1. Ovarian Cancer: A new look at an old veteran
Sana Al-Sukhun, MD, MSc.
Assistant Professor, Medical Oncology/ Hematology
University of Jordan
Best of ASCO
July 11th 2009

2. Ovarian Cancer First line treatment: Relapsed setting:
Standard Tx : Carboplatin / paclitaxel.
Relapsed setting:
Choice of relapsed disease treatment is dependent on interval since prior platinum-based therapy
Relapse within 6 months: platinum-resistant disease
Relapse over 6 months: platinum-sensitive disease
Carboplatin-paclitaxel is standard in platinum-sensitive disease
Ozols RF et al, J Clin Oncol 2003, 21:

3. Is carboplatin / liposomal doxorubicin a replacement doublet for carboplatin / paclitaxel?

4. Introduction
Single-agent pegylated liposomal doxorubicin (PLD) is a standard option for platinum resistant relapsed ovarian cancer 1.
Combination of carboplatin and PLD is highly active as second-line chemotherapy in patients with advanced ovarian cancer in late relapse 2-3
1Gordon AN et al, J Clin Oncol 2001, 19:
2Ferrero JM et al, Proc Am Soc Clin Oncol 2002
3Ferrero JM et al, Ann Oncol 2007, 18:
4Gordon AN et al, J Clin Oncol 2001, 19:

5. Carboplatin plus Paclitaxel versus Carboplatin plus Stealth Liposomal Doxorubicin in patients with advanced ovarian cancer: activity and safety results of the MITO-2 randomized multicenter trial
S. Pignata1, G. Scambia2, A. Savarese3, R. Sorio4, E. Breda5,
G. Ferrandina2, V. Gebbia6, P. Musso7, C. Gallo8, F. Perrone9
1Istituto Nazionale Tumori, Napoli; 2Università Cattolica del Sacro Cuore, Roma; 3Istituto Regina Elena, Roma;
4CRO, Aviano; 5Ospedale Fatebenefratelli, Isola Tiberina, Roma;
6Casa di Cura La Maddalena, Università di Palermo; 7Ospedale Oncologico M.Ascoli A.R.N.A.S., Palermo;
8Seconda Università di Napoli; 9Istituto Nazionale Tumori di Napoli,Italy.

6. Study design Control arm Random Experimental arm
Carboplatin AUC 5, day 1
Paclitaxel 175 mg/m2, day 1
Treatment repeated every 21 days, for 6 cycles
1:1
Experimental arm
Carboplatin AUC 5, day 1
PLD 30 mg/m2, day 1
Treatment repeated every 21 days, for 6 cycles
Strata:
Center
PS (0-1, 2)
Stage (IC, II, III, IV)
Residual disease after surgery
(absent, 1 cm, 1 cm, no surgery)

7. Study design Random Control arm Experimental arm
Carboplatin AUC 5, day 1
Paclitaxel 175 mg/m2, day 1
1:1
Experimental arm
Carboplatin AUC 5, day 1
PLD 30 mg/m2, day 1
Is carboplatin plus PLD more effective than carboplatin plus paclitaxel as first-line treatment of patients with advanced ovarian cancer?
Objective : To demonstrate improvement in PFS from 18 to 22.5 months ( HR 0.8, 80% power).

8. Study population Inclusion criteria Main exclusion criteria
Cyto/histological diagnosis of ovarian cancer
FIGO Stage IC – II – III – IV
Age  75
ECOG Performance Status 0-2
No previous chemotherapy
Main exclusion criteria
ANC  2000/L, platelets  /L
Creatinine  1.25 x UNL, SGOT and SGPT  1.25 x UNL
Life expectancy of less than 3 months

9. Study endpoints Primary endpoint Progression-free survival (PFS)
Secondary endpoints
Overall survival (OS)
Objective response rate (RECIST)
Toxicity (NCI – CTC v2.0)
Quality of Life (EORTC QLQ C30)

10. Baseline characteristics
Carbo + Paclitaxel
Carbo + PLD
(n = 410)
(n=410)
Age median (range) 57
(21-77)
(25-77)
ECOG Performance Status
0-1
398
(97%)
397 2 12
(3%) 13
FIGO Stage IC 38
(9%) II 40
(10%) 37
III
243
(59%)
247
(60%) IV 89
(22%) 88
Residual disease after surgery
Absent
152
(37%)
150
 1 cm 68
(17%) 69
(19%)
 1 cm
117
(28%)
114
No surgery 73
(18%) 67
(16%)

11. Treatment compliance: delays
Carboplatin + Paclitaxel
Carboplatin + PLD
Number of
patients
Delays due to non hematologic toxicity
Delays due to hematologic toxicity
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Completed 6 cycles : 82% Carboplatinum / PLD Vs 88% receiving Carboplatinum / Paclitaxel P= 0.39

12. Toxicity (2) Any grade Severe (G3) C+P C+PLD p* Allergy 6% 5% 0.60 2%
0.86
Heart 4%
0.26
0.3%
0.06
Fatigue
44%
43% 3%
0.94
Constipation
32%
0.99 1%
0.73
Nausea
47%
51%
0.21
0.95
Vomiting
29%
30%
0.83
0.42
Diarrhoea
13%
0.001 -
0.25
Hair loss
63%
14%
Skin toxicity
20%
0.01
Stomatitis 9%
0.5%
0.62
Neurotoxicity
15%
0.2%
0.004
C+P: carboplatin + paclitaxel, 399 patients; C+PLD: carboplatin + PLD, 386 patients
*Chi square or Fisher exact test as appropriate

13. Objective response – RECIST Women with target lesions
Carbo
+ Paclitaxel
(n=156)
+ PLD
(n=134)
p (2)*
Objective response
92 (59%)
76 (57%)
0.70
Complete response
24 (15%)
22 (16%)
Partial response
68 (44%)
54 (40%)
No response
64 (41%)
58 (43%)
Stable disease
45 (29%)
41 (31%)
Progressive disease
9 (6%)
7 (5%)
Not evaluated
10 (6%)
10 (7%)
*Objective response vs no response

14. Activity Women not eligible for RECIST
Carbo
+ Paclitaxel
+ PLD
p (2)
Non-target lesions only
Complete response (CR)
27 / 83 (33%)
29 / 99 (29%)
0.64*
No CR / No PD
46 / 83 (55%)
48 / 99 (48%)
Progressive disease
2 / 83 (2%)
4 / 99 (4%)
Not evaluated
8 / 83 (10%)
18 / 99 (18%)
Elevated Ca125 only
Ca125 normalized
73 / 88 (83%)
69 / 80 (86%)
0.56**
* Complete response vs not
** Ca125 normalized vs not

15. Primary endpoint
Number of events required for final analysis (632) has not been reached yet
As of May 4, 2009, with a median follow-up of 35 months, 531 progressions have been recorded
Only overall curves are shown

16. Progression-free survival*
Patients
Events
Median PFS
(months)
1-yr
PFS
2-yr
820
531
17.7
(95%CI )
65.0%
41.9%
Patients at risk
820
531
258
134 69 21 -
Months
*May 2009

17. What have we learned?
Three weekly Carboplatinum / PLD is associated with:
More delays- mainly due to hematological toxicity.
More skin toxicity and stomatitis.
Less hair loss and neurotoxicity.
RECIST response and complete remission – similar.
PFS ?

18. What is the standard for platinum sensitive relapse?
ICON 4 / OVAR 2.2
Platinum VS platinum / paclitaxel.
Carboplatin VS carboplatin / gemcitabine.
OVAR 2.5

19. on behalf of all GCIG collaborators
CALYPSO trial
Carboplatin & Pegylated Liposomal Doxorubicin (PLD) versus Carboplatin & Paclitaxel in Relapsed, Platinum-sensitive Ovarian Cancer
Eric Pujade-Lauraine
on behalf of all GCIG collaborators

20. Treatment continues longer
CALYPSO Study Schema
International, Intergroup, Open-label, Randomized Phase III Study R A N D O M I Z E
Experimental arm: CD
PLD 30 mg/m2 IV d 1
Carboplatin AUC 5 d 1
Ovarian cancer in late relapse (> 6 months) after 1st- or 2nd-line platinum-based therapy (previous taxane required)
Q 28 days x 6 courses*
Control arm: CP
Paclitaxel 175 mg/m2 IV d 1
Carboplatin AUC 5 d 1
Stratification:
Therapy-free interval (6-12 mo vs > 12 mo)
Measurable disease (yes vs no)
Center
Treatment continues longer if
SD or Responsive.
Q 21 days x 6 courses*
*or progression in patients with SD or PR

21. NON-INFERIORITY study design
CALYPSO Study Schema
NON-INFERIORITY study design
International, Intergroup, Open-label, Randomized Phase III Study R A N D O M I Z E
Experimental arm: CD
PLD 30 mg/m2 IV d 1
Carboplatin AUC 5 d 1
Ovarian cancer in late relapse (> 6 months) after 1st- or 2nd-line platinum-based therapy (previous taxane required)
Q 28 days x 6 courses*
Control arm: CP
Paclitaxel 175 mg/m2 IV d 1
Carboplatin AUC 5 d 1
- Primary endpoint:
PFS.
- Secondary endpoints:
QOL OS
Q 21 days x 6 courses*
*or progression in patients with SD or PR

22. Baseline Characteristics (1)
CD (n=466)
CP (n=508)
Number of patients (%)
Age, median
ECOG performance status* 1 2
Primary site of disease
Ovarian
Papillary/Serous histology
Initial FIGO stage*
I/II
III/IV
Number of previous lines One
Two
60.5
286 (61)
159 (34)
13 (3)
415 (89)
334 (72)
52 (11)
401 (86)
408 (88)
58 (12)
61.0
317 (62)
164 (32)
15 (3)
451 (89)
366 (72)
59 (12)
427 (84)
421 (83)
87 (17)
* Missing values to attain 100%.

23. Baseline Characteristics (2)
CD (n=466)
CP (n=508)
Number of patients (%)
Prior taxane
Interval since prior therapy, median
6-12 months
> 12 months
Measurable disease
Yes No
Tumour size
< 5 cm > 5 cm
Number of sites
1 > 1
462 (99)
162 (35)
304 (65)
281(60)
185 (39)
377(81)
89(19)
217(47)
249 (53)
500 (99)
182 (36)
326 (64)
321 (63)
188 (37)
419 (82)
90 (18)
245(48)
264(52)

24. Treatment Feasibility
CD (n=465)**
CP (n=501)**
Total treatment duration, median wk* 21 16
Relative dose intensity %
Carbo: 99 PLD: 99
Carbo: 99 Paclitaxel: 98
Patients with ≥ 6 cycles, n (%)*
395 (85)
392 (78)
Patients with ≥ 9 cycles, n (%)
36 (8)
36 (7)
Treatment discontinuation
70 (15)
110 (22)
Toxicity - related treatment discontinuation*
27 (6)
73 (15)
Hypersensitivity reactions*
(5)
(19)
Hypersensitivity - related discontinuation*
(1)
(4)
* P< 0.001; ** Patients receiving at least one cycle

25. Progression-Free Survival (ITT)CD CP
Median PFS, mo
11.3
9.4
HR (95% CI)
0.82 (0.72, 0.94)
Log-rank p-value (superiority)
0.005
P-value (non-inferiority)
<0.001

26. Combination chemotherapy for platinum sensitive disease

27. What have we learned?
Four weekly Carboplatinum / PLD is associated with:
Less hematologic toxicity.
More skin toxicity and stomatitis.
Less hair loss and neurotoxicity.
The combination of PLD-carboplatin was not inferior in term of PFS to paclitaxel-carboplatin, BUT the question of superiority remains open.
18% reduction in risk of recurrence (HR 0.82; P=0.005).
Overall survival data & QOL pending.

28. What’s the implication?
What have we learned?
What’s the implication?
Carboplatinum / PLD is associated with different toxicity profile from carboplatin/ paclitaxel.
More delays- mailnly due to hematologic toxicity.
More skin toxicity and stomatitis.
Less hair loss and neurotoxicity.
First line setting … may be equivalent.
RECIST response and complete remission – similar.
PFS ?
Relapsed setting …. Definitely not inferior.
Discuss options with patient !
How does this compare to weekly Paclitaxel?

29. Randomized phase III trial of conventional paclitaxel and carboplatin (c-TC) versus dose dense weekly paclitaxel and carboplatin (dd-TC) in women with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer: Japanese Gynecologic Oncology.
Print this page Sub-category:Ovarian Cancer Category:Gynecologic Cancer
Meeting:2008 ASCO Annual Meeting Abstract No:5506
Citation:J Clin Oncol 26: 2008 (May 20 suppl; abstr 5506)
Author(s):S. Isonishi, M. Yasuda, F. Takahashi, N. Katsumata, E. Kimura, D. Aoki, T. Jobo, F. Terauchi, H. Tsuda, T. Sugiyama
Abstract:Background: Tri-weekly administration with paclitaxel and carboplatin (c-TC) is considered the standard of care for treatment of ovarian carcinoma. We compared the c-TC with dose dense weekly administration with TC (dd-TC) as first-line chemotherapy for stage II-IV epithelial ovarian, fallopian tube or primary peritoneal cancer. Methods: We randomly assigned patients to receive carboplatin to an area under the plasma concentration-time curve of 6 with either paclitaxel at 180 mg/m2 on day 1 or paclitaxel at 80 mg/m2 on days 1, 8, and 15. The treatments were repeated every 3 weeks for six cycles; in responding patients, additional three cycles were administered. Primary endpoint was progression-free survival (PFS) to be compared by log-rank test. Assuming 300 eligible patients in each arm, the study had 0.8 power to detect 5 months increase in median PFS at 0.05 two-sided alpha. Results: Of 637 patients who underwent randomization, 631 were eligible. After median follow-up of 29 months, median duration of PFS in the c-TC group and dd-TC group was 17.1 and 27.9 months, respectively (P= by the log-rank test), and overall survival at 2 years was 77.7% and 83.6%, respectively (P=0.05). Among 282 patients with measurable disease, objective response rates were 53.3% and 55.8% in the c-TC and dd- TC groups respectively (P=0.91). Grade 3 and 4 anemia was reported more frequently in the dd-TC group, and other toxicities were similar in both groups. Conclusions: The dd-TC improves PFS as compared with c-TC in patients with advanced epithelial ovarian cancer. Abstract Disclosures
Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy and are designated with a caret symbol (^) here and in the print version.   Associated Presentation(s):
Isonishi et al, ASCO 2008

30. Thank You
Sana Al Sukhun, MD, MSc.