synopsis rxponder

RxPONDER
Etude de phase III randomisée comparant une hormonothérapie adjuvante
standard +/- chimiothérapie chez des patientes atteintes de cancer du sein
localisé avec 1-3 N+, RH+ et Her2- dont le score de rechute selon Oncotype DX™
est inférieur ou égal à 25
Sponsor
Unicancer Breast group en France
SWOG aux USA (et CALCG/NSABP)
Coordonateur international : AM Gonzales-Angulo (MD Anderson
Cancer Center, Houston)
PI France
Dr Suzette Delaloge, Institut Gustave Roussy, Villejuif
Objectifs
Objectif primaire:
1. Déterminer l’effet de la chimiothérapie adjuvante chez des
patients atteintes de cancer du sein localisé avec 1 à 3 ganglions
envahis, des récepteurs hormonaux positifs et Her2 négatif, qui
ont un score de recurrence Oncotype DX® faible ou
intermédiaire. Si le bénéfice dépend du score de récurrence (RS),
l’étude déterminera le point à partir duquel une chimiothérapie
adjuvante est recommandée.
Objectifs secondaires:
2. Comparer la survie globale, la survie sans rechute
métastatique et l’intervalle sans maladie locale selon
l’administration ou non d’une chimiothérapie adjuvante et son
interaction avec le RS.
3. Comparer la toxicité observée selon le bras de traitement
4. Développer d’autres tests biologiques pour mesurer le bénéfice
potentiel de la chimiothérapie adjuvante et prédire la survie sans
rechute, la survie sans rechute métastatique, l’intervalle sans
maladie locale et comparer en fonction du score RS.
5. Evaluations prospectives de l’anxiété, la qualité de vie, la
fatigue, la cognition, etc selon le bras de traitement.
Etude
Etude de phase III randomisée internationale ouverte
Hypothèse clinique
Le rapport bénéfice/risque n’est probablement pas en faveur de
l’administration d’une chimiothérapie adjuvante chez les femmes
ayant un cancer du sein localisé RH+ Her2- 1-3 N+ lorsque le RS
est < 25.
Background
rationale
and Indications of adjuvant chemotherapy after excision of localized
breast cancer have been widely expanded. Indeed, prospective
randomized trials indicate that patients with HR+ primary breast
cancer benefit from the addition of chemotherapy to adjuvant
endocrine treatment overall.
However, 70-90% of patients who receive chemotherapy do not
derive a direct individual benefit from it, since they would not
have relapsed in the absence of this treatment, or they do
relapse despite it. Adjuvant chemotherapy is also associated with
major potential short-term, mid-term and eventually long-term
harms. A considerable effort has therefore been made to identify
those patients who really need chemotherapy and will really
benefit form it.
Several retrospective analyses of prospective clinical trials
indicate that some patients may not benefit from chemotherapy.
Specifically, patients with well-differentiated tumors, low grade,
those with high expression of HR, or those with low or
intermediate Recurrence Score (RS) as defined by the Oncotype
DX® assay. Oncotype Dx® assay has reached level 2a of
prognostic biomarkers in breast cancer and is currently used to
decide for adjuvant chemotherapy among HR+ N- breast cancer
patients. Beside prognosis, this score has been associated with a
strong capability to predict for the expected benefit of
chemotherapy (Albain et al 2010).
The present trial aims at evaluating the safety of avoiding
chemotherapy among patients with 1-3 positive nodes and HRpositive disease but an intermediate or low recurrence score (<
25). The trial is designed to determine whether there might be a
benefit among sub-risk categories within that population.
Background: Data from SWOG 8814 (Albain et al Lancet
Oncol 2010)
Références principales
- 1 Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of
tamoxifen-treated, nodenegative
breast cancer. N Engl J Med 2004 ;351:2817-26. PMID: 15591335.
2 Paik S, Tang G, Shak S, et al. Gene expression and benefit of
chemotherapy in women with
node-negative, estrogen receptor–positive breast cancer. J Clin Oncol 2006 ;
24:3726-34. PMID:
16720680.
3 Albain KS, Barlow WE, Shak S, Hortobagyi GN, et al. Prognostic and
predictive value of the 21gene recurrence score assay in postmenopausal women with node-positive,
oestrogen-receptorpositive
breast cancer on chemotherapy: a retrospective analysis of a randomized trial,
Lancet
Oncology 2010 ;11:55-65, PMID: 20005174.
- 4 Berry DA, Cirrincione C, Henderson IC, et al. Estrogen-receptor status and
outcomes of modern
chemotherapy for patients with node-positive breast cancer. JAMA
2006;295:1658-67. PMID: 16609087.
5 Parker JS, Mullins M, Cheang MC, et al. Supervised risk predictor of
breast cancer based on intrinsic
subtypes. J Clin Oncol 2009 ; 27 :1160-7. PMID : 1920420
Indication
Cancer du sein localisé RH+ Her2- 1-3 N+ M0, décision de
traitement adjuvant
Critères de jugement
Critère principal : survie sans rechute invasive
Critères secondaires :
-
Survie globale
Survie sans métastase à distance
Intervalle libre sans rechute locale
-
Design de l’étude et
plan de traitement
Tolerance
Qualité de vie
Questionnaires spécifiques d’anxiété, fatigue, cognition,
etc
Toutes les femmes éligibles à l’étape 1 se voient proposer un test
Oncotype DX centralisé.
-
Les femmes ayant un RS > 25 reçoivent une
chimiothérapie
-
Les femmes ayant un RS < 25 se voient proposer une
randomisation pour chimiothérapie versus pas de
chimiothérapie.
Divers schémas de chimiothérapie sont autorisés, de seconde ou
troisième génération, dont
-
schéma type 3/4 FEC 100 suivis – 3/4 docetaxel/21 jours
ou 12 paclitaxel hebdomadaire
-
6 TAC
-
4-6 TC
Les patientes pourront être incluses dans d’autres essais
cliniques ou études.
Une radiothérapie loco-régionale adéquate selon les critères en
vigueur doit être administrée.
Toutes les patientes recevront une hormonothérapie pour au
moins 5 ans adaptée aux standards en cours et à leur statut
ménopausique.
Le schéma global de l’étude est le suivant:
•
•
•
•
N+ (1-3)
RH-pos
HER2-neg
Pre et Post Menop.
Test OncotypeDx
SR > 25
SR ≤ 25
Chimio
Discussion
avec la
patiente
N=9400
(1200 en France
dans 80 centres)
Accepte
(N=4000)
Refus -> suivi
Critères d’inclusion
principaux
CRITERES D INCLUSION PRINCIPAUX: ETAPE 1 POST OPERATOIRE
- femme de 18 ans et plus
- cancer du sein de type adénocarcinome infiltrant localise
operable, T < T4D, 1-3 ganglions envahis (incluant pN1mi)
- cancer du sein infiltrant ER+
- pas de surexpression ou amplification de Her2
- pas de métastase à distance au bilan
- PS < 2, fonctions rénale, hématologique, cardiaque et
hépatique adéquates
- enregistrement dans les 56 jours de la chirurgie définitive
- consentement éclairé signé
- disponibilité d’un échantillon de tissu tumoral fixé en paraffine
archive tissue pour la mesure centralisée de Oncotype DX®
CRITERES D INCLUSION PRINCIPAUX: ETAPE 2 RANDOMISATION
-
RS < 25
Statistiques
-
Consentement éclairé signe
-
Randomisation à 84 jours maximum de la chirurgie
-
Les patientes incluses et randomisées dans le bras sans
chimiothérapie peuvent être aussi incluses dans d’autres essais,
incluant traitements locaux ou thérapies ciblées, mais à l’exclusion
d’études de chimiothérapie. Les patientes incluses et randomisées
dans le bras avec chimiothérapie peuvent aussi entrer dans des
études de comparaison de chimiothérapies.
9400 femmes doivent être incluses, dont 5600 devraient avoir un
RS < 25. 4000 d’entre elles devraient accepter la randomisation
1/1 soit 2000 recevant et 2000 ne recevant pas de
chimiothérapie.
L’étude est construite pour pouvoir démontrer un bénéfice
éventuel de la chimiothérapie même dans certains sous-groupes
de RS et pour évaluer le rapport bénéfice/risque de la
chimiothérapie adjuvante selon le RS.
Les principes généraux des hypothèses statistiques sont
en annexe 1 en fin de synopsis
Critères de stratification:
Study duration
-
RS 0-13 (bas) vs 14-25 (intermédiaire)
-
Statut ménopausique (pré- versus post)
-
Type de geste axillaire : GS seul versus curage
Durée des inclusions: 6 ans
Durée de suivi: 15 ans
Procédures
Cft ci-dessous
Annexe 1 : principes généraux du plan statistique
The primary question is to test whether chemotherapy benefit (if it exists) depends
on the Recurrence Score.
This interaction is tested in a Cox regression model of DFS. If the interaction of chemotherapy
and the linear RS term is statistically significant (two-sided α) and there is a point of
equivalence between the two randomized treatments for some RS value in the range 025, then additional steps are undertaken. Based on simulation work, power to find a
significant interaction with an equivalence point is 81%. Assuming there is a significant
predictive effect of RS on chemotherapy benefit, then a clinical cutpoint for
recommending chemotherapy will be estimated. This estimated cutpoint is the upper
bound of the 95% confidence interval on the point of equivalence. Kaplan-Meier curves
comparing randomized arms will be generated separately for RS values below and above
this cutpoint and tested with stratified log-rank tests. Additionally, Kaplan-Meier curves
will be generated for specific RS values (possibly grouped due to sparseness), and
modeled 5-year and 10-year estimates by RS and treatment will be provided. If there is
no statistical interaction between linear RS and chemotherapy, then chemotherapy will be
tested in a Cox model adjusting for RS, but without an interaction term. This test will be
conducted at a 1-sided α=0.025 since chemotherapy would be expected to improve
outcomes.
Compliance and dropout. Despite the required discussion between patient and physician
prior to randomization, some patients will still be noncompliant after randomization. The
estimated sample size includes a 5% crossover rate and assumes that noncompliance
depends on RS. For patients randomized to chemotherapy, the assumption is that 5%
do not receive chemotherapy and that a patient with RS 0-11 is twice as likely to refuse
as one who has RS 12-25. For patients randomized to not receive chemotherapy, the
assumption is 5% do receive chemotherapy and that a patient with RS 18-25 is twice as
likely to receive chemotherapy as one who has RS 0-17. The assumption is that the
noncompliant patients remain in the study and provide follow-up. Thus, in the intent to
treat analysis 5% of patients in each treatment group have a treatment opposite to their
randomized assignment. This crossover rate was incorporated into the simulations which
used a sample size of 3,800. The 3,800 was increased to 4,000 to also accommodate
dropout, ineligibility, or withdrawal of consent.
Early termination for futility. Apart from statistical testing of outcomes, low accrual and
crossovers post-randomization affect the viability of the trial. It is also possible that
differential acceptance of randomization across the range of RS from 0 to 25 may affect
the statistical power of this study. With respect to accrual the study will employ the usual
CTEP guideline to judge whether accrual is within expectations and whether the protocol
needs to be amended. After two years of accrual, a committee of five statisticians (one
SWOG, two from other cooperative groups, and two from CTEP) will meet and discuss
viability of the trial based on accrual, acceptance of randomization, and crossover rate.
The result of this discussion will be presented to CTEP and the Data and Safety
Monitoring Committee (DSMC) for action. With respect to crossover rate (randomized
participants receiving the opposite treatment), the upper limit is set at 15% in the first
year and 12% after 2 years. The trial will terminate if the crossover rate exceeds this
unless NCI determines that the high crossover rate has been corrected and that the trial
remains viable. Crossover rates between 5% and the upper limit can be addressed by
longer follow-up without increasing accrual. The target crossover rate is less than 5%
total.
Interim analysis. Under the assumptions above, we would expect 706 events for the
primary analysis of the interaction of RS and chemotherapy. The first interim analysis
would be after 24% of the events have been observed or approximately 6 years after
initiation of the study. This would correspond to the end of accrual if accrual is uniform
and at the expected level. There would be subsequent annual interim analyses thereafter
with 36%, 50%, 65%, and 82% in years 7-10 with the final analysis in year 11. The
analyses will use the Lan-Demets spending function with a truncation bound. To achieve
a cumulative 0.025 1-sided significance level, the interim test α‘s will be 0.0005, 0.0005,
0.00089, 0.00474, 0.01145, respectively, and the final α= 0.0206 so there is little loss of
power due to the interim analyses. All of these analyses are expected to be after accrual
has finished so a decision to publish early would be based on the interim analysis. We
also want to monitor the upper RS group of 14-25 to avoid harming patients if there is
early evidence of efficacy in this group. An analysis will be conducted at 4 years to
evaluate efficacy of chemotherapy in patients with RS 14-25 to determine if there is a
potential significant benefit of chemotherapy early in the trial. If this comparison is
statistically significant at p=0.05 (2-sided) then further randomization in patients with RS
14-25 would be suspended. A similar comparison would then also be performed in the
RS 0-13 group to determine if the trial should suspend accrual completely. Otherwise, all
other analyses would occur after accrual is complete.
A Data and Safety Monitoring Committee will oversee the conduct of the study. The
Committee consists of four members from outside of the Southwest Oncology Group, 3
Southwest Oncology Group members, 3 non-voting representatives from the National
Cancer Institute (NCI), and the Group Statistician (non-voting). The members of this
Committee will receive confidential reports every 6 months from the Southwest Oncology
Group Statistical Center, and will meet at the Group's bi-annual meetings as necessary.
The Committee will be responsible for decisions regarding possible termination and/or
early reporting of the study.