Etude Intergroupe (SFCE-GSF-GETO) OS 2006 Zolédronate-Ostéosarcome. Protocole de traitement des ostéosarcomes de l’enfant, de l’adolescent et de l’adulte comportant : un essai randomisé et des études biologiques

Essai OS 2006 SARCOME 09

COORDINATION SCIENTIFIQUE

Médecins coordonnateurs :

Dr Laurence BRUGIERES – IGR – Villejuif - / Pédiatrie

Dr Sophie PIPERNO-NEUMANN – Institut Curie – Paris / Adultes

Statisticien : Dr Marie-Cécile LE DELEY – IGR - Villejuif

METHODOLOGIE

1.   Essai randomisé

–  Phase III, randomisée, ouverte, multicentrique, comparant l’effet de Zometa® ajouté ou non au traitement standard de l’ostéosarcome de haut grade de l’enfant, de l’adolescent et de l’adulte.

–  Nombre de centres déclarés : 50 –  Nombre de patients à randomiser : 470 (235 par bras) –  Durée des inclusions : 6 ans

–  Durée du suivi : 3 ans

2.   Enregistrement de tous les patients incluables ou non dans l’essai randomisé.

3.   Etudes biologiques optionnelles

SCHEMA DE L’ETUDE

* : BR = Bon Répondeur (-10 % de cellules tumorales résiduelles) MR = Mauvais Répondeur (+ 10 % de cellules tumorales résiduelles ou patient non opérable ou métastatique)

Randomisation

Sans Zometa®

< 18 ans

MTX ou API – AI Au choix du centre

MTX-VP-IFO 13 semaines

Avec Zometa®

18 - 25 ans > 25 ans < 18 ans 18 - 25 ans > 25 ans

MTX ou API – AI Au choix du centre

API-AI 13 semaines

BR BR MR/méta MTX VP-IFO 6 mois

MTX -AP 6 mois

AI-IP 3 mois

VP-IFO 4 mois

MTX-VP-IFO Zometa®

13 semaines

BR BR MR/méta MR/méta MTX VP-IFO Zometa®

6 mois

MTX -AP Zometa®

6 mois

AI-IP Zometa®

3 mois

VP-IFO Zometa®

4 mois

API-AI Zometa®

13 semaines

Chirurgie Chirurgie Chirurgie Chirurgie

MR/méta

SARCOME 09: Objectifs

•  Objectif principal Survie sans évènement à 3 ans (55 % avec le traitement de référence) Pour différence absolue d’EFS de 13 %: 235 patients/groupe soit 470 patients

•  Objectifs secondaires Survie globale Réponse histologique à la chimiothérapie Toxicité à court et long terme, Qualité de vie Constituer une base de données commune adulte-enfant

•  3 analyses intermédiaires d’efficacité programmées à 25, 50 et 75% d’évènements

•  Etudes biologiques associées

Facteurs de pronostic et prédictifs de réponse: allélotypage, CGH array, transcriptome et TMA Facteurs angiogéniques (bFGF et VEGF) Impact du Zometa® sur lymphocytes T δγ, expression des antigènes tumoraux Pharmacocinétique du Zometa® chez l’enfant Paramètres biologiques de la résorption osseuse Pharmacogénétique du MTX

Accrual by MARCH 2014: 318  randomised    pa/ents,  158  Z-­‐  160  Z+  

Stop < 15 years old

Suspension Random°

Accrual < Expected

Some other collaborative groups are considering joining the trial

Participant flow

Did not meet eligibility criteriaN=70*

Without zoledronateN=158

With zoledronateN=160

Suspension of randomisationN=17

Not included in the randomised trial- Because of refusal

N=69- For miscellaneous reasons

N=5**- Unknown reason

N=42

Assessed for eligibilityN=521

Included in the randomised trialN=318

Potentially eligibleN=434

Did not meet eligibility criteriaN=70*

Without zoledronateN=158

With zoledronateN=160

Suspension of randomisationN=17

Not included in the randomised trial- Because of refusal

N=69- For miscellaneous reasons

N=5**- Unknown reason

N=42

Assessed for eligibilityN=521

Included in the randomised trialN=318

Potentially eligibleN=434

* Contra-indication (n=35), osteosarcoma of the maxillary (n=7), initial surgery (n=6), non resectable metastases even after chemotherapy (n=5), pre-treatment (n=5), low grade osteosarcoma (n=4) …

(73%)

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Baseline characteristics

Patient characteristics

Treatment group All Z- Z+

N=158 N=160 N=318 % Gender

93 88 181 57 Male Female 65 72 137 43 Age and planned chemotherapy

109 110 219 69 Less than 18y - HDMTX 18-25 years - HDMTX 18 19 37 12 18-25 years - API-AI 12 11 23 7 > 25 years - API-AI 19 20 39 12 Initial staging (as reported at the time of randomisation)

119 120 239 75 Localised Osteosarcoma Doubtful lesion 14 12 26 8 Metastases, a priori resectable 25 28 53 17 Primary non resectable 3 4 7* 2 Risk group defined at randomisation

132 129 261 82 Non metastatic and resectable Metastatic or primary non resectable 26 31 57 18 Consent for biological studies 152 155 307 97

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Patient characteristics

Treatment group

All Z+ Z+

N=143 N=14

1 N=284 % Site of the primary tumour (33 MD) Femur diaphysa 11 13 24 8 Femur lower extremity 67 65 132 42 Femur upper extremity 6 1 7 2 Tibia upper extremity 23 24 47 15 Humerus upper extremity 8 15 23 7 Other 28 24 52 16 Initial staging (according to the detailed data) (MD=34) Localised Osteosarcoma 96 99 195 61 Doubtful lesion 22 21 43 14 Metastases, a priori resectable 25 21 46 14 Lung scan (MD=34) No metastasis 101 103 204 64 Doubtful lesion(s) 18 20 38 12 Metastasis(ses) 24 18 42 13

Patient characteristics (1)

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Patient characteristics (2)

Patient characteristics

Allocated treatment by

random

All Z- Z+

N=143 N=141 N=284 % Bone lesion on the technecium bone scan (MD=53) No bone fixation 124 124 248 78 Single lesion doubtful 8 4 12 4 Single meta confirmed 1 3 4 1 > 5 metastases . 1 1 0 Alkaline phosphatases (MD=13) Normal level 80 73 153 48 Above the upper limit (> 1xULN) 59 65 124 39 LDH (MD=58) Normal level 78 79 157 49 Above the upper limit (> 1xULN)

54 49 103 32

Pre-operative treatment

 HDMTX  protocol        API-­‐AI  protocol  

! Median  interval  7me  between  biopsy  and  start  of  treatment:  15  days  

!   Time  interval  between  courses:    Delay  >  5  days  in  138/1971  courses  (7%),  mainly  due  to  toxicity  

!   No  significant  difference  between  Z+  and  Z-­‐  arms,  in  terms  of  dura7on  of  preopera7ve  chemo,  or  dose-­‐intensity    

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Toxicity during pre-operative treatment

"  Hypocalcemia grade 2-4 is significantly more frequent in Z+ arm

•  per course: OR = 10.8, 95%CI, 6.9 – 16.9, p<0.001

•  per patient: RR = 4.7, 74% Z+ vs 16% Z- pts, p<0.0001

•  9 patients experienced grade 4 hypocalcemia, 7 Z+ & 2 Z-

"  No significant increase of toxicity regarding the other toxicity items

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Toxicity reported after zoledronate Zoledronate dose per injection equal to the protocol dose (+/-10%) for 408/474 injections (86%)

•  Hypocalcemia grade 4 (n=6), grade 3 (n=17), grade 2 (n=144) •  Hyposphophoremia grade 4 (n=1), grade 3 (n=17) and grade 2 (n=49) •  Fever grade 3 (n=4), grade 2 (n=29), grade 1 (n=57)

Histologic analysis of the resection of the primary tumour

Z- Z+ Total N=134 N=129 N=263

Margins (5 MD)

Radical/wide 119 104 223 (83%) Marginal 11 17 28 (11%) Intralesional 4 3 7 (3%)

Histologic response (2 MD ) Good response (<10% viable cells) 88 (66%) 84 (65%) 172 (65%) Poor response 45 44 89 (33%)

Proportion of good histologic response similar in Z+ and Z- pts Good histologic response significantly more frequent in the HDMTX group than in the API-AI group: 151/210 = 73% versus 20/50 = 40%, p<0.0001 Conservative surgery: 240 / Amputation: 22 / No surgery: 14

Post-operative treatment

 HDMTX  protocol        API-­‐AI  protocol  

GR

PR

-­‐  10  injec7ons  planned  in  the  Z+  arm:  4  pre-­‐op+  6  post-­‐op  -­‐    End  of  treatment  form  completed  for  124  /  160  Z+  pts:    55  pts  received  <  10  injec7ons  (including  22  pts  <  5  injec7ons)  -­‐    Z  dose  per  injec7on  equal  to  the  protocol  dose  (+/-­‐10%)    for  443/539  post-­‐op  injec7ons  (82%)  -­‐  Hypocalcemia  (gr  2  -­‐  4)  significantly  more  frequent  in  the  Z+  arm  per  cycle  and  per  pa7ent:    RR  =  2.6,  50%  Z+  pts  versus  20%  Z-­‐  pts,  p<0.00001  -­‐    No  significant  increase  of    other  toxici7es    

MTX 12 g/m² I: Ifosfamide (Ifo) 3g/m² x 4d V: VP16 75mg/m² x 4d A: Adriamycin (Adria) 37.5 mg/m² x 2d

P: Cis-platinum (Cis-plat) 120 mg/m² x 1d

Surgery GR*

PR**

A: Adria 60 mg/m² D1

P: Cis-plat 100 mg/m² D1 I: Ifo 3 g/m² D2-D3

Surgery GR*

PR**

A: Adria 60 mg/m² D1 I: Ifo 3 g/m² D2-D3

P: Cis-plat 100 mg/m² D1 I: Ifo 3 g/m² D2-D3 I: Ifo 4g/m² x 3d

V: VP16 100 mg/m² x 3d

* : GR = Good histological response (<10% viable cells) **: PR = Poor histological response (≥10% viable cells) and patients with not resectable tumour or metastatic disease

Statistical analysis

"   Primary  endpoint:  Event-­‐free  survival    (7me  to  progression,  relapse,  2nd  cancer,  and  death  whatever  the  cause  )    "   169  events  expected  for  the  final  analysis  "   64  events  at  the  7me  of  the  1st  interim  analysis  performed  in  2012  

" 111  events  reported  to  the  data  base  including  22  early  progression  

"   A_er  adjudica7on  by  the  Endpoint  Commiaee,    14  “early  progressions”  were  reclassified  as  non-­‐events  (10  Z-­‐  /  4  Z+)  "   106  events  currently  considered  in  the  main  analysis  (63%  of  the  total  expected  number  )  

⇒   Second  interim  analysis    

•   Nominal  alpha  =  0.0113  •   Early  stopping  rule  for  rejec7on  of  H0  •   No  fu7lity  analysis  planned  

Outcome of the whole population 3 endpoints

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Type of events by randomised group

*  Toxic  death  (#84,),  Cancer-­‐related  death  (#188  and  #224)    

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Treatment effect on Event-Free Survival after review (106 events)

HR  Z+  vs.  Z-­‐  in  a  Cox  stra/fied  model:  1.31  [0.79  –  2.18],  p=0.17  

   

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Treatment effect on Overall Survival (58 deaths)

HR  Z+  vs.  Z-­‐  in  a  Cox  stra/fied  model:  1.42  [0.70  –  2.88],  p=0.21  

   

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Outcome  in  localized  pa/ents    by    chemotherapy  group  and  histological  response  

Figure  1.  EFS  MTX  GR  versus  PR  

Figure  2.  OS  MTX  GR  versus  PR  

Figure  3.  EFS  API-­‐AI  GR  versus  PR  

Figure  4.  OS  API-­‐AI  GR  versus  PR  

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Conclusion of the second interim analysis

"   Trend  for  a  harmful  effect  of  Zoledronate  

"   On  the  three  efficacy  endpoints  

"   With  stable  results  a_er  exclusion  of  the  8  pa7ents  allocated  to  Z+      who  received  no  zoledronate  or  only  1  injec7on  

"   With  no  heterogeneity  across  the  different  strata        considered  at  the  7me  of  randomisa7on  

"   Boundaries  defining  a  significant  harm  not  crossed  

"   Recommenda/on  of  early  stopping  for  fu/lity?    

"   Probability  of  demonstra7ng  a  benefit  <0.0001  (even  under  H1)  

   

Stop for futility

Stop for efficacy

Stop for harm

Current Test Statistic

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Conclusion "  Accrual rate remains lower than expected

"  Very few patients "lost to follow-up" Quality and completeness of the data base rather good

"  No safety concern apart from the expected higher incidence of hypocalcemia

"  Overall results (EFS, OS) consistent with previous studies both in children and adults patients

"  Futility analysis, performed on DSMB request, showed that the probability of demonstrating a benefit was <0.0001. Following DSMB recommendation, the trial steering committee decided to stop accrual in the trial on APR 4, 2014.

"  Conclusion: With current follow-up, the addition of zoledronate to chemotherapy did not reduce the risk of failure in osteosarcoma patients.

"