,meanabsoluteneutrophilcounts(ANC)increasedfrom3.0x109/L on day 1 to
n Frombaselinetoday11hour24,furtherdecreasesinproteasomeactivityto26%,38%,
marrow transplantation.
n Dr.AndersonisaconsultantforCelgeneCorporation,Novartis,Mil enniumPharmaceuticals,and
Subtype, n (%)
4.2 x 109/L on day 11.
45%, and 32% were observed (Figure 3).
Bristol-MyersSquibb.Hereceivesresearchfundingfrom:CelgeneCorporation,Novartis,Mil ennium
­ Prior bortezomib was al owed and patients were categorized at study entry as
IgG
51 (71)
Pharmaceuticals,andBristol-MyersSquibb,andhehasreceivedhonorariafrom:CelgeneCorporation,Novartis,
n
Grade 1 or 2 peripheral neuropathy was observed in 15 patients (21%) and no Grade 3/4
bortezomib-naive, bortezomib-pretreated, or bortezomib-refractory.
IgA
19 (26)
Figure 3. Proteasome Activity by Dose Level for Al Patients on Day 11
Mil ennium Pharmaceuticals, and Bristol-Myers Squibb.
IgD
1 (1)
peripheral neuropathy was observed.
n Adverseevents(AEs)associatedwithpriorchemotherapy,surgery,orradiotherapyhad
Nonsecretory
4 (6)
80
n
No severe constipation or anorexia was observed.
toberesolvedtoNationalCancerInstituteCommonTerminologyCriteriaforAdverse
ß microglobulin mg/dL, median (range)*
3.6 (1­15)
1 Hour
2
Events(NCICTCAE)v3.0Grade2.
Table 3. AEs Occurring in 20% of Patients and Selected AEs (N=72)
70
Acknowledgments
Months since diagnosis, median (range)

50(10­238)
)
4 Hour
Study design
Adverse Event, %
Al Grades
Grade 3/4*
Baseline
24 Hour
No baseline measurable disease, n (%)
2 (3)
(% 60
n
We would like to thank the research nurses, physicians, coordinators, and other staff
n
Open-label, dose escalation, multicenter clinical trial of tanespimycin
Diarrhea
60
7
of
atthestudysites:Dana-FarberCancerInstitute;Roswel ParkCancerInstitute;Emory
Prior regimens, median (range)
5 (1­15)
n
Patients received bortezomib (0.7, 1.0, or 1.3 mg/m2) administered by a rapid bolus,
Nausea
49
4
Stem cel transplant, n (%)
50 (69)
50
University,WinshipCancerInstitute;CityofHope;Sut erRegionalCancerInstitute;
fol owed by a 1-hour infusion of tanespimycin (100, 150, 220, 275, or 340 mg/m2) on days
Thalidomide, n (%)

64(89)
Fatigue
49
7
Activity
Quest Diagnostics Nichols Institute; and Bristol-Myers Squibb.
Lenalidomide, n (%)
12 (17)
1,4,8,and11ineach21-daycycle(Figure 1).
Thrombocytopenia
40
25
40
Bortezomib-naive, n (%)
22 (31)
Deviation
n
We would like to thank the patients and their families.
n Tanespimycininjection,aCremophor-containingproduct,wasusedatal doselevels.
AST elevation
28
4
Bortezomib-pretreated, n (%)
24 (33)
30
n
This study was sponsored by Bristol-Myers Squibb (and previously Kosan Biosciences).
A tanespimycin concentrate for suspension for injection was used in 23 patients at the
Bortezomib-refractory, n (%)
26 (36)
Dizziness
28
1
Hsp90 inhibitors, n (%)
9 (13)
highest tested dose (340 mg/m2 tanespimycin + 1.3 mg/m2 bortezomib).
Back pain
24
4
20
Hsp90, heat shock protein 90; KPS, Karnofsky performance status.
Muscle spasms
24
0
Standard Proteasome
Figure 1. Study Design
*N=70; data were unavailable on 2 patients.
+
Vomiting
24
1
10
References
+
+
+
+
Dyspnea
22
3
Dose-finding results
Mean
0
1. Zhang H, et al. J Mol Med.2004;82:488-499.
Peripheral edema
22
0
150
220
275
340
2. Modi S et al. J Clin Oncol.2007;25:5410-5417.
n
Patients were treated for an average of 4.7 cycles with a maximum of 20 cycles.
3.YenariMA.In:AlzheimerC,ed.MolecularandCellularBiologyofNeutropeniaintheCNS.NewYork:Landes
Pyrexia
22
1
Dose (mg/m2)
Bioscience,KluwerAcademic/PlenumPublishers;2002:281-300.
n
Cycle
The highest tested dose was 340 mg/m2 tanespimycin and 1.3 mg/m2 bortezomib with no
Constipation
21
0
4.KellyS,etal.CurrMedResOpin.2002;18Suppl2:s55-60.
significanttoxicitiesobserved.
5. Brown IR. Ann N Y Acad Sci.2007;1113:147-158.
Peripheral neuropathy
21
0
Assess
6.MitsiadesCS,etal.Blood.2006;107:1092-1100.
n
Tanespimycin Bortezomib
Tanespimycin Bortezomib
Tanespimycin Bortezomib
Tanespimycin Bortezomib
TheCremophor-basedandsuspensionformulationswereusedforthehighesttested
Anemia
15
7
7. Richardson PG, et al. J Clin Oncol.2009;27:8503.
doseandappearedtobesimilarbasedonpharmacodynamics,safety,andefficacy.
Anorexia
6
0
8.RichardsonPG,etal.New Engl J Med.2003;348:2609-2617.
9. Richardson PG, et al. New Engl J Med.2005;352:2487-2498.
AEs,adverseevents;AST,aspartateaminotransferase.
10. Orlowski RZ, et al. J Clin Onc.2007;25:3892-3901.
Day 1
4
8
11
21
*With the exception of thrombocytopenia and AST elevation, al other adverse events were Grade 3.
11.ZhongZ,etal.In:20thEORTC-NCI-AACRSymposiumonMolecularTargetsandCancerTherapeutics.
Geneva,Switzerland;2008.
n
Steroid and antihistamine premedications were given 30 minutes prior to tanespimycin
infusiontoreducethechanceofCremophor-inducedhypersensitivityreactionsinpatients
receivingCremophorformulation.
­ No premedication was required for the tanespimycin suspension formulation.
n
Doses of each drug were escalated based on tolerability and safety.
Abstract 2890
n
Phase 2 expansion occurred at the highest tested dose for each study drug.
51st Annual Meeting of the American Society of Hematology
n
Treatment continued until evidence of progressive disease, unacceptable
treatment-related toxicity, or patient withdrawal from the study.
New Orleans, LA, USA, December 5­8, 2009

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