carboplatin & pegylated liposomal doxorubicin (pld) versus carboplatin & paclitaxel in...
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Carboplatin & Pegylated Liposomal Doxorubicin (PLD)
versus Carboplatin & Paclitaxel
in Relapsed, Platinum-sensitive
Ovarian CancerEric Pujade-Lauraineon behalf of all GCIG collaborators
CALYPSO trial
Background
• Despite response to 1st-line treatment, relapse is eventual for most patients with advanced ovarian cancer (AOC)
• 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
Rationale for PLD-Carboplatin Doublet
• Due to risk of cumulative neuropathy and of hair loss, other carboplatin combinations have been explored
• Pegylated liposomal doxorubicin (PLD) is a rational choice for combined therapy– PLD outperformed topotecan in platinum-
sensitive population in large randomized trial (significant benefit in PFS and OS)1,2
– Phase II trial of PLD-carboplatin verified safety and efficacy3
1Gordon et al. J Clin Oncol. 2001;19:3312-3322; 2Gordon et al. ECCO 12. September 2003 (poster); 3Ferrero et al. Ann Oncol. 2007;18:263-268.
CALYPSO Study Schema
Ovarian cancer in late relapse (> 6 months) after 1st- or 2nd-line
platinum-based therapy (previous taxane
required)
International, Intergroup, Open-label, Randomized Phase III Study
Stratification:
•Therapy-free interval (6-12 mo vs > 12 mo)
•Measurable disease (yes vs no)
•Center
RANDOMIZE
Experimental arm: CD
PLD 30 mg/m2 IV d 1
Carboplatin AUC 5 d 1
Control arm: CP
Paclitaxel 175 mg/m2 IV d 1
Carboplatin AUC 5 d 1
Q 28 days x 6 courses*
Q 21 days x 6 courses*
*or progression in patients with SD or PR
Key Eligibility Criteria
• Age ≥ 18 years• ECOG performance status ≤ 2• Histologically proven diagnosis of cancer of
the ovary, fallopian tube, or extra-ovarian papillary serous tumors
• Disease progression > 6 months after 1st- or 2nd-line platinum-based therapy
• Previous taxane exposure• Measureable disease (RECIST criteria) or CA
125 assessable disease (GCIG criteria) or histologically proven diagnosis of relapse
Endpoints. Statistical discussions
Primary endpoint• Progression-free survival (PFS)
Statistical considerations• Two-arm, parallel, NON-INFERIORITY study design• Statistical assumptions based on PFS from
ICON4/AGO-OVAR 2.2 trial1 • Declare non-inferior if HR one-side 95% CI <1.23
(CD:CP) for PFS• Power of 90% and one-sided confidence level of
95%• Number of events required : 745
1Parmar et al. Lancet. 2003;361:2099-2106.
Endpoints
Secondary endpoints• Qualitative and quantitative toxicities• Quality of life (EORTC QLQ-C-30 version
3.0 and OV-28 questionnaire version 1.0)
• Overall survival (OS)
Accrual
N=976
CALYPSO Worldwide CollaborationAustria, Australia, Belgium, Canada, Denmark, Finland, France,
Germany, Italy, New Zealand, Saudi Arabia, Spain, Sweden, Switzerland, Turkey
Accrual by Groups
49
76
317
227
71
17
22
137
60
Baseline Characteristics (1)
CharacteristicCD (n=466) CP (n=508)
Number of patients (%)
Age, medianECOG performance status* 0 1 2Primary site of disease Ovarian
Papillary/Serous histology Initial FIGO stage* I/II III/IVNumber 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%.
Baseline Characteristics (2)
CharacteristicCD (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)
Treatment Exposure
CD (n=465)** CP (n=501)**
Total treatment duration, median wk* 21 16
Relative dose intensity % Carbo: 99PLD: 99
Carbo: 99Paclitaxel: 98
Patients with ≥ 6 cycles, n (%)* 395 (85) 392 (78)
Patients with ≥ 9 cycles, n (%) 36 (8) 36 (7)
* P< 0.001; ** Patients receiving at least one cycle
Hematologic Toxicity
Toxicity, grade(gr)
CD (n=464)
CP (n=500) P Value
Number of patients (%)
Neutropenia, gr 3
gr 4
144 (31)
20 (4)
121 (24)
108 (22)
<0.01
Febrile neutropenia, gr 3-4
10 (2) 21 (4) NS
Infection, gr 3-4 11 (3) 14 (3) NS
Thrombocytopenia, gr 3-4 73 (16) 31 (6) <0.01
Bleeding, gr 3-4 3 (0.6) 0 (0) NS
Anemia, gr 3-4 37 (8) 27 (5) NS
NS=not significant.
Selected Non-Hematologic Toxicities During Treatment
*P< 0.001
CD (n=466) CP (n=501)Grade 2 Grade3/4 Grade 2 Grade 3/4
Nausea/vomiting* 31% 4% 20% 4%
Constipation 19% 2% 20% 2%
Diarrhea 4% 2% 6% 2%
Arthralgia/myalgia* 4% 0% 18% 1%
Hand-foot syndrome* 11% 2% 2% 0%
Mucositis* 13% 2% 6% 1%
Fatigue 31% 7% 34% 7%
Cardiac disorders 2% 1% 3% 1%
Selected Non-Hematologic Toxicities During Treatment
CD (n=466) CP (n=501)
Alopecia grade 2* 7% 84%
Alopecia
*P< 0.001
Long-Lasting Toxicity
CD (n=466) CP (n=501)
Grade 2 Grade 3/5 Grade 2 Grade 3/5
Neuropathy* 4% 1% 24% 4%
Neuropathy score over time
EORTC OV28 – QoL Peripheral Neuropathy
*P< 0.001
Early Treatment Discontinuation
ReasonCD (n=466) CP (n=501)
Number of patients (% of total)
Toxicity*
Patient/investigator choice
Progressive disease
Intercurrent disease
TOTAL*
27 (6)
16 (3)
26 (6)
1 (<1)
70 (15)
73 (15)
14 (3)
22 (4)
1 (<1)
110 (22)
* P< 0.001
Carboplatin Hypersensitivity Reactions
CD (n=466) CP (n=501)
Grade 2 Grade 3/5 Grade 2 Grade 3/5
Hypersensitivity* 3% 2% 10% 9%
One drug stopped - 2%
Both drugs stopped 1% 4%
*P< 0.001
Protocol included EORTC guidelines for re-challenge after a hypersensitivity reaction to carboplatin
Follow-up and Number of Events
• Median follow-up 22 months
• Number of events – Progressions or deaths 824 (85%)– Deaths 322 (33%)
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
Symmetry of Tumor Assessments
Sensitivity PFS analysis
Multivariate Analysis of Baseline Predictive Factors on PFS
Significant predictors of PFS included
Baseline Factor NMultivariate Cox Regression Model
HR 95% CI P-value
Therapy-free interval
6-12 mo 342 1.00(0.48, 0.65) < 0.001
> 12 mo 617 0.56
Measurable Disease
No 362 1.00(1.27, 1.70) < 0.001
Yes 597 1.47
CA 125< 100 316 1.00
(1.52, 2.07) < 0.001≥100 643 1.77
Treatment arm
CP 499 1.00(0.71, 0.93) 0.003
CD 460 0.80
Key findings• In patients with platinum-sensitive relapsing ovarian
cancer, the combination of PLD-carboplatin was not inferior in term of PFS to paclitaxel-carboplatin, and even was found significantly superior– 18% reduction in risk of recurrence (HR 0.82; P=0.005)
• Overall survival data immature, with only 322 deaths to date
• Paclitaxel-carboplatin associated with more severe toxicity (carboplatin hypersensitivity), alopecia, and long-lasting toxicity (neuropathy)
• Moderate reversible HFS, mucositis, and nausea/vomiting more frequent with PLD
Conclusions
• Carboplatin-PLD demonstrated a superior therapeutic index (benefit/risk ratio) versus current standard, carboplatin-paclitaxel
• PLD- carboplatin offers an evidence-based option for patients with platinum-sensitive recurrent ovarian cancer
Study Office B. Votan G. Elser G. Andersen M. Bacon J. Martin B. Volger A. Demeester J. Bryce R. Fossati N. Le Fur P. Schantl C. Jeppesen C. Goudreau K. Carlton J. Ulmer
Investigators
Acknowledgement Patients and their families, and …
E. Pujade -LauraineA. LortholaryF. JolyB.WeberL. GladieffA. FloquetR. LargillierM. FabbroA. Goupil R. DelvaE. GuardiolaF. PriouG.De RauglaudreD. Coeffic …
E. EisenhauerL. ElitP. SauthierJ. BentleyA. OzaH. ChalchalA. SugimotoM. HeywoodP. BessetteD. PopkinL. KaizerW. GotliebP. Walde …
G. KristensenJ. KaernR. SandveiJ. HerrstedtE. Aavall -LundqvistT. HogbergB. LundK. BomanH. HavsteenM. HansenJ. Maenpaa …
J. PfistererJ. SehouliA. Du BoisP. WimbergerB. SchmalfeldtJ. HuoberS. MahnerM. Gropp M. ThillK. BaumannA. BurgesA. StaehleR. KreienbergA. BelauM. Beckmann S. LoiblA. HasenburgG. EmonsW. AulitzkyL. Spaetling …
C. MarthA. ZeimetA. ReinthallerL. Angleitner -BoubenizekH. SchauerP. SeveldaE. Petru…
I. VergoteN. ReedK. Van EygenP. OttevangerM. Van der BurgA. Casado Herraez
S. PignataG. ScambiaR. SorioE. BredaA. De Matteis
A. FerreroN. ColomboN. DonadelloD. Gueli AllettiA. LissoniS. Siena
DSMBM. Gore
M. BradyM. Seiden
P. VaseyB. FitzharrisM. BuckT. BonaventuraM. VaughanM. DavyA. O’DonnellC. SteerM. QuinnM. Friedlander A. GoldrickF. Kirsten …
Supported by
Shering Plough InternationalS. Stopatschinskaja C. DohertyB. Winograd B. Hartley
K. Djazouli
K. RehmanM. FehrG. Tulunay
StatisticsV. GebskiC. Brown
Data ManagementH. Karsenty L. Bertel, B. VoulazS. Perrin
Web siteD. Pihan
Coordinating Centre
A. BonvoisinE. PlançonF. PinotN. Chiannilkulchai
GINECO AGO-OVAR NSGO NCIC-CTG ANZGOG AGO-Austria EORTC MITO MANGO
Safety OfficeS. Azouz
T. Tran