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Clinical and pharmacological background
• Microtubule stabilizing (and destabilizing) agents have relevant role in the treatment of breast cancer (and other tumors)
• They are natural compounds discovered serendipitously or in large-scale screens from plant, microbial, and marine sources
• Increased knowledge of the molecular bases of their mechanisms of action and tumor resistance has allowed rational approaches to the development of new analogues or chemotypes with innovative pharmacological and clinical properties
Why target microtubules?• Microtubules are key components of the cytoskeleton• Perform multiple basic cellular functions
(maintenance of cell shape, transport of vesicles, mitochondria throughout cells, cell signaling, cell division and mitosis)
• Fill the area from nucleus to plasma membrane• Their polymerization dynamics are tightly regulated both
spatially and temporally• At least 3 distinct binding sites for tubulin-targeting
drugs• Disruption of microtubule dynamics leads to mitotic
arrest and cell death
Structure and function of microtubulesand mechanism of action of tubulin-binding
agents
Mitotic chromosome
Centriole
Microtubules
Subunits
-tubulin
-tubulin
Mitotic center
(+) end
(-) end
Top view
Tubulin dimers
24 nm
8 nm
Microtubules
Taxanes(stabilizers)
Tubulin
Vinca alkaloids
(destabilizers)
Polymerization
Polymerization
From Morris PG & Fornier MN, 2008, modified
Effect of microtubule-targeting agents on cell cycle
ChromosomesMicrotubulesKinetochores
*Some chromosomes remain at spindle poles Jordan MA, et al. Nat Rev Cancer. 2004
Prometaphase
Anaphase
Metaphase withpaclitaxel*
Telophase
Metaphase withvinflunine*
Early metaphase
• The reduced dynamic movements of chromosomes reduces the tension on the kinetochores, centromeres and the conjoined chromosomes.
• These changes are associated with the blocking of mitosis at the metaphase–anaphase transition.
Effects of tubulin targeting drugs on cancer cells
Kavallaris M et al., Drug Resit Updat 4:392-401, 2001
MDR = multidrug-resistance phenotype; Pgp = P-glycoprotein; MRP = multidrug resistance-associated proteins; MAP = microtubule-associated proteins.
Antimitotic drugs bind to microtubules at diverse sites
Jordan Ma & Wilson L, Nat Rev Cancer 4:253-265, 2004
a | A few molecules of vinblastine bound to high-affinity sites at the microtubule plus end suffice to suppress microtubule dynamics. b | Colchicine forms complexes with tubulin dimers and copolymerizes into the microtubule lattice, suppressing microtubule dynamics. c | A microtubule cut away to show the interior surface is shown. Paclitaxel binds along the interior surface of the microtubule, suppressing its dynamics.
Taxanes in clinical uses
Paclitaxel Docetaxel
Indications:
• adjuvant treatment of breast cancer• locally advanced or metastatic breast cancer • locally advanced or metastatic NSCLC• hormone refractory metastatic prostate cancer• metastatic gastric adenocarcinoma• locally advanced squamous cell carcinom of the head & neck
Indications: • advanced ovarian cancer • adjuvant treatment of node positive breast cancer • metastatic breast cancer • advanced NSCLC • advanced AIDS-related Kaposi’s sarcoma From EMEA/FDA product information
Disadvantages of first-generation taxanes
• Poor bioavailability• Low solubility in water• Need of surfactant agents (cremophor
EL, Tween80) believed to be responsible for severe allergic reactions
• Relevant toxicity• Treatment failure due to intrinsic or
acquired multidrug resistance
Cellular changes associated with multidrug and taxane resistance
• Overexpression of members of the ATP-binding cassette family of drug transporters– eg, p-glycoprotein
• Alterations in microtubule/tubulins– Tubulin mutations– Overexpression of tubulin isotypes with more
dynamicity (-III)– Changes in the expression of microtubule-
associated proteins (MAPs)
Fojo AT, et al. 2005; Dumontet C, et al. 1999
Microtubule destabilizers and stabilizers
and their binding sites on tubulin
Morris PG & Fornier MN, Clin Cancer Res 22:7167-7172, 2008
MICROTUBULE DESTABILIZERS MICROTUBULE STABILIZERS
Vinca alkaloidsVincristineVinblastineVinorelbineVinflunine
Halicondrins(eribulin mesylate)CryptophycinsDolastatinsHemiasterlins
Vinca binding
site
Colchicine binding
site
Taxane binding
site
Laulimalide
binding site
Epothilones
Epothilone B
(Patupilone)
Epothilone D
(KOS-862)Combrestatins
Taxanes
2-MethoxyestradiolSulphonamides
• Dehydelone (KOS-1584)
LaulimalidePeloruside A
EleutherobinSarcodictyins A+BCyclostreptin
• Paclitaxel • Docetaxel• ABI-007• CT-2103• Taxoprexin• Larotaxel• Cabazitaxel
Ixabepilone Sagopilone BMS-310705
Colchicine
DiscodermolideDictyostatin
Natural-product microtubule-stabilizing agents and their sources
Agent Chemical structure
Source
Paclitaxel Diterpene Taxus brevifolia Pacific yew tree
Docetaxel* Diterpene Taxus baccata European yew tree
Epothilones Macrolides Sorangium cellulosum Myxobacterium
Discodermolide
Lactone Discodermia dissoluta Sponge
Dictyostatin Lactone Spongia sp Sponge
Eleutherobin Diterpene Eleutherobin aurea Coral
Sarcodictyns Diterpenes Sarcodictyon roseum Coral
Cyclostreptin Polyketide Streptomyces sp Actinobacterium
Laulimalide Lactone Fasciospongia rimosa/ Cacospongia mycofijiensis
Sponge
Peloruside A Polyketide Mycale sp Sponge
Taccalonolides Lactones Tacca plantagine/chantrieri
Plant
* semi-synthetic analogue from 10-deacetyl baccatin III
Summary of defined microtubule stabilizing agents
From Zhao Y et al., 2009, modified
MDR: Multi-drug resistance; P-gp: P-glycoprotein
Compounds Binding site Effect on MDR tumour cells
P-gp overexpression
-tubulin related factors
Paclitaxel, docetaxel
Taxol-binding site - -
Second/third generation taxanes
Taxol-binding site + +/-
Epothilones Taxol-binding site + +
Discodermolide Taxol-binding site or overlapped
+ +
Dictyostatin Same as discodermolide (probably)
+ +
Eleutherobin Taxol-binding site (probably) - -
Sarcodictyins Taxol-binding site (probably) + +
Cyclostreptin Taxol-binding site (irreversibly) + +
Laulimalide Laulimalide-binding site + +
Peloruside A The same or overlapped laulimalide-binding site, or a new site
+ +
New paclitaxel formulations
Name Compound Clinical stage
ABI-007 (Abraxane)
Nanoparticle-albumin bound paclitaxel
Approved (treatment of metastatic breast cancer in patients who have failed first-line treatment for metastatic disease and for whom standard, anthracycline containing therapy is not indicated)
Paclitaxel poliglumex (CT-2103, Opaxio, Xyotax)
Poly(L-glutamic acid)-paclitaxel Phase III trials for NSCLC and phase II trials for ovarian cancer reported
Docosahexaenoyl-paclitaxel (taxoprexin)
Docosahexaenoic acid (DHA)-conjugatedpaclitaxel
Phase III trials ongoing(treatment of NSCLC)Phase II trials for other cancers reported
nab-paclitaxel (ABI-007)• Paclitaxel bound to albumin nanoparticles • Advantages:
– Cremophor free formulation– Lower risk of hypersensitivity reactions– No premedications needed– Shorter infusion time– Linear, predictable PK– Greater amount of drug delivered to the target cells
• Might make use of gp60-albumin mediated receptor transport across endothelial cells
Morris and Fornier, 2008; Ibrahim et al., 2002; Desai et al Clin Cancer Res 2006
nab-paclitaxel
Trial No. ptsSettin
gSchedule
RR (%)
Med TTP (wks)
Ibrahim1 63 No limit300 mg/m2
Q3w48 27
Mirtsching2 23 1st line125 mg/m2 QW
(3 out of 4 wks)
57 NR
Gradishar3
nab-paclitaxel vs paclitaxel
225 vs 229 1st line260 mg/m2 vs. 175 mg/m2 Q
3W33 vs 19 23 vs 17
Significant differences in RR = response rate (p=0.001) and TTP= time to progression (p=0.006);
NR= not reported
1Ibrahim, JCO 2005; 2Mirtsching Breast Ca Res Treat Suppl 2006; 3Gradishar JCO 2005
Adverse events
Gradishar WJ et al., J Clin Oncol 23:7794-7803, 2005SD, standard deviation; ANC, absolute neutrophil count; * p<0.05
A) all grades reported in more than 20% of patients in either treatment group
B) grade 3 and 4 reported in ≥ 5% of patients in either
group
• The incidence of grade 4 neutropenia was significantly lower for ABI-007 compared with standard paclitaxel (9% vs 22%, p=0.001)• Grade 3 sensory neuropathy was more common in the ABI-007 arm than in the standard pazlitaxel arm (10% vs 2%, p=0.001) but was easily managed and improved rapidly (median 22 days)•No hypersensitivity reactions occurred with ABI-007 despite the absence of premedication and shorter administration time
• ABI-007 showed superior efficacy to paclitaxel in a phase III study in metastatic breast cancer.
• Although ABI-007 use was associated with less neutropenia, its use did increase the risk of peripheral neuropathy.
• ABI-007 is now approved by FDA and EMEA for the treatment of metastatic breast cancer.
• A phase II study of ABI-007 in combination with trastuzumab and carboplatin in patients with metastatic breast cancer is ongoing.
• An adjuvant phase II trial of doxorubicin and cyclophosphamide followed by ABI-007, all in combination with bevacizumab, for breast cancer patients has recently completed accrual.
• The incorporation of ABI-007 into standard taxane-based regimens could potentially remove the need for premedication with steroids and could allow more rapid infusion times.
nab-paclitaxel
Phase II study nab-paclitaxel vs. docetaxel
Comparisons Comparisons (N=300)(N=300)
nabnab-paclitaxel vs. -paclitaxel vs. docetaxeldocetaxel ( (A, B, CA, B, C vs.vs. D D))
weekly vs. every-3-weekly vs. every-3-weeks weeks nabnab-paclitaxel-paclitaxel ( (B, CB, C vs.vs. AA))
low vs. high dose low vs. high dose weekly weekly nabnab--paclitaxelpaclitaxel ((BB vs.vs. C C) )
Arm A: nab-paclitaxel 300 mg/m2 q3w(n=76)
Arm B: nab-paclitaxel 100 mg/m2
weekly 3 out of 4(n=76)
Arm C: nab-paclitaxel 150 mg/m2
weekly 3 out of 4(n=74)
Arm D: docetaxel 100 mg/m2 q3w(n=74)
RR
AA
NN
DD
OO
MM
II
ZZ
EE
first-line metastatic breast cancer patients randomized to 4 first-line metastatic breast cancer patients randomized to 4 arms:arms:
Arms A, C and D administered at the MTDArms A, C and D administered at the MTD
Gradishar W, et al. ASCO 2007. Abstract 1032.
Phase II study evaluating various doses of nab-paclitaxel vs.
docetaxelABX 300 mg/m2 q3w ABX 100 mg/m2 qw3/4ABX 150 mg/m2 qw3/4Docetaxel 100 mg/m2 q3w
P = .016
P = .007P = .003
P = .002100
90
80
70
60
50
40
30
20
10
0
Resp
on
se R
ate
(%
)
Treatment
43
62
n = 76 76 74 74
70
38
Gradishar W, et al. ASCO 2007. Abstract 1032.
Phase II study evaluating various doses of nab-paclitaxel vs. docetaxel
Months
Progression-free SurvivalInvestigator Assessments
Pro
port
ion
Not
Imp
roved
30 6 9 12 15 180.0
0.25
0.50
1.0
75% of patients off-study
0.75
AB CD
Gradishar W, et al. ASCO 2007. Abstract 1032.
• PFS statistically superior with 150 mg/m2 (P = .002) and 300 mg/m2 nab-paclitaxel (P = .046) compared with docetaxel in MBC
• PFS statistically superior with 150 mg/m2 nab-paclitaxel compared with 100 mg/m2 nab-paclitaxel (P = .009)
• Lower incidence of neutropenia and fatigue with all schedules of nab-paclitaxel compared with docetaxel
• Randomized phase III trial comparing weekly nab-paclitaxel 150 mg/m2 vs. docetaxel 100 mg/m2 in MBC planned
New taxanes in phase III clinical trials
Larotaxel (XRP9881, RPR 109881A) Cabazitaxel (XRP-6258, TXD258)
• Phase III trials completed for the treatment of breast and pancreatic cancer – results not yet published
• Phase III trials ongoing for the treatment of bladder cancer
• Favorable therapeutic index in taxane-pretrated metastatic breast cancer(Dieras V et al., 2008)
• A phase III trial completed in combination with prednisone for the treatment of hormone-refractory metastatic prostatic cancer
• Results recently published (ASCO GU 2010)
• Oral route
New taxanes in phase II trials
TPI-287 (NBT-287)Ortataxel
(BAY 59-8862/IDN5109)
Milataxel (MAC-321)
Tesetaxel (DJ-927)
Phase II trials ongoing for the treatment of pancreatic, prostate cancer and melanoma
Phase II trials ongoing for the treatment of NHL, NSCLC, breast, kidney, renal cell carcinomaOral route
Phase II trials ongoing for the treatment of colorectal, gastric cancer and melanoma. IV/Oral route
Phase II trials ongoing for the treatment of mesothelioma, NSCLC and colorectal cancerIV/Oral route
BMS-275183Phase II trials ongoing for the treatment of NSCLCOral route
New taxanes in phase I trials
Simotaxel (TL909) TL-310
BMS-184476BMS-188797
Chemical structures of the natural epothilones and the synthetic epothilones currently in
clinical development
Structural differences among the natural moieties are indicated with gray circles. Within epothilone B and D derivatives, structural differences from natural epothilones are indicated using gray ellipses. From Michaud LB, Ann Pharmacother 43:1249-309, 2009, modified
Natural epothilones
Epothilone A Epothilone B(Patupilone)
Epothilone C Epothilone D(KOS-862)
Ixabepilone(Aza-epothilone B)
Sagopilone(ZK-EPO) BMS 310705
Semi- & FullySynthetic Derivatives
Dehydelone KOS-1584
Epothilones: mechanism of action
• Induce microtubule stabilization– Bind to -tubulin– Compete with same binding site as paclitaxel on
-tubulin– Binding mode different from above– Accumulate in G2/M
• Induces conformational changes in Bax (pro-apoptotic protein)
• Bcl-2-dependent• Potential for synergism with Bcl-2 inhibitors
Pharmacologic considerations
• Epothilone A and B– High in vitro tumor activity– Modest in vivo activity– Metabolic instability– Unfavorable PK– Narrow therapeutic window
• Analogs developed to optimize product
Class-specific advantages
• Low susceptibility to tumor resistance mechanisms– MRP-1 and P-gp efflux pumps– (III) tubulin overexpression– -tubulin mutations
Summary of phase II trials of ixabepilone in metastatic breast
cancer
0Roché1
After adjuvant anthracycline
Low2
Taxane-pretreated MBC
Thomas3
Taxane-resistant MBC
Perez4
Anthracycline-, taxane-, and capecitabine-
resistant
Bunnell5
Multiresistant MBC w/capecitabine
42
22
12
30
18a
5
10
15
20
25
30
35
40
45
Overa
ll R
esp
on
se R
ate
(%)
1. Roché H, et al. J Clin Oncol. 2007;25:3415. 2. Low JA, et al. J Clin Oncol. 2005;23:2726. 3. Thomas E, et al. J Clin Oncol. 2007;25:3399. 4. Perez EA, et al. J Clin Oncol. 2007;25:3407. 5. Bunnell CA, et al. J Clin Oncol. 2006;24:Abstract 10511. Graphic courtesy of Hope S. Rugo, MD.
12b
aInvestigator assessed; bIndependent assessed.
0
20
40
60
80
100
BMS 009NCI 0229BMS 010BMS 081BMS 031
Diarrhea at 1 to 11%
Grade 3/4 neutropenia 35 to 58%
Febrile neutropenia 3-14% with 14 % on NCI0229
Sensory neuropathy ranged from 3-22%
Severe myalgias range from 3-26%
Fatigue variable at 6 to 34%
Ixabepilone phase II trialsGrade 3/4 toxicity in metastatic breast
cancer
1. Thomas E, et al. J Clin Oncol. 2007;25:3399. 2. Low JA, et al. J Clin Oncol. 2005;23:2726. 3. Roché H, et al. J Clin Oncol. 2007;25:3415. 4. Perez EA, et al. J Clin Oncol. 2007;25:3407. 5. Bunnell CA, et al. J Clin Oncol. 2006;24:Abstract 10511.
IxabepilonePhase III data
FDA approved ixabepilone in October 2007 as a single agent for triple-resistant metastatic
breast cancer, and in combination with capecitabine
for anthracycline- and taxane-resistant diseaseEMEA CHMP gave a negative opinion and did not recommend a marketing authorization for
ixabepilone for the treatment of locally advanced breast cancer (November 20, 2008)
BMS Pharma EEIG withdrawn its marketing authorization application for ixabepilone
(March 18, 2009)
What were the main concerns of the CHMP?
• The CHMP was concerned that ixabepilone’s benefits in terms of increasing the time until the cancer got worse did not outweigh the concerns over the medicine’s safety.
• In particular, the Committee was concerned over the risk of patients developing neuropathy (damage to nerve cells), which was a severe and common side effect in patients taking the medicine.
• Therefore, at the time of the withdrawal, the CHMP’s view was that the benefits of ixabepilone in the treatment of breast cancer did not outweigh the identified risks.
Ixabepilone(40 mg/m2 IV over 3 hr d1 q3wk)
+Capecitabine
(2000 mg/m2/day PO 2 divided doses d1-d14 q3wk)
N = 375
Capecitabine(2500 mg/m2/day PO 2 divided doses
d1-d14 q3wk)N = 377
Metastatic or locally advanced breast cancer
RESISTANT to anthracyclines
and taxanesN = 752
Stratification •Visceral metastases•Prior chemotherapy for MBC
Study Design: International, Randomized,
Open-label, Phase III Trial
•Anthracycline resistance•Study site
Resistance to Prior TherapyStrict definition: patients whose tumors rapidly progressed in the adjuvant
or metastatic setting after receiving both anthracyclines and taxanes
Setting Anthracycline Taxane
Metastatic ≤3 months of last dose≤4 months of last
dose
Neo/adjuvant
≤6 months of last dose≤12 months of last
dose
Any
Minimum cumulative dose
Doxorubicin: 240 mg/m2
Epirubicin: 360 mg/m2
Median 95% CI
Ixabepilone + Capecitabine
5.8 mo (5.5–7.0)
Capecitabine 4.2 mo (3.8–4.5)
Progression-free Survival by Independent Radiologic Review
P=0.0003
HR: 0.75 (0.64–0.88)
Pro
port
ion
Pro
gre
ssio
n F
ree 1.0
0.8
0.6
0.4
0.2
00 4 8 12 16 20 24 28 32 36
Months
Response Rate
% Response
Investigator IRR
Ixabepilone +
Capecitabine N=375
Capecitabine
N=377
Ixabepilone +
Capecitabine N=375
Capecitabine
N=377
ORR (CR + PR) 42 23 35 14
P<0.0001 P<0.0001
Stable disease 36 38 41 46
Progressive disease
14 29 15 27
Unable to determine
8 10 9 12
.001
.011
<.0001
.005
<.0001
P Value
5
8
68
10
57
<1Febrile neutropenia
4Thrombocytopenia
11Neutropenia
4.5Anemia
6Leukopenia
CapecitabineN = 368
Ixabepilone + Capecitabine
N = 369Toxicity (%)a
aBy worst CTCAE v3 grade.
Grade 3/4 Hematologic Toxicities
Thomas E, et al. J Clin Oncol. 2007;25:5210.
Peri
phera
Peri
phera
l l neuro
pat
neuro
pat
hyhy
23
0
Mya
lgi
Mya
lgi
aa8
0.3
Han
d-
Han
d-
foot
foot
syndro
m
syndro
mee
18 17
Dia
rrhe
Dia
rrhe
aa
69
Muco
siti
Muco
siti
ss
2 2
Vom
itin
Vom
itin
gg
4 2
Fati
gu
Fati
gu
ee
9
3
Nau
sea
Nau
sea
3 2
Art
hra
lgi
Art
hra
lgi
aa
30
0
% P
ati
en
ts
Ixabepilone + capecitabine (n = 369)
Capecitabine (n = 368)
20
40
60
80
Grade 3/4 Nonhematologic toxicities
Thomas E, et al. J Clin Oncol. 2007;25:5210
• Ixabepilone for metastatic breast cancer is an example of a cancer drug that adds "a small benefit at a high cost“
• This editorial accompanies a new cost-efficacy study in the same issue of the journal that found that the addition of ixabepilone to capecitabine adds about $31,000 to the overall medical costs of metastatic breast cancer while providing about 1 more month of "quality-adjusted" survival (Reed et al., 2009).
AgentEpothilone
AnalogClinical Toxicities
Current Development
Phase
Patupilone (EPO906)
Epothilone B Diarrheaa, fatigue, nausea, vomiting III
(ovarian cancer)
II
(ongoing in mBC)
BMS-310705 Epothilone B Hypersensitivity reaction,pancytopenia, neuropathy, arthralgia/myalgia, asthenia, diarrheaa, ataxia, neutropeniaa, hyponatremiaa, vomitinga
I/II
(OR observed in mBC)
Sagopilone (ZK-EPO)
Epothilone B Neuropathya, nausea, ataxiaa II
(ongoing in mBC)
KOS-862 Epothilone D Fatigue, nausea/vomiting, neuropathy, impaired gaita, cognitive/perceptual abnormalitiesa, chest paina
II
(14% PR in A&T resistant mBC)
Drug development discontinued
Dehydelone (KOS-1584)
Epothilone D I
(ongoing)
Epothilones in clinical development
a, dose limiting toxicity; mBC, metastatic breast cancer; A&T, anthracycline & taxane