1. Novel Therapeutics in Gynecological Malignancies
Tamar Safra, MD
Tel Aviv Sourasky Medical Center, Tel Aviv

2. Ovarian Cancer- New Treatments Uterine Cancer – Evolving Treatment

3. Ovarian Cancer The most lethal of gynecologic malignancies
Future goals
Early detection
Development of novel agents

4. 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

5. Mitotic Spindle Inhibitors

6. 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

7. Paclitaxel Poliglumex (PPX)
Conjugate of paclitaxel with poly-L-glutamic acid
Enhances distribution in tumor
Prolonged release of free paclitaxel
Greater activity
Active in tumors with MDR (Multi-Drug Resistance) gene
Shorter administration

8. 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

9. Different Schedules of old drugs

10. 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

11. Topotecan Mechanism of Action
When DNA replicates in the presence of the stabilized complex, double-strand DNA breaks occur, and the resulting fragmentation of DNA causes cell death.
Topoisomerase I creates DNA breaks for repair and replication
Topotecan binds to topoisomerase I creating DNA breaks
Damage to DNA causes cell death

12. Topotecan Daily

13. Multicenter, prospective, randomized
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:

14. Time to Progression topotecan(n=112) Paclitaxel (n=114) P =.072
Time (weeks)
topotecan(n=112)
Paclitaxel (n=114)
1.0
0.2
0.4
0.6
0.8
0.0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80
Proportion
P =.072
Median TTP
19.8w
14.7w
Is it non-inferiority study or superiority?
Ten Bokkel Huinink. Ann Onc. 2004;15:100-3

15. Hematological Side Effects
Ten Bokkel Huinink. J Clin Oncol 1997;15: 43

16. Topotecan Continuous Infusion (CI)

17. 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
Please add reference
Hochster H. J Clin Oncol. 1999;17:

18. Topotecan Weekly

19. Weekly Topotecan in Patients with Recurrent or Persistent Epithelial Ovarian Cancer
Phase-II Study
Safra T, Inbar M, Levy T et al

20. Objectives
To investigate the safety and efficacy of weekly topotecan in relapsed and persistant EOC
Safra T, Inbar M, Levy T et al

21. Treatment Regimen 4 mg/m² topotecan D1,8,15 Q28d
Safra T, Inbar M, Levy T et al

22. Patients Characteristics
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

23. RESULTS Response Rates
Safra T, Inbar M, Levy T et al 17

24. Time to Progression Median TTP 4.43m (95%CI, 3.64-5.23)
Safra T, Inbar M, Levy T et al

25. Overall Survival 1Y OS - 76% 2Y OS - 50% OS – median 11.6+ m (0.57-31)
Safra T, Inbar M, Levy T et al

26. Toxicity (1) Ten Bokkel Huinink. Ann Onc. 2004;15:100-3
(2) Hochster H. J Clin Oncol. 1999;17: 10

27. 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 50

28. Multiple Drug Resistance (MDR)

29. Using Erlotinib To Overcome ABCG2-Mediated Chemoresistance To Topotecan
Rebecca Kosloff, MD

30. ABCG2 Examples of TKI’s: ABCG2 is one of the MDR genes Erlotinib
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

31. Hypothesis Erlotinib ABCG2
Erlotinib to reverse ABCG2-mediated resistance to topotecan in ovarian cancer
Topotecan Topotecan
Intracellular extracellular
ABCG2
Erlotinib

32. Phase I and II and pharmacokinetics are on the way

33. Biologics/targeted drug therapy

34. Epidermal Growth Factor Receptor (EGFR)

35. Effects of HER1/EGFR Activation
Proliferation, invasion, metastasis, angiogenesis, and inhibition of apoptosis
Src PLCg GAP Grb2 Shc Nck Vav Grb7 Crk
PKC
Ras
JNK
Abl
PI3K Akt
Extracellular
Intracellular
Transactivation
MAPK P
After HER1/EGFR ligand binding, dimerization, and TK phosphorylation, a complex signaling cascade involving many molecules begins.
HER1/EGFR activation can produce a range of effects in tumor cells depending on the ligand involved and the dimer formed. Although not fully understood, certain signal transduction pathways are associated with specific cellular effects.
The cellular effects of activation include increased cellular proliferation, invasion, metastasis, angiogenesis, and inhibition of apoptosis.1
There is evidence that somatic mutations in the TK domain of the HER1/EGFR gene increase activation in response to ligand binding.2
Finally, tumor cells driven by a HER1/EGFR pathway, particularly one involving an autocrine feedback loop, can become resistant to radiotherapy, chemotherapeutic agents or hormones, so making them resistant to conventional therapy.3,4
1. Woodburn J. Pharmacol Ther. 1999;82:
2. Lynch TJ, Bell DW, Sordella R, et al. New Engl J Med. 2004;350.
3. Knowlden JM, Hutcheson IR, Jones HE, et al. Endocrinology 2003;144:
4. Chakravarti A, Chakladar A, Delaney MA, et al. Cancer Res. 2002;62:

36. Anti-HER1/EGFR- blocking antibodies
EGFR targeted therapy
Various approaches are being investigated to target members of the HER family, particularly HER1/EGFR and HER2.
These include receptor sub-type specific monoclonal antibodies (MAbs) and small-molecule TK inhibitors (TKIs), which target the HER axis either outside or inside the tumor cell, respectively.
MAbs block the extracellular ligand-binding region of the receptor. Several MAbs are specific for either HER1/EGFR or HER2.1 Different antibody- based approaches use MAbs or HER ligands conjugated with cellular toxins.2
Small-molecule TKIs act at an intracellular level, inhibiting TK phosphorylation and preventing downstream receptor signaling. There are agents that inhibit HER1/EGFR specifically, HER1/EGFR and HER2, or all members of the HER family (pan HER-TK inhibitors).3-5
Agents are being developed to interfere with HER activity at a nuclear level by blocking signal transduction and/or translation. The most promising methods are antisense oligonucleotides, ribozyme-mediated DNA inhibition, and gene therapy.6
1. Slamon DJ, Leyland-Jones B, Shak S, et al. N Engl J Med. 2001;344:
2. Mendelsohn J, Baselga J. Oncogene. 2000;19:
3. Noonberg SB, Benz CC. Drugs. 2000;59:
4. Raymond E, Faivre S, Arman JP. Drugs. 2000;60(Suppl 1):15-23.
5. Arteaga C. J Clin Oncol. 2001;19:32s-40s.
6. Pedersen MW, Meltom M, Damstrup L, et al. Ann Oncol. 2001;12: P P
TKIs P
Anti-ligand-
blocking
antibodies
Ligand–
toxin
conjugates P
Antibody–
toxin
conjugates
Anti-HER1/EGFR- blocking antibodies 3 2 4 1 5
Noonberg SB, Benz CC. Drugs 2000;59:753–67

37. Anti-HER monoclonal antibodies
Cell membrane
HER1/EGFR
HER2
Erbitux
Herceptin
Tyrosine-kinase domain
Erlotinib
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

38. 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
EMD 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

39. Small Molecules – TKI’s (Tyrosine Kinase Inhibitors)

40. 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)

41. Anti-angiogenic therapies

42. 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

43. Anti-VEGF antibody X Bevacizumab (Avastin) - a monoclonal antibody
Prevents interaction VEGF with its receptors
Prevents activation of downstream signalling pathways
Vascular regression
Bevacizumab
– P P–
VEGF X
Growth
Proliferation
Migration
Survival
The humanised anti-VEGF MAb Avastin (bevacizumab) prevents the interaction of VEGF with its receptors, VEGF receptor-1 and VEGF receptor-2 on the surface of vascular endothelial cells. This prevents activation of the VEGF receptors and of the downstream signalling pathways that would normally lead to the growth, proliferation, migration and survival of endothelial cells. This ultimately leads to a reduction in microvascular growth, inhibits progression of metastatic disease and reduces intratumoral pressure, which may improve the delivery of cytotoxic agents.

44. Blocking VEGF may cause existing tumour blood vessels to regress and lead to tumour shrinkage
Shrinking
tumour
Tumour blood vessels regress when VEGF cannot bind to its receptors, reducing tumour vessel density and cutting off the tumour’s blood supply.1 As a result, the tumour may shrink or become dormant.
Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy. Nat Med 2001;7:987–9.
Regressing
vasculature
Jain RK. Nat Med 2001;7:987–9

45. Carboplatin and Paclitaxel With or Without Bevacizumab in Treating Patients With Stage III or Stage IV Ovarian Epithelial or Primary Peritoneal Cancer

46. GOG 218: Bevacizumab Plus Standard Chemotherapy
Randomization
Carboplatin plus
Paclitaxel q 21 d x 6
Placebo
q 21 d x 15 mo
Patients with previously untreated suboptimal advanced stage epithelial ovarian cancer or primary peritoneal cancer
(N =2000)
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

47. Endocrine Therapy

48. Tamoxifen Several positive phase II studies using tamoxifen
RR=17%*
2 patients having greater than a 5 year response*
GOG Phase III trial of tamoxifen compared with thalidomide in EOC
* Ahlgren, et al. Journal of Clinical Oncology 1993, 11:

49. 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:
** Papadimitriou, et al. Oncology 2004, 66(2):112-7.

50. Locally Advanced Endometrial cancer Chemotherapy Radiotherapy or Combination

51. adriamicin and cisplatin
GOG #122
396 patients
Randomized
208 patients
whole abdomen RT
194 patients
adriamicin and cisplatin

52. Disease Free Survival
P=0.007

53. Overall Survival
P=0.004

54. GOG#122 WAI AP Overall 54 50 Pelvic 13 18 Abdominal 16 14
Sites of Relapse (%)
WAI AP
Overall 54 50
Pelvic 13 18
Abdominal 16 14
Extra-abdomianl 22

55. 5-year Diseases-free Survival
GOG#122
5-year Diseases-free Survival
WAI AP P
Un-adjusted
38%
42% ?
Stage-adjusted*
50%
0.007
* More unfavorable stages in AP arm
Randall M JCO, 2006

56. Adverse Treatment Effects
Feasibility of GOG#122
Adverse Treatment Effects
Grade 3-4
WAI (%)
AP (%)
WBC 4 62
ANC
<1 85 GI 13 20
Hepatic 3 1
Cardiac 15
Neurologic 7
Tx-related deaths
N=4
N=8

57. 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?

58. 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)

59. Endometrial Cancer Front-line Randomized Trials Advanced/Recurrent
Median OS (mos)
GOG 163
Doxorubicin/Cisplatin
40%
12.4
Doxorubicin/Paclitaxel
44%
13.6
34%
12.1
Doxorubicin/Paclitaxel/Cisplatin/G-CSF
57%
15.3

60. 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

61. Tel-Aviv Medical Center, Tel-Aviv, ISRAEL

62. Thank You