novel therapeutics in gynecological malignancies tamar safra, md tel aviv sourasky medical center,...

Novel Therapeutics in Gynecological Malignancies

Tamar Safra, MD

Tel Aviv Sourasky Medical Center, Tel Aviv

Tamar Safra, MD

Tel Aviv Sourasky Medical Center, Tel Aviv

Ovarian Cancer- New Treatments

Uterine Cancer – Evolving Treatment

Ovarian Cancer- New Treatments

Uterine Cancer – Evolving Treatment

Ovarian CancerOvarian Cancer

• The most lethal of gynecologic malignancies

• Future goals – Early detection– Development of novel

agents

• The most lethal of gynecologic malignancies

• Future goals – Early detection– Development of novel

agents

Ovarian CancerOvarian 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

• 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 TaxanesNew 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

• 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

• 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

GOG 212 Phase III Study : Maintenance Chemotherapy

for EOC

Paclitaxel 175 mg/m2

q 28 days x 12Paclitaxel 175 mg/m2

q 28 days x 12

PPX 175mg/m2

q 28 days x 12PPX 175mg/m2

q 28 days x 12

ObservationObservation

EOC with CR after 6 cycles of chemotherapy

Different Schedules of old

TopotecanTopotecan

• 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

• 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

Topoisomerase I creates DNA

breaks for repair and replication

Topotecan binds to topoisomerase I

creating DNA breaks

Topotecan binds to topoisomerase I

creating DNA breaks

Damage toDNA causes

cell death

Damage toDNA causes

cell death

Topotecan Daily

Study DesignStudy Design

TopotecanTopotecan

1.5 mg/m1.5 mg/m22/d D1-5 /d D1-5 Q21dQ21d30-minute infusion30-minute infusion

TopotecanTopotecan

1.5 mg/m1.5 mg/m22/d D1-5 /d D1-5 Q21dQ21d30-minute infusion30-minute infusion

Ten Bokkel Huinink. J Clin Oncol 1997;15:2183-93

Multicenter, prospective, randomizedMulticenter, prospective, randomized phase-III studyphase-III study

Stratification by age, ascites and previous response to Stratification by age, ascites and previous response to platinum-based therapyplatinum-based therapy

PaclitaxelPaclitaxel

175 mg/m175 mg/m22 D1 D1

Q21dQ21dover 3 hoursover 3 hours

PaclitaxelPaclitaxel

175 mg/m175 mg/m22 D1 D1

Q21dQ21dover 3 hoursover 3 hours

Time to ProgressionTime to ProgressionTime to ProgressionTime to Progression

Time (weeks)

topotecan(n=112)

Paclitaxel (n=114)

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80

P =.072

Ten Bokkel Huinink. Ann Onc. 2004;15:100-3

Median TTP

Hematological Side Hematological Side EffectsEffects

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

G-CSF administration treatment/ prophylaxis

20.5%/34.8%

0.9%/0.9%

Thrombocytopenia (grade 4) 25.2% 1.8%

Sepsis 5.4% 1.8%

Deaths 1.8% 0%

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

G-CSF administration treatment/ prophylaxis

20.5%/34.8%

0.9%/0.9%

Thrombocytopenia (grade 4) 25.2% 1.8%

Sepsis 5.4% 1.8%

Deaths 1.8% 0%

Ten Bokkel Huinink. J Clin Oncol 1997;15:2183-93Ten Bokkel Huinink. J Clin Oncol 1997;15:2183-93

Topotecan Continuous Infusion

Continuous Infusion Phase-II

Response

• RR - 35% (95% CI, 15% to 54%)

• TTP - 26 weeks

Response

• RR - 35% (95% CI, 15% to 54%)

• TTP - 26 weeks

Hochster H. J Clin Oncol. 1999;17:2553-61Hochster H. J Clin Oncol. 1999;17:2553-61

0.4 mg/m2/24h, D1-21 Q28d N=24

Grade III-IV toxicity• 31% neutropenia• 52% anemia

requiring transfusion

• 4% thrombocytopenia

Grade III-IV toxicity• 31% neutropenia• 52% anemia

requiring transfusion

• 4% thrombocytopenia

Topotecan Weekly

Weekly Topotecan in Patients with Recurrent or

Persistent Epithelial Ovarian Cancer

Phase-II Study

Weekly Topotecan in Patients with Recurrent or

Persistent Epithelial Ovarian Cancer

Phase-II Study

Safra T, Inbar M, Levy T et alSafra T, Inbar M, Levy T et al

Objectives Objectives

To investigate the safety and efficacy

of weekly topotecan in relapsed and

persistant EOC

To investigate the safety and efficacy

of weekly topotecan in relapsed and

persistant EOC

Safra T, Inbar M, Levy T et al

Treatment RegimenTreatment Regimen

4 mg/m² topotecan D1,8,15 Q28d

Patients CharacteristicsPatients 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)

• 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 alSafra T, Inbar M, Levy Taet al

RESULTSResponse 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

Total patients , n 45

CR, (n) % (4) 8.9

PR, (n) % (12) 26.6

RR, (n) % (16) 35.5

SD, (n) % (21) 48.8

Time to Progression Time to Progression

Median TTP 4.43m

(95%CI, 3.64-5.23)

Overall SurvivalOverall Survival

1Y OS - 76%

2Y OS - 50%

OS – median 11.6+ m (0.57-31)

1Y OS - 76%

2Y OS - 50%

OS – median 11.6+ m (0.57-31)

ToxicityToxicity

(2 )Hochster H. J Clin Oncol. 1999;17:2553-61 (2 )Hochster H. J Clin Oncol. 1999;17:2553-61(1 )Ten Bokkel Huinink. Ann Onc. 2004;15:100-3 (1 )Ten Bokkel Huinink. Ann Onc. 2004;15:100-3

Ten Bokkel et al., 2004

Hochster H et al.,

1999(2)

Safra T et al.

Total patients, n 226 24 45

Dose Intensity, mg/m /wk 2.5 2.8 3

RR, (% )

Median TTP, week

19 26 19

Hematologic Toxicity:

Grade 3/ 4-

Neutropenia

Thrombocytopenia

Anemia

23%(G2)

Nonhematologic Toxicity:

Alopecia

Nausea

Fatigue

Ten Bokkel et al., 2004

Hochster H et al.,

1999(2)

Safra T et al.

Total patients, n 226 24 45

Dose Intensity, mg/m /wk 2.5 2.8 3

RR, (% )

Median TTP, week

19 26 19

Hematologic Toxicity:

Grade 3/ 4-

Neutropenia

Thrombocytopenia

Anemia

23%(G2)

Nonhematologic Toxicity:

Alopecia

Nausea

Fatigue

Conclusions 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

• 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

Multiple Drug Resistance (MDR)

Using Erlotinib To Overcome ABCG2-

Mediated Chemoresistance To

Topotecan

Using Erlotinib To Overcome ABCG2-

Mediated Chemoresistance To

TopotecanRebecca Kosloff, MDRebecca Kosloff, MD

ABCG2ABCG2

– 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

– 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

HypothesisHypothesis

Erlotinib to reverse ABCG2-mediated resistance to topotecan in ovarian cancer

Topotecan Topotecan

Intracellular extracellular

Erlotinib to reverse ABCG2-mediated resistance to topotecan in ovarian cancer

Topotecan Topotecan

Intracellular extracellular

ErlotinibErlotinib

Phase I and II and pharmacokinetics are

on the way

Phase I and II and pharmacokinetics are

on the way

Biologics/targeted drug therapy

Epidermal Growth Factor Receptor

(EGFR)

Epidermal Growth Factor Receptor

(EGFR)

Effects of HER1/EGFR Activation

Proliferation, invasion, metastasis, angiogenesis, and inhibition of apoptosis

Src PLCGAPGrb2 Shc Nck Vav Grb7 Crk

PKC Ras

JNK AblPI3K Akt

Extracellular

Intracellular Transactivation

EGFR targeted therapy

Anti-HER1/EGFR-blocking antibodies

Anti-ligand-blocking

antibodies

TKIs Ligand–toxin

conjugatesAntibody–

toxinconjugates

Noonberg SB, Benz CC. Drugs 2000;59:753–67

Anti-HER monoclonal antibodiesAnti-HER monoclonal antibodies

• 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;2:127–37Baselga J. Cancer Cell 2002;2:93–95

Cell membraneCell membrane

HER1/EGFRHER1/EGFR HER2HER2

ErbituxErbitux HerceptinHerceptin

Tyrosine-kinase domain

ErlotinibErlotinib

Anti-EGFR studies have been initiated – most are not yet

published

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

• 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* Bookman et al. J Clin Oncol. 21(2):283-90, 2003

Small Molecules – TKI’s (Tyrosine Kinase

Inhibitors)

Small Molecules – TKI’s (Tyrosine Kinase

Inhibitors)

Erlotinib (Tarceva)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 **

• 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 developmentThe angiogenic switch in tumor development

Adapted from Bergers G, et al. Nature 2002;3:401–10

Angiogenic switchResults in over-expressionof pro-angiogenic signals,such as VEGF

Small tumor (1–2mm)• Avascular• Dormant

Larger tumor• Vascular• Metastatic potential

Anti-VEGF antibodyAnti-VEGF antibody

• Bevacizumab (Avastin) - a monoclonal antibody

• Prevents interaction VEGF with its receptors

• Prevents activation of downstream signalling pathways

• Vascular regression

• Bevacizumab (Avastin) - a monoclonal antibody

• Prevents interaction VEGF with its receptors

• Prevents activation of downstream signalling pathways

• Vascular regression

Bevacizumab

– P– P– P– P

P– P– P– P–

VEGFVEGF

Growth

Proliferation

Migration

Survival

Growth

Proliferation

Migration

Survival

ShrinkingtumourShrinkingtumour

Regressing vasculatureRegressing vasculature

Jain RK. Nat Med 2001;7:987–9Jain RK. Nat Med 2001;7:987–9

Blocking VEGF may cause existing tumour blood vessels to regress and lead to tumour

shrinkage

Blocking VEGF may cause existing tumour blood vessels to regress and lead to tumour

shrinkage

Carboplatin and Paclitaxel With or Without

Bevacizumab in Treating Patients With Stage III or

Stage IV Ovarian Epithelial or Primary Peritoneal

Cancer

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

Carboplatin plusPaclitaxel q 21 d x 6

Carboplatin plusPaclitaxel q 21 d x 6plus Bevacizumab

15 mg/kg cycles 2-6

Placeboq 21 d x 15 mo

Bevacizumabq 21 d x 15 mo

Patients with previously untreated suboptimal advanced stage epithelial ovarian cancer or primary peritoneal cancer(N =2000)

RandomizationRandomization

Endocrine TherapyEndocrine Therapy

TamoxifenTamoxifen

• 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

• 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 inhibitorsAromatase 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.

• 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

Locally Advanced Endometrial cancer

Chemotherapy Radiotherapy

or Combination

GOG #122GOG #122

396 patients 396 patients

208 patientswhole abdomen RT

194 patientsadriamicin and cisplatin

Randomized

Disease Free Survival

P=0.007

Overall SurvivalOverall Survival

P=0.004

GOG#122Sites of Relapse (%)

WAI AP

Overall 54 50

Pelvic 13 18

Abdominal 16 14

Extra-abdomianl 22 18

WAI AP P

Un-adjusted 38% 42% ?

Stage-adjusted* 38% 50% 0.007

GOG#1225-year Diseases-free Survival

* More unfavorable stages in AP arm

Randall M JCO, 2006

Grade 3-4 WAI (%) AP (%)

WBC 4 62

ANC <1 85

GI 13 20

Hepatic 3 1

Cardiac 0 15

Neurologic <1 7

Tx-related deaths N=4 N=8

Feasibility of GOG#122

Adverse Treatment Effects

Feasibility of GOG#122

Adverse Treatment Effects

How to Improve Treatment in Uterine

Adenocarcinoma

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?

• 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 ?

• Adriamycin

• Cisplatin

• Carboplatin

• Paclitaxel

• 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)

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)

Phase II studies have identified several active agents:Phase II studies have identified several active agents:

Endometrial CancerFront-line Randomized Trials

Advanced/Recurrent

Endometrial CancerFront-line Randomized Trials

Advanced/Recurrent

RRMedian OS

GOG 163

Doxorubicin/Cisplatin 40% 12.4

Doxorubicin/Paclitaxel 44% 13.6

GOG 163

Doxorubicin/Cisplatin 34% 12.1

Doxorubicin/Paclitaxel/Cisplatin/G-CSF

57% 15.3

ConclusionConclusion

• 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

• 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 YouThank You

novel therapeutics in gynecological malignancies tamar safra, md tel aviv sourasky medical center,...

paclitaxel activity

investigation slide

topotecan daily slide

tel aviv slide

eoc paclitaxel

treatment slide

cycles of chemotherapy

days q

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