UNANSWERED QUESTIONS IN UPFRONT THERAPY CHEMOTHERAPY ISSUES: WEEKLY DOSING

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UNANSWERED QUESTIONS IN UPFRONT
THERAPYCHEMOTHERAPY ISSUES WEEKLY DOSING

• Andrés Poveda, MD
• Fundación Instituto Valenciano de Oncología
• apoveda_at_fivo.org
• On behalf of GEICO and GCIG
• Ovarian Cancer Clinical Trials Planning Meeting
• Friday, May 29, 2009

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3rd InternationalOvarian Cancer Consensus
Conference
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• 4-A4 Which regimen / kind of regimens can be
  regarded as standard
• comparator for future first-line trials?
• Within a given trial the chemotherapy regimen
  should be standardized and consistent
• with respect to drugs, dose, and schedule.
• The recommended standard comparator for trials on
  medical treatment in advanced
• ovarian cancer (FIGO IIB-IV) is
  carboplatin-paclitaxel
• The recommended regimen is carboplatin with a
  dose of AUC 5 - 7.5 and paclitaxel 175
• mg/m²/ 3h given every three weeks for 6 courses
• The recommended standard in early stage ovarian
  cancer (FIGO I-IIA) patients in whom
• adjuvant chemotherapy is indicated should
  contain at least carboplatin AUC 5 -7.5
• Level of Acceptance 13 / 13

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UNANSWERED QUESTIONS IN UPFRONT THERAPYWEEKLY
DOSINGRATIONALE

• Antiangiogenic property of Paclitaxel independent
  of its anti-proliferative action Lau DH et al.
  Proc ASCO 174141, 1998
• Antiangiogenic scheduling chemotherapy improves
  efficacy against experimental drug-resistant
  cancer Browder T, Cancer Res 2000
• Norton-Simon hypothesis a more frequent drug
  administration would be a more effective way of
  avoiding the regrowth of cell populations
  resistant to the agents used (Gomperzian model of
  tumor growth).
• Proven activity in other tumours (Breast
  Cancer,..)
• Better tolerance schedule

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Mechanisms of Paclitaxel-induced cell death are
concentration dependent

• Paclitaxel-mediated cell death may result from
  two different mechanisms
• At low Paclitaxel concentrations (lt9 nM), cell
  death may occur after an aberrant mitosis by
  Raf-1 independent pathway
• At higher Paclitaxel concentrations (gt9 nM) cell
  death may be the result of a terminal mitotic
  arrest occurring by a Raf-1 dependent pathway
• Torres R and Horwitz B Cancer Res 1998, 583620

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Potential Advantages of Weekly Paclitaxel

• Greater dose intensity greater
  inhibition of mitotic cellular activity
• Higher frequency of administration
  Higher cellular exposure in M phase
  Higher inhibition of mitotic cellular activity
• Cause of cellular death mediated by other
  mechanisms (apoptosis)
• Inhibition of neovascularization
• Better pharmacodynamic profile

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WEEKLY PACLITAXEL NO INCREASE IN
MYELOSUPPRESSION WITH DOSE ESCALATION
ANC (?1000/µL)
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12
10
8
6
4
2
0
I
II
III
IV
V
Level
Fennelly et al. JCO 15 187-92 1997
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UNANSWERED QUESTIONS IN UPFRONT THERAPYWEEKLY
DOSINGPHASE II STUDIES paclitaxel in
platinum-resistant ovarian cancer
Schedule (mg/m2) PP N RR PFS OS
1) 60-80 weekly 100 32 53 6.1 10.4
2) 80 weekly 100 48 21 3.6 -
3) 80 weekly x 3/ 4 10 14 28
4) 80 weekly 100 53 25 24 w 58 w
5) 80 weekly x 6/ 8 96 28 50 6 8
6) 80-100 weekly (1) 45 27 70 4.8 13.5
7) 80 weekly 68 57 56 5 13.7
1) Canada Le. Gyn Oncol 2005 2) GOG Markman. Gyn
Oncol 2006 3) Japan Kita Gyn Oncol 2004 4)
Markman at Cleveland. Markman. JCO 2002 5)
Roswell Park. Ghamande. Int J Gynecol Cancer
2003 in responders 6) Royal Mardsden Lynch.
Gyn Oncol 2008 including the platinum
sensitive patients (1) retrospective 7)
Norwegian Kaern Eur J Gynecol Oncol 2002
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UNANSWERED QUESTIONS IN UPFRONT THERAPYWEEKLY
DOSINGPHASE II STUDIES paclitaxel in combination
in platinum-resistant ovarian cancer
TDose/m2/wk C AUC Author N RR DFS months OS months
T90 C AUC4 d1,8,q 21 Cadron Gynecol Oncol 2007 8 38 6.75 8
T80 C AUC2 d1,8,15, q 28 Havrilesky, Gynecol Oncol 2003 8 37.5 3.2 11.4
T90 C AUC4 d1,8,15, q 28 Van der Burg, Int J Gynecol Cancer, 2005 23 61 11 15
T80 C AUC3 d1,8,15 q28 Roxburgh P ESMO 08 A 668 54 50-63 4.7-7.5 7.5-9
T70 C AUC 3 d1,8,15, q28 Sharma R Br J Cancer 2009 20 60 7,9 13,3
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UNANSWERED QUESTIONS IN UPFRONT THERAPYWEEKLY
DOSINGRANDOMIZED PHASE II STUDIES 3weekly vs
weekly paclitaxel in ovarian cancer
Author N Scenario T Doses/m2 Conclusion
Wu, 2001 29 Front-line T175 C AUC6 T60 C AUC 2 Equal RR Less toxicity
Rosenberg, 02 208 Second-line T 200 T 67 Equal RR,TTP, OS Less toxicity
Shen, 05 CGOG 125 Front-line TC Twkly C Equal RR,TTP, OS Less toxicity

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UNANSWERED QUESTIONS IN UPFRONT THERAPYWEEKLY
DOSINGPHASE II STUDIES paclitaxel in combination
in front-line ovarian cancer
Author N Scenario T Doses/m2 Conclusion
Pignata, 2008 (MITO5) 26 Front-line elderly T60 C AUC2 d1,8,15 q28 RR 38,5 mPFS 13,6m mOS 32 m
Sehouli, 2008 (NOGGO) 129 Front-line IIb-IV radical resected T100 C AUC2 d1,8, q21 RR 74 mPFS 21m mOS 43m
Safra, 2009 (Tel Aviv) 64 Front-line Ic-IV T 80 C AUC2 d1,8,15 q28 RR 92,1 mPFS25,5m mOS 52m

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What else?
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UNANSWERED QUESTIONS IN UPFRONT THERAPYWEEKLY
DOSINGRandomized PHASE III TC vs DDTC in
first-line AOC patients a JGOG Study Isohishi S
et al . ASCO 2008,Abstract-5506
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UNANSWERED QUESTIONS IN UPFRONT THERAPYWEEKLY
DOSINGRandomized PHASE III TC vs DDTC in
first-line AOC patients a JGOG Study

• Endpoint PFS
• n 637 pts
• PFS (median follow up 29 m)
• 17,1m vs 27,9m (p0.0014) log-rank test
• OS (at 2 years)
• 77,7 vs 83,6 (p0.05)
• RR similar
• Toxicity Anemia G3-4 in weekly arm more freq

Isohishi S et al . ASCO 2008,Abstract-5506 (Oral)
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JGOG Conventional TC vs Dose-Dense TC in
ADOVCAProgression-free survival
Treatment n Event Median PFS P value HR 95CI
c-TC 319 200 17.2 mos.
dd-TC 312 160 28.0 mos. 0.0015 0.714 0.581-0.879
Isohishi et al, ASCO 2008 (abstract 5506, oral)
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UNANSWERED QUESTIONS IN UPFRONT THERAPYWEEKLY
DOSINGONGOING STUDIES in front-line ovarian
cancer
Group Study Design Tmg/m2 n Primary Objetive Secondary Objetives Status
Intergroup MO22225 (OCTAVIA) GEICO, GINECO, NSGO, MITO Phase II T80 d1,8,15 q21 C AUC 6 q21 Beva 7.5q21 180 PFS ORR RR Duration OS Safety Open in June 09
MITO-7 Particip MANGO Phase III R C AUC6 T175 vs T60 d1,8,15, q21 C AUC 2 q 21 500 QoL ORR PFS, OS Safety Open

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UNANSWERED QUESTIONS IN UPFRONT THERAPYWeekly
DosingConclusion

• Results of trials with impact in FRONT-LINE
• TC remains standard since 2003 and after many
  trials including more than 6000 patients!!!
• CP vs TC GOG-111, OV10
• Carbo T vs Cis T GOG, AGO, SWOG
• Weekly T C (JGOG) improved PFS (phase III)
• Ongoing Triplet TC Avastin
• ICON-7 (recently closed)
• GOG-218
• GOG-213

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UNANSWERED QUESTIONS IN UPFRONT THERAPYWeekly
DosingOpen Questions

• Which is the optimal weekly dose?
• Which drugs should be administered in a weekly
  schedule
• Only Taxane?
• Taxane carboplatin?
• How to incorporate weekly dose to
• i.p strategy?
• biologic agents combination?
• How to determine the appropriate duration of
  weekly dose therapy?

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