Transcript Novel Therapeutics in Ovarian Cancer

Novel Therapeutics in
Gynecological
Malignancies
Tamar Safra, MD
Tel Aviv Sourasky Medical Center, Tel Aviv
Ovarian Cancer- New
Treatments
Uterine Cancer – Evolving
Treatment
Ovarian Cancer
• The most lethal of gynecologic
malignancies
• Future goals
– Early detection
– Development of novel agents
Ovarian Cancer
• New drugs and analogs of old drugs
• New schedules for old drugs
• Methods to overcome drug resistance
• Biological agents
• Combination of chemotherapy with
biological therapy
• Hormonal therapy
Mitotic Spindle
Inhibitors
New Taxanes
• Taxanes and epothilones - under active clinical
development
–
–
–
–
Overcome drug resistance
Enhance tumor delivery
Reduced neuropathy
Reduced alopecia
• Xyotax, a polyglutamate conjugated to paclitaxel activity without alopecia
• Abraxane - nanoparticle paclitaxel forumulation is
under investigation
Paclitaxel Poliglumex (PPX)
• Conjugate of paclitaxel with poly-Lglutamic acid
• Enhances distribution in tumor
• Prolonged release of free paclitaxel
• Greater activity
• Active in tumors with MDR (Multi-Drug
Resistance) gene
• Shorter administration
GOG 212 Phase III Study :
Maintenance Chemotherapy for
EOC
Paclitaxel 175 mg/m2
q 28 days x 12
EOC with CR
after 6 cycles of
chemotherapy
PPX 175mg/m2
q 28 days x 12
Observation
Different Schedules
of old drugs
Topotecan
• An S-phase specific drug
• Activity and toxicity are schedule
dependent
• Investigated methods
• Daily administration – 5 days q 3 weeks
• Low-dose continuous infusion (CI)
• Weekly schedule
Topotecan Mechanism of
Action
Topoisomerase I
creates DNA
breaks for repair
and replication
Topotecan binds
to topoisomerase I
creating DNA
breaks
Damage to
DNA causes
cell death
Topotecan
Daily
Study Design
Multicenter, prospective, randomized
phase-III study
Stratification by age, ascites and previous response to
platinum-based therapy
Paclitaxel
175 mg/m2 D1
Q21d
over 3 hours
Topotecan
1.5 mg/m2/d D1-5
Q21d
30-minute infusion
Ten Bokkel Huinink. J Clin Oncol 1997;15:2183-93
Time to Progression
1.0
Median TTP
0.8
Proportion
0.6
topotecan(n=112)
19.8w
Paclitaxel (n=114)
14.7w
P =.072
0.4
0.2
0.0
0
4
8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80
Time (weeks)
Ten Bokkel Huinink. Ann Onc. 2004;15:100-3
Hematological Side Effects
Topotecan
(n = 111)
Paclitaxel
(n = 112)
Neutropenia (grade 4)
79.3%
23.2%
Febrile neutropenia
5.4%
0.9%
Grade 4 neutropenia
with > grade 2 infection
19.6%
3.5%
20.5%/34.8%
0.9%/0.9%
Thrombocytopenia (grade 4)
25.2%
1.8%
Sepsis
5.4%
1.8%
Deaths
1.8%
0%
G-CSF administration
treatment/prophylaxis
Ten Bokkel Huinink. J Clin Oncol 1997;15:2183-93
Topotecan
Continuous Infusion
(CI)
Continuous Infusion Phase-II
0.4 mg/m2/24h, D1-21 Q28d
N=24
Response
• RR - 35%
(95% CI, 15% to 54%)
• TTP - 26 weeks
Grade III-IV toxicity
• 31% neutropenia
• 52% anemia requiring
transfusion
• 4% thrombocytopenia
Hochster H. J Clin Oncol. 1999;17:2553-61
Topotecan
Weekly
Weekly Topotecan in Patients
with Recurrent or Persistent
Epithelial Ovarian Cancer
Phase-II Study
Safra T, Inbar M, Levy T et al
Objectives
To investigate the safety and efficacy of
weekly topotecan in relapsed and
persistant EOC
Safra T, Inbar M, Levy T et al
Treatment Regimen
4 mg/m² topotecan D1,8,15 Q28d
Safra T, Inbar M, Levy T et al
Patients Characteristics
• N=45
• Age – median 64y (range 42-87)
• Stage – Ic-IIc in 4 (9%) patients
III-IV in 41 (91%) patients
• Platinum status – Sensitive 56%
Resistant 44%
• Previous chemotherapy – median 1(range 1-5)
Safra T, Inbar M, Levy Taet al
RESULTS
Response Rates
Total patients , n
45
CR, (n) %
(4)
8.9
PR, (n) %
(12) 26.6
RR, (n) %
(16) 35.5
SD, (n) %
(21) 48.8
Safra T, Inbar M, Levy T et al
Time to Progression
Median TTP 4.43m
(95%CI, 3.64-5.23)
Safra T, Inbar M, Levy T et al
Overall Survival
1Y OS - 76%
2Y OS - 50%
OS – median 11.6+ m
(0.57-31)
Safra T, Inbar M, Levy T et al
Toxicity
(1) Ten Bokkel Huinink. Ann Onc. 2004;15:100-3
(2) Hochster H. J Clin Oncol. 1999;17:2553-61
Conclusions
• Weekly topotecan is efficacious in relapsed and
persistent EOC
• Weekly topotecan is very feasible
- Low rate of grade III-IV hematological toxicity
- Mild non-hematological toxicity with no alopecia
Safra T, Inbar M, Levy T et al
Multiple Drug
Resistance (MDR)
Using Erlotinib To
Overcome ABCG2-Mediated
Chemoresistance To
Topotecan
Rebecca Kosloff, MD
ABCG2
– ABCG2 is one of the
MDR genes
– Half-transporter
structure causing efflux
of the drug to the
extracellular material
– Higher affinity for TKIs
then other MDR1
– Examples of TKI’s:
• Erlotinib
• Gefitinib
• Imatinib
Hypothesis
Erlotinib to reverse ABCG2-mediated
resistance to topotecan in ovarian cancer
Topotecan
Intracellular
ABCG2
Erlotinib
Topotecan
extracellular
Phase I and II and
pharmacokinetics are on
the way
Biologics/targeted drug
therapy
Epidermal Growth
Factor Receptor
(EGFR)
Effects of HER1/EGFR Activation
Extracellular
Intracellular
Transactivation
P
Src
PLCg
GAP
PKC
Grb2
P
Shc
Nck
Vav
Grb7
Crk
Ras
PI3K
Akt
MAPK
JNK
Proliferation, invasion, metastasis, angiogenesis, and
inhibition of apoptosis
Abl
EGFR targeted therapy
Anti-HER1/EGFRblocking antibodies
1
Anti-ligandblocking
antibodies
2
TKIs
3
Ligand–
toxin
conjugates
4
Antibody–
toxin
conjugates
5
Noonberg SB, Benz CC. Drugs 2000;59:753–67
Anti-HER monoclonal antibodies
Erbitux
Herceptin
Cell membrane
Erlotinib
Tyrosine-kinase
domain
HER1/EGFR
•
•
•
•
HER2
Inhibit cell-cycle progression; potentiate apoptosis
Decrease production of angiogenic factors
Recruit natural killer cells to tumours
Enhance receptor internalisation
Agus D, et al. Cancer Cell 2002;2:127–37
Baselga J. Cancer Cell 2002;2:93–95
Anti-EGFR studies have been initiated –
most are not yet published
• Anecdotal responses noted in phase I studies, encouraging
phase II studies
– Cetuximab (Erbitux)
– Trastuzumab (Herceptin) - RR only 7.3%*
– EMD72000
• GOG - a phase II study of cetuximab
• EMD72000 - a phase II trial , completed but not yet reported
• Combinations with chemotherapy are being studied in small scale
* Bookman et al. J Clin Oncol. 21(2):283-90, 2003
Small Molecules – TKI’s
(Tyrosine Kinase
Inhibitors)
Erlotinib (Tarceva)
• TKI –EGFR indicated in metastatic disease of pancreas and NSCLC
• Inhibitor of ABCG2
– Preclinical data with topotecan
• Some response as a single agent in ovarian cancer *
– N=34 pts , heavily pretreated
• RR 6%
• SD 44%
• Median OS 8 m
• Erlotinib in combination with docetaxel and carboplatin as first line
treatment for ovarian cancer shown some response **
* Gordon et al, Int J Gynecol Cancer 2005;15:785–792
**Finkler et al., ASCO Ann Meeting Proc 2001; 20:208a (abstr 831)
Anti-angiogenic
therapies
The angiogenic switch in
tumor development
Small tumor (1–2mm)
• Avascular
• Dormant
Larger tumor
• Vascular
• Metastatic potential
Angiogenic switch
Results in over-expression
of pro-angiogenic signals,
such as VEGF
Adapted from Bergers G, et al. Nature 2002;3:401–10
Anti-VEGF antibody
•
Bevacizumab (Avastin) - a
monoclonal antibody
•
Prevents interaction VEGF with
its receptors
•
Prevents activation of
downstream signalling
pathways
•
Vascular regression
VEGF
Bevacizumab
X
–P
–P
P–
P–
X
Growth
Proliferation
Migration
Survival
Blocking VEGF may cause existing tumour blood
vessels to regress and lead to tumour shrinkage
Shrinking
tumour
Regressing
vasculature
Jain RK. Nat Med 2001;7:987–9
Carboplatin and Paclitaxel With
or Without Bevacizumab in
Treating Patients With Stage
III or Stage IV Ovarian
Epithelial or Primary Peritoneal
Cancer
GOG 218: Bevacizumab Plus Standard
Chemotherapy
Randomization
Patients with
previously untreated
suboptimal advanced
stage epithelial
ovarian cancer or
primary peritoneal
cancer
(N =2000)
Carboplatin plus
Paclitaxel q 21 d x 6
Placebo
q 21 d x 15 mo
Carboplatin plus
Paclitaxel q 21 d x 6
plus Bevacizumab
15 mg/kg cycles 2-6
Placebo
q 21 d x 15 mo
Carboplatin plus
Paclitaxel q 21 d x 6
plus Bevacizumab
15 mg/kg cycles 2-6
Bevacizumab
q 21 d x 15 mo
Endocrine Therapy
Tamoxifen
• Several positive phase II studies using
tamoxifen
– RR=17%*
– 2 patients having greater than a 5 year
response*
• GOG-0198 - Phase III trial of tamoxifen
compared with thalidomide in EOC
* Ahlgren, et al. Journal of Clinical Oncology 1993, 11:1957-68.
Aromatase inhibitors
• A phase II study of Letrozole (Femara) 2.5 mg/d in 50
patients showed:
– Ten patients with SD on CT for at least 12 weeks*
– Response correlated with - higher estrogen receptors, lower
erbB2, and higher EGFR*
• Another phase II study ** of letrozole 2.5 mg/d with
27 patients showed:
– RR of 15%
– No correlation was found between response and
estrogen/progesterone receptor expression
• Aromatase inhibitors - need to be examined in Phase
III studies and in combination with cytotoxic agents.
* Bowman, et al. Clinical Cancer Research 2002, 8:2233-9.
** Papadimitriou, et al. Oncology 2004, 66(2):112-7.
Locally Advanced
Endometrial cancer
Chemotherapy
Radiotherapy
or
Combination
GOG #122
396 patients
Randomized
208 patients
whole abdomen RT
194 patients
adriamicin and cisplatin
Disease Free Survival
P=0.007
Overall Survival
P=0.004
GOG#122
Sites of Relapse (%)
WAI
AP
Overall
54
50
Pelvic
13
18
Abdominal
16
14
Extra-abdomianl
22
18
GOG#122
5-year Diseases-free Survival
WAI
AP
P
Un-adjusted
38%
42%
?
Stage-adjusted*
38%
50%
0.007
* More unfavorable stages in AP arm
Randall M JCO, 2006
Feasibility of GOG#122
Adverse Treatment Effects
Grade 3-4
WBC
ANC
GI
Hepatic
Cardiac
Neurologic
Tx-related deaths
WAI (%)
AP (%)
4
<1
13
3
0
<1
N=4
62
85
20
1
15
7
N=8
How to Improve Treatment
in Uterine Adenocarcinoma
•
Adjuvant Chemotherapy (CT) is at least as
good as radiotherapy (RT)
•
Should we omit pelvic RT?
•
How best to combine RT and CT?
•
What is the best CT?
What is the best chemotherapy
Regimen ?
Phase II studies have identified several active agents:
• Adriamycin
• Cisplatin
• Carboplatin
• Paclitaxel
Combination improves RR with limited improvements
in PFS and OS in patients with advanced/recurrent
disease.
The GOG has conducted several phase III trials
comparing Adria to Adria/Cis (GOG 107), AC to AT
(GOG 163), AC to TAP (GOG 177)
Endometrial Cancer
Front-line Randomized Trials Advanced/Recurrent
RR
Median OS (mos)
Doxorubicin/Cisplatin
40%
12.4
Doxorubicin/Paclitaxel
44%
13.6
Doxorubicin/Cisplatin
34%
12.1
Doxorubicin/Paclitaxel/Cisplatin/G-CSF
57%
15.3
GOG 163
GOG 163
Conclusion
•
Adjuvant CT should be used in most pts
with advanced endometrial cancer
•
That shouldn’t be done at the expense of
adjuvant RT
•
New strategies to combine CT and RT are
needed
•
IMRT may provide a venue to combine CT
and RT concurrently
Tel-Aviv Medical Center, Tel-Aviv, ISRAEL
Thank You