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Welcome!
Please take a moment to complete the short
pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests:
Presenter, MD: Research: Pharma Company; Consultant: Pharma Company
TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:
This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests:
Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis
Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech
Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests:
Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose
Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to:
Review the recently updated clinical practice guidelines for advanced ovarian cancer
Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data
Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin
GOG Protocol 111[1]
EORTC-NCIC OV 10[2]
Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy
AGO Trial[3]
GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6.
2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708.
3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329.
4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy
Intraperitoneal chemotherapy
Weekly dosing
Adding a targeted agent (e.g. bevacizumab)
Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy
Intraperitoneal chemotherapy
Weekly dosing
Adding a targeted agent (e.g. bevacizumab)
Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer
FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking
(not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival
Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial
PDS: 29 months
IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy
Intraperitoneal chemotherapy
Weekly dosing
Adding a targeted agent (e.g. bevacizumab)
Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin.
1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal
Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03
Rx Group Lost to Alive Dead Total Follow-up
IV 5 78 127 210
IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP
c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2)
Paclitaxel 135 mg/m2 (d1, 3h)
Paclitaxel 60 mg/m2 (d8, IP)
Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer
Optimal Stage III
No prior therapy
Phase III
PFS primary endpoint Open: 27 Jul 2009
Closed: 30 Nov 2011
Accrual: 1100
Study Chair: J Walker III II Carboplatin AUC=6 (IP)
Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV)
Paclitaxel 80 mg/m2 (d1, 8, 15 3h)
Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel
Neoadjuvant chemotherapy
Intraperitoneal chemotherapy
Weekly dosing
Adding a targeted agent (e.g. bevacizumab)
Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2
Carbolatin AUC = 6 Carbolatin AUC = 6
Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal
Stage II - IV
No prior therapy
Stratfied: residual disease, stage, and histology
Primary endpoint: PFS
Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy
Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R
A
N
D
O
M
I
Z
E n = 625
Primary Endpoint = Progression free survival
Activated: Sep 27 2010
Study Chair: J Chan
Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel
Neoadjuvant chemotherapy
Intraperitoneal chemotherapy
Weekly dosing
Adding a targeted agent (e.g. bevacizumab)
Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer
Stage III optimal (macroscopic)
Stage III
suboptimal
Stage IV
n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables:
GOG performance status (PS)
Stage/debulking status RANDOM
I
Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance
(16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables:
Stage/surgery
Time since surgery
GCIG group *Might vary based on GCIG group
**Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer
Stage I-IIA (Gr 3 or CC)
Stage IIB/C
Stage III
Stage IV
n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints:
PFS
Secondary endpoints: OS, RR, safety, QOL,
cost-effectiveness,
translational
No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496.
Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006).
Perren T et al. N Engl J Med. 2011;365:2484-2496.
First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel
Neoadjuvant chemotherapy
Intraperitoneal chemotherapy
Weekly dosing
Adding a targeted agent (e.g. bevacizumab)
Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete
clinical remission
Paclitaxel 175 mg/m2
every 28 days × 3 months Paclitaxel 175 mg/m2
every 28 days × 12 months RANDOM
I
Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex
of paclitaxel poliglumex
Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin
(Planned n = 1400-1550) Paclitaxel
Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex
Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery
Attempt at maximal surgical cytoreduction
Neoadjuvant chemo before surgery is an option for poor surgical candidates
Chemotherapy
6-8 cycles taxane-platinum combination is standard
IP admin benefits patients with low volume (optimal) disease but has increased toxicity
NED patients treated with IP have a median survival of over 9 years
Weekly (dose-dense) paclitaxel improves outcome in one study
Confirmatory North American trials recently completed
Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0.
What would you recommend for this patient?
Neoadjuvant chemotherapy
Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy
Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998)
81 cohorts (Stage III/IV)
n = 6885 patients
Results
Expert centers have high optimal rates
Optimal vs not: 11 mos (50% increase)
Each 10% in cytoreduction = 5.5% in survival
Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50)
log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49)
log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7)
n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well…
The pathology shows a high-grade serous carcinoma.
The surgeon noted small volume residual (5-9mm) disease throughout the abdomen.
What would you recommend for this patient at this point?
IP chemotherapy
IV chemotherapy
Adding bevacizumab to either IV or IP
Case 1 Question 2 What would you recommend for this patient at this point?
IP chemotherapy
IV chemotherapy
Adding bevacizumab to either IV or IP
All the above answers are reasonable treatment choices.
When would you start the bevacizumab?
Cycle 1, 2 or 3?
After the chemotherapy (maintenance)?
Case 2: Platinum Sensitive Ovarian Cancer 52-year-old woman with high-grade serous carcinoma of the fallopian tube
Optimally debulked in 2010
Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011
CA125
at presentation 5800
nadir post therapy 7
In 2012 : Increasing Ca125 (1200)
Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy
Symptomatic: abdominal bloating, early satiety, and mild shortness of breath
Disease free interval: 10-12 months
Genetic testing: BRCA1/2 negative
Case 2 Question 1 What treatment would you recommend for this patient?
Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin
PLD, carboplatin and bevacizumab
Gemcitabine and carboplatin
Gemcitabine, carboplatin and bevacizumab
Paclitaxel and carboplatin
Weekly paclitaxel and carboplatin
Paclitaxel, carboplatin and PARP inhibitor Case 2, Question 1 What treatment would you recommend for this patient?
Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin (PLD and carboplatin is a reasonable option based on results of the CALYPSO study showing superiority to paclitaxel and carboplatin)
PLD, carboplatin and bevacizumab (PLD, carboplatin and bevacizumab has not been tested in a randomized phase III trial)
Gemcitabine and carboplatin (Gemcitabine and carboplatin: this is reasonable based on a comparison with carboplatin alone (Pfisterer et.al. 2005)
Gemcitabine, carboplatin and bevacizumab (Higher response rates and improved PFS are seen when bevacizumab is added to gem/carbo but OS is not improved (OCEANS trial)
Paclitaxel and carboplatin (Paclitaxel and carboplatin can be used but based on prior taxane and results of CALYPSO, is used less)
Weekly paclitaxel and carboplatin (Weekly paclitaxel has shown improved outcome when used with carboplatin for newly diagnosed patients but has not been rigorously tested in recurrent disease
Paclitaxel, carboplatin and PARP inhibitor (PARP inhibitors are not yet FDA approved , so can only be obtained on a clinical trial. However, this is a very promising direction in ovarian cancer and a clinical trial of paclitaxel and carboplatin +/- olaparib showed improved PFS (Oza et.al. ASCO 2012) She Asks You Whether There Is Any Role for Surgery for Her Which of the following are true regarding secondary debulking?
It is not considered for patients like her who relapse 10-12 months after completing initial chemotherapy
The finding of carcinomatosis is a relatively strong contraindication to secondary debulking surgery
Survival is improved for secondary debulking even if all disease can’t be removed at surgery
Mediastinal and pleural disease are relatively strong contraindications to secondary debulking surgery
1 and 3
2 and 4
All of the above Secondary Debulking Candidate Selection Onda et al. J Cancer. 2005;92:1026. Pujade-Lauraine, Ann Oncol. 2011;22(Supplement 8):viii61–viii64. RANDOM
I
Z E GCIG CALYPSO Trial Ovarian Cancer
Platinum Sens.
Stratify:
≤ 0.5 cm
> 0.5-2 cm
PLD 30 mg/m2
Carboplatin AUC = 5
q 28 days x 6 Paclitaxel 175 mg/m2
Carboplatin AUC = 5
q 21 days x 6 GCIG = Gynecologic Cancer Intergroup
PFS = progression-free survival
PLD = pegylated liposomal doxorubicin Accrual 864 pts PFS primary endpoint Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. GCIG CALYPSO Trial Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Selected Non-hematologic Toxicities During Treatment Alopecia *P< 0.001 Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Targeted Agents in Ovarian Cancer Signaling/Angiogenesis
Bevacizumab/Aflibercept
RTKI’s:
Pazopanib
Cabozantinib
Sorafenib, etc
Cediranib
Nintedanib
Trebananib, MEDI-3617
PI3K/Akt/mTOR
MEKi Folate:
Vintafolide (EC-145)
Farletuzumab
NKTR-102
Taxanes/epothilones
Immunotherapy – vaccines and inducers
EP-100
PARPi
ErbB3
CG + PL OCEANS: Study schema CG for 6 (up to 10) cycles Stratification variables:
Platinum-free interval (6–12 vs >12 months)
Cytoreductive surgery for recurrent disease (yes vs no) Platinum-sensitive recurrent OCa
Measurable disease
ECOG 0/1
No prior chemo for recurrent OC
No prior BV
(n=484) BV = bevacizumab; PL = placebo
aEpithelial ovarian, primary peritoneal, or fallopian tube cancer G 1000 mg/m2, d1 & 8 C AUC 4 PL q3w until progression C AUC 4 BV 15 mg/kg q3w until progression G 1000 mg/m2, d1 & 8 CG + BV Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 242 177 45 11 3 0 CG + PL OCEANS: Primary Analysis of PFS Months No. at risk 242 203 92 33 11 0 CG + BV 1.0
0.8
0.6
0.4
0.2
0 Proportion progression free 0 6 12 18 24 30 Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 1.0
0.8
0.6
0.4
0.2
0 OCEANS: Third Interim OS Analysisa 0 6 12 18 24 30 36 42 48 54 60 242 235 221 190 159 117 77 44 23 7 0
242 239 226 201 171 127 78 48 27 7 0 Number at risk:
GC + PL
GC + BV aData cutoff date: March 30, 2012. Median follow-up 41.9 months in PL arm and 42.3 months in BV arm, with 286 deaths (59.1% of patients) Proportion surviving Months Aghajanian et al. ESMO 2012. Asymptomatic relapse Single-agent farletuzumab
Until progression Single-agent ORR Compare lengths of first and second remissions Farletuzumab - MORAb-003-002 Phase II: Design Epithelial Ovarian Cancer
First platinum-sensitive relapse
First remission of 6-18 months
Evaluable disease by CA125 Symptomatic relapse Original Carbo/Taxane regimen
Plus farletuzumab x 6 Farletuzumab maintenance Rx
For responders Combination ORR White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. MorAb-003-002: Study Conclusions Overall response rate 70%
Response rate similar in early (6-12 month) and late (12+ months) recurrent patients
High rates of CA-125 normalization (89%)
1/5 patients had a PFI2 ≥ PFI1
Phase III studies
Platinum-sensitive: fully enrolled
Platinum-resistant (weekly paclitaxel): met futility endpoint White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. n=66 Randomized, Open-label, Phase II Study in Patients With Platinum-sensitive, Advanced Serous Ovarian Cancer Paclitaxel 175 mg/m2 (iv, d1)
+ carboplatin AUC6 (iv d1) Randomization (1:1) All patients followed for objective radiologic progression and survival Maintenance phase
Olaparib 400 mg bid continuously Completion of 4–6 x 21-day cycles of chemotherapy Arm B Arm A n=81 n=81 n=55 Multinational study; 43 sites in 12 countries
* Capsule formulation Patients with:
Platinum-sensitive advanced ovarian cancer
A serous histology or serous component
Measurable disease
≤3 previous platinum-containing regimens
Progression free for ≥6 months following completion of last platinum-containing regimen Maintenance phase
No further study treatment Olaparib 200 mg bid* (d1–10 every 21 days)
+ paclitaxel 175 mg/m2 (iv, d1)
+ carboplatin AUC4 (iv, d1) Oza A. ASCO 2012; Abstract 5001. Paclitaxel Carboplatin (P/C) vs P/C Plus Olaparib (O/P/C) In Platinum Sensitive Recurrent Ovarian Cancer: PFS Time from randomization (months) 0 Proportion of patients progression free 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 2 4 6 8 10 12 16 20 Number of patients at risk Olaparib + P + C (AUC4) P + C (AUC6) 14 18 81 80 76 71 55 37 34 3 0 20 0 81 68 65 57 40 18 15 2 0 8 1 O/P/C P/C Oza A. ASCO 2012; Abstract 5001. GOG 9927: Phase I Combination Platinum sensitive recurrent EOC
Chemotherapy based on CALYPSO
Primary endpoint: 1st or 2nd cycle DLT
Secondary endpoints: RR, PFS, Toxicity
TR: PARPi in PBMCs, BRCA status PLD 30 mg/m2
Carboplatin AUC 5
Arm I
Veliparib PO daily continuously
Cycles: 28 days
Planned administration: 6 cycles
Arm II
Veliparib PO daily D1-7
Cycles: 28 days
Planned administration: 6 cycles www.clinicaltrials.gov/ct2/show/NCT01459380. Summary for Platinum-sensitive Recurrent Ovarian Cancer Consider Secondary Debulking
Platinum retreatment is standard
Treatment with a platinum-based doublet improves response rate, progression-free survival, and possibly overall survival
Options:
Taxane Carboplatin: Paclitaxel, Docetaxel (?), Weekly Paclitaxel (?)
Gemcitabine Carboplatin +/- Bevacizumab
PLD Carboplatin Case 3: Platinum Resistant Ovarian Cancer 60-year-old woman with extensive pelvic and peritoneal implants, ascites and large volume disease at the root of the mesentery
Diagnosis of ovarian cancer made by paracentesis
Deemed unresectable by a gynecologic oncologist
Treated with neoadjuvant paclitaxel and carboplatin x 3 without response
Then treated with topotecan (daily x 5 regimen) x 3 without response
Required paracentesis weekly for palliation
CA-125=6916
What treatment would you recommend? Case 3 Question 1 What treatment would you recommend for this patient?
Pegylated liposomal doxorubicin (PLD, doxil, lipodox)
Weekly paclitaxel
Gemcitabine
Bevacizumab
Weekly paclitaxel and bevacizumab
Gemcitabine, carboplatin and bevacizumab Case 3 Question 1 What treatment would you recommend for this patient?
Pegylated liposomal doxorubicin (PLD, doxil, lipodox) (PLD is a reasonable choice but expected response rate is 6-16% in a less heavily pretreated population)
Weekly paclitaxel (Weekly paclitaxel is also a reasonable option. In GOG protocol 126-N weekly paclitaxel had a response rate of 21% although eligibility limited to one prior treatment regimen)
Gemcitabine (although single agent gemcitabine is not FDA approved for treatment of ovarian cancer, the combination of gemcitabine and carboplatin is approved for platinum sensitive patients thus gemcitabine alone is frequently used. Response rates in this population are expected to be less than 10%)
Bevacizumab (Bevacizumab is a reasonable choice. In GOG protocol 170D bevacizumab showed a response rate of 21% in this population)
Weekly paclitaxel and bevacizumab (Based on Aurelia, the combination of weekly paclitaxel and bevacizumab would be expected to have a higher response rate than weekly paclitaxel alone. Survival data is not yet available. It is not yet clear whether sequential chemotherapy and bevacizumab or the combination is preferable)
Gemcitabine, carboplatin and bevacizumab (platinum-based therapy is not indicated in this patient with platinum-refractory disease.) Assume You Will Be Using Treatment With Bevacizumab: Which of the Following Are True Statements About Bevacizumab for Her 1. She will be at increased risk for bowel perforation
2. There is an increased risk of thrombo-embolic phenomena with bevacizumab
3. The response rate of ovarian cancer to single-agent bevacizumab is greater than for any other solid tumors tested to date
4. Hypertension and proteinuria are common side effects of bevacizumab
5. All of the above
All the above are true statements in this case. Annals of Oncology 22 (Supplement 8): viii61–viii64, 2011. Active Agents in Ovarian Cancer Platinum-resistant Ovarian Cancer Cytotoxic Therapy Thresholds: 10%, 25% *Median of 3 prior lines *1 prior line Vergote IB et al. J Clin Oncol 2010;28:15s(suppl; abstr 5013). Bevacizumab in Relapsed Ovarian Cancer *Burger RA et al. J Clin Oncol 2007; 25: 5165–5171.
**Garcia AA et al. J Clin Oncol 2008; 26: 76–82.
***Cannistra SA et al. J Clin Oncol 2007; 25: 5180–5186. Ovarian Cancer: Targeted Therapy 1Tew et al. J Clin Oncol 2007;25:(suppl; abstr 5508). 2Biagi et al. Ann Oncol. 2011;22:335-340. 3Matulonis UA et al. J Clin Oncol. 2009;27:5601-5606. 4Buckanovich et al. J Clin Oncol. 2011;29(suppl; abstr 5008).
5Friedlander et.al. Gyn Oncol. 2010,. 6Ledermann et al. J Clin Oncol. 2011;29:3798. PD Recurrent Ovarian Cancer Randomized Phase II Studies Weekly Paclitaxel
AMG-386 10 mg/kg IV weekly
n=53 Weekly Paclitaxel
AMG-386 3 mg/kg IV weekly
n=53 Weekly Paclitaxel
Placebo
n=55 Paclitaxel 80 mg/m2 IV weekly, 3 weeks on/1 week off AMG-386
10 mg/kg IV
weekly RANDOM
I
Z E Ovarian, primary peritoneal, or fallopian tube cancer
n=161
1-3 prior lines Karlan BY et al. J Clin Oncol. 2010;28:15s(suppl; abstr 5000). Recurrent Ovarian Cancer Randomized Phase II Studies Primary endpoint: PFS *1-3 prior lines www.clinicaltrials.gov Olaparib: An Orally Active PARP Inhibitor in Ovarian Cancer Provides clinical evidence of activity in ovarian cancer patients with and without BRCA1/2 mutations 1. Fong PC et al. J Clin Oncol 2010;28:2512–2519. 2. Audeh MW et al. Lancet 2010;376:245–251. 3. Gelmon KA et al. Lancet Oncol 2011;12:852–861. *Complete response (CR) + partial response (PR) + stable disease (SD) RANDOM
I
Z E AURELIA: A randomized phase III trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer (OC) Recurrent EOC
platinum resistant
≤ 2 prior therapies
no clinical or radiologic evidence of bowel involvement Non-Platinum Chemotherapy Non-Platinum Chemotherapy + Bevacizumab 15 mg/kg Chemotherapy Options
Paclitaxel 80 mg/m2 d 1,8,15, 22 q28
Topotecan 4 mg/m2 d 1, 8 ,15 q28 or
Topotecan 1.25 mg/m2 d 1-5 q21
PLD 40 mg/m2 d 1 q28 Stratified
chemotherapy
PFI (< 3 vs 3-6 mo)
prior anti-angiogenesis Treat to progression Treat to progression N = 361 Pujade-Lauraine E et al. J Clin Oncol. 2012;Suppl. Abstract LBA5002. AURELIA Progression-free Survival Pujade-Lauraine E et al. J Clin Oncol. 2012;Suppl. Abstract LBA5002. Response Rates For Chemotherapy Alone Weekly Paclitaxel, Pegylated Liposomal Doxorubicin or Topotecan) or With Bevacizumab (BEV + CT) aTwo-sided chi-square test with Schouten correction P=0.001a P<0.001a P<0.001a Patients (%) Pujade-Lauraine E et al. J Clin Oncol. 2012;Suppl. Abstract LBA5002. Questions about AURELIA Given known single agent response to bevacizumab, how would a bevacizumab alone arm compare?
Is it better to use chemo with bevacizumab rather than sequentially?
This should be answered by the overall survival data due in 2013, since patients on the chemo alone arm could subsequently get bevacizumab
Should we limit this therapy to patients at low risk of GI perforation?
Will these same benefits be seen in patients who had bevacizumab with initial chemotherapy? Randomized
1:1:1 Olaparib
200 mg bid
n=32 PD or withdrawal from treatment for other reason As above or max lifetime cumulative dose reached Primary objective: Compare efficacy (PFS) of 2 dose levels of olaparib
(200 mg and 400 mg bid) with pegylated liposomal doxorubicin (PLD) Phase II Trial of Olaparib vs PLD in BRCA-associated Recurrent Ovarian Cancer Olaparib
400 mg bid
n=32 Patients:
BRCA1/2 germline mutation
Recurrent Ovarian Cancer Patients in PLD group were allowed to cross-over to
olaparib 400 mg bid on confirmed PD One cycle=28 days Kaye SB et al. J Clin Oncol. 2012;30:372-379. PLD 50 mg/m2 IV
n=33 RECIST and CA-125 Responses *GCIG criteria is confirmed ≥50% reduction in CA-125 levels that had to be maintained for ≥28 days;
†CA-125 response in the absence of RECIST progression Kaye SB et al. J Clin Oncol. 2012;30:372-379. PRECEDENT: Randomized phase II PLD +/- Vintafolide (EC145) in platinum-resistant ovarian cancer patients n= 149 patients 2:1 Randomization Vintafolide + PLD PLD only Optional
etarfolatide
(EC20) Scan Vintafolide = 2.5mg TIW wks 1, 3
PLD=50 mg/m2 (IBW) q 28 d PLD= 50 mg/m2 (IBW) q 28 d n= 94 patients PI: Naumann, RW Primary Endpoint: PFS (investigator-assessed)
Secondary Endpoint: OS, RR, response duration
Exploratory Endpoint: Scan result and outcome Naumann et al. J Clin Oncol. 2011(suppl; abstr 5045).
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