UNANSWERED QUESTIONS IN UPFRONT THERAPY CHEMOTHERAPY ISSUES: WEEKLY DOSING Andrés Poveda, MD Fundación Instituto Valenciano de Oncología [email protected].

UNANSWERED QUESTIONS IN UPFRONT THERAPYCHEMOTHERAPY ISSUES:

WEEKLY DOSING

Andrés Poveda, MD

Fundación Instituto Valenciano de Oncología

[email protected]

On behalf of GEICO and GCIG

Ovarian Cancer Clinical Trials Planning Meeting

Friday, May 29, 2009

3rd InternationalOvarian Cancer Consensus Conference

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

UNANSWERED QUESTIONS IN UPFRONT THERAPYWEEKLY DOSING

RATIONALE

• Antiangiogenic property of Paclitaxel independent of its anti-proliferative action Lau DH et al. Proc ASCO 17:4141, 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

Mechanisms of Paclitaxel-induced cell death are concentration dependent

• Paclitaxel-mediated cell death may result from two different mechanisms:– At low Paclitaxel concentrations (<9 nM), cell death

may occur after an aberrant mitosis by Raf-1 independent pathway

– At higher Paclitaxel concentrations (>9 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, 58:3620

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

0

2

4

6

8

10

12

14

I II III IV V

ANC (1000/µL)

Level

Fennelly et al. JCO 15: 187-92; 1997

WEEKLY PACLITAXEL: NO INCREASE IN MYELOSUPPRESSION WITH DOSE ESCALATION

UNANSWERED QUESTIONS IN UPFRONT THERAPYWEEKLY DOSING

PHASE 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 KitaGyn 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

UNANSWERED QUESTIONS IN UPFRONT THERAPYWEEKLY DOSING

PHASE II STUDIES paclitaxel in combination in platinum-resistant ovarian cancer

TDose/m2/wk C AUC

AuthorN RR

%

DFS

months

OS

months

T90 C AUC4

d1,8,q 21Cadron Gynecol Oncol 2007

8 38 6.75 8

T80 C AUC2

d1,8,15, q 28Havrilesky, Gynecol Oncol 2003

8 37.5 3.2 11.4

T90 C AUC4

d1,8,15, q 28Van der Burg, Int J Gynecol Cancer, 2005

23 61 11 15

T80 C AUC3

d1,8,15 q28Roxburgh P ESMO 08 A # 668

54 50-63 4.7-7.5 7.5-9

T70 C AUC 3

d1,8,15, q28Sharma R Br J Cancer 2009

20 60 7,9 13,3

UNANSWERED QUESTIONS IN UPFRONT THERAPYWEEKLY DOSING

RANDOMIZED 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 RRLess toxicity

Rosenberg, 02 208 Second-line T 200T 67

Equal RR,TTP,

OS Less toxicity

Shen, 05CGOG

125 Front-line TCTwkly C

Equal RR,TTP, OS Less toxicity

UNANSWERED QUESTIONS IN UPFRONT THERAPYWEEKLY DOSING

PHASE 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: 21mmOS: 43m

Safra, 2009(Tel Aviv)

64 Front-line Ic-IV T 80 C AUC2 d1,8,15 q28

RR: 92,1%mPFS:25,5mmOS: 52m

AGO Ovarian Cancer Study Group (AGO-OVAR)

What else?What else?

UNANSWERED QUESTIONS IN UPFRONT THERAPYWEEKLY DOSING

Randomized PHASE III TC vs DDT+C in first-line AOC patients: a JGOG Study Isohishi S et al . ASCO 2008,Abstract-5506

UNANSWERED QUESTIONS IN UPFRONT THERAPYWEEKLY DOSING

Randomized PHASE III TC vs DDT+C in first-line AOC patients: a JGOG Study

• Endpoint: PFS• n: 637 pts• PFS (median follow up 29 m):

– 17,1m vs 27,9m (p:0.0014) log-rank test• OS (at 2 years):

– 77,7% vs 83,6% (p:0.05)• RR: similar• Toxicity: Anemia G3-4 in weekly arm more freq

Isohishi S et al . ASCO 2008,Abstract-5506 (Oral)

Treatment n Event Median PFS P value HR 95%CI

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)

JGOG: Conventional TC vs Dose-Dense TC in ADOVCAProgression-free survival

UNANSWERED QUESTIONS IN UPFRONT THERAPYWEEKLY DOSING

ONGOING 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 ORRRR DurationOSSafety

Open in June 09

MITO-7Particip:MANGO

Phase III R C AUC6+ T175vsT60 d1,8,15, q21 C AUC 2 q 21

500 QoL ORRPFS,OSSafety

Open

UNANSWERED QUESTIONS IN UPFRONT THERAPYWeekly Dosing

Conclusion

• 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

UNANSWERED QUESTIONS IN UPFRONT THERAPYWeekly Dosing

Open 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?