Novel Therapeutics in Gynecological Malignancies

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Novel Therapeutics in Gynecological Malignancies

• Tamar Safra, MD
• Tel Aviv Sourasky Medical Center, Tel Aviv

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Ovarian Cancer- New TreatmentsUterine Cancer
Evolving Treatment
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Ovarian Cancer

• The most lethal of gynecologic malignancies
• Future goals
• Early detection
• Development of novel agents

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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

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Mitotic Spindle Inhibitors
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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

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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

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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
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Different Schedules of old drugs

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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

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Topotecan Mechanism of Action
Topoisomerase I creates DNA breaks for repair and
replication
Topotecan binds to topoisomerase I creating DNA
breaks
Damage toDNA causescell death
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Topotecan Daily
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Study Design
Multicenter, prospective, randomized phase-III
study
Stratification by age, ascites and previous
response to platinum-based therapy

• Topotecan
• 1.5 mg/m2/d D1-5 Q21d
• 30-minute infusion

Paclitaxel 175 mg/m2 D1 Q21d over 3 hours
Ten Bokkel Huinink. J Clin Oncol 1997152183-93
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Time to Progression
Median TTP 19.8w 14.7w
Ten Bokkel Huinink. Ann Onc. 200415100-3
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Hematological Side Effects
Ten Bokkel Huinink. J Clin Oncol 1997152183-93
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Topotecan Continuous Infusion (CI)
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Continuous Infusion Phase-II
0.4 mg/m2/24h, D1-21 Q28d N24

• 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. 1999172553-61
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Topotecan Weekly
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Weekly Topotecan in Patients with Recurrent or
Persistent Epithelial Ovarian Cancer Phase-II
Study
Safra T, Inbar M, Levy T et al
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Objectives

• To investigate the safety and efficacy of
  weekly topotecan in relapsed and persistant EOC

Safra T, Inbar M, Levy T et al
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Treatment Regimen

• 4 mg/m² topotecan D1,8,15 Q28d

Safra T, Inbar M, Levy T et al
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Patients Characteristics

• N45
• 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
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RESULTSResponse Rates
Safra T, Inbar M, Levy T et al
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Time to Progression
Median TTP 4.43m (95CI, 3.64-5.23)
Safra T, Inbar M, Levy T et al
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Overall Survival

• 1Y OS - 76
• 2Y OS - 50
• OS median 11.6 m (0.57-31)

Safra T, Inbar M, Levy T et al
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Toxicity
(2) Hochster H. J Clin Oncol. 1999172553-61
(1) Ten Bokkel Huinink. Ann Onc. 200415100-3
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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
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Multiple Drug Resistance (MDR)
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Using Erlotinib To Overcome ABCG2-Mediated
Chemoresistance To Topotecan

• Rebecca Kosloff, MD

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ABCG2

• Examples of TKIs
• Erlotinib
• Gefitinib
• Imatinib

• 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

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Hypothesis

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

ABCG2
Erlotinib
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• Phase I and II and pharmacokinetics are on the
  way

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Biologics/targeted drug therapy

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Epidermal Growth Factor Receptor (EGFR)

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Effects of HER1/EGFR Activation
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EGFR targeted therapy
P
P
P
TKIs
Anti-ligand- blocking antibodies
Ligand toxin conjugates
P
Antibody toxin conjugates
Anti-HER1/EGFR-blocking antibodies
3
4
2
1
5
Noonberg SB, Benz CC. Drugs 20005975367
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Anti-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 2002212737Baselga
J. Cancer Cell 200229395
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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
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Small Molecules TKIs (Tyrosine Kinase
Inhibitors)
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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
  
• N34 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
200515785792 Finkler et al., ASCO Ann
Meeting Proc 2001 20208a (abstr 831)
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Anti-angiogenic therapies
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The angiogenic switch in tumor development

• Larger tumor
• Vascular
• Metastatic potential

• Small tumor (12mm)
• Avascular
• Dormant

Angiogenic switch Results in over-expressionof
pro-angiogenic signals,such as VEGF
Adapted from Bergers G, et al. Nature
2002340110
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Anti-VEGF antibody

• Bevacizumab (Avastin) - a monoclonal antibody
• Prevents interaction VEGF with its receptors
• Prevents activation of downstream signalling
  pathways
• Vascular regression

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Blocking VEGF may cause existing tumour blood
vessels to regress and lead to tumour shrinkage
Shrinking tumour
Regressing vasculature
Jain RK. Nat Med 200179879
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Carboplatin and Paclitaxel With or Without
Bevacizumab in Treating Patients With Stage III
or Stage IV Ovarian Epithelial or Primary
Peritoneal Cancer
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GOG 218 Bevacizumab Plus Standard Chemotherapy
Randomization
Placebo q 21 d x 15 mo
Carboplatin plus Paclitaxel q 21 d x 6
Patients with previously untreated suboptimal
advanced stage epithelial ovarian cancer or
primary peritoneal cancer (N 2000)
Placebo q 21 d x 15 mo
Carboplatin plus Paclitaxel q 21 d x 6 plus
Bevacizumab 15 mg/kg cycles 2-6
Carboplatin plus Paclitaxel q 21 d x 6 plus
Bevacizumab 15 mg/kg cycles 2-6
Bevacizumab q 21 d x 15 mo
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Endocrine Therapy
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Tamoxifen

• Several positive phase II studies using tamoxifen
  
• RR17
• 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, 111957-68.
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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,
82233-9. Papadimitriou, et al. Oncology
2004, 66(2)112-7.
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Locally Advanced Endometrial cancerChemotherapy
Radiotherapy or Combination
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GOG 122
396 patients
Randomized
194 patients adriamicin and cisplatin

• 208 patients
• whole abdomen RT

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Disease Free Survival
P0.007
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Overall Survival
P0.004
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GOG122 Sites of Relapse ()
WAI AP
Overall 54 50
Pelvic 13 18
Abdominal 16 14
Extra-abdomianl 22 18
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GOG122 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
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Feasibility of GOG122 Adverse Treatment Effects
Grade 3-4 WAI () AP ()
WBC 4 62
ANC lt1 85
GI 13 20
Hepatic 3 1
Cardiac 0 15
Neurologic lt1 7
Tx-related deaths N4 N8
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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?

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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)
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Endometrial CancerFront-line Randomized Trials
Advanced/Recurrent
RR Median OS (mos)
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
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Conclusion

• Adjuvant CT should be used in most pts with
  advanced endometrial cancer
• That shouldnt 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

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Tel-Aviv Medical Center, Tel-Aviv, ISRAEL
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Thank You