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-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

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 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

Topotecan Daily

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;15:2183-93

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

Hematological Side Effects Ten Bokkel Huinink. J Clin Oncol 1997;15:2183-93 43

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 Please add reference 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 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 Safra T, Inbar M, Levy T et al 17

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 10

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

Multiple Drug Resistance (MDR)

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

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

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

Phase I and II and pharmacokinetics are on the way

Biologics/targeted drug therapy

Epidermal Growth Factor Receptor (EGFR)

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;82:241-250. 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;144:1032-1044. 4. Chakravarti A, Chakladar A, Delaney MA, et al. Cancer Res. 2002;62:4307-4315.

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;344:783-792. 2. Mendelsohn J, Baselga J. Oncogene. 2000;19:6550-6565. 3. Noonberg SB, Benz CC. Drugs. 2000;59:753-767. 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;12:745-760. 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

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

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 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.

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

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 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

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

adriamicin and cisplatin 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 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

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

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

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 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

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

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