M. Le Deley

Relapses of childhood anaplastic large-cell lymphoma: Treatment results in a series of 41 children - a report from the French Society of Pediatric Oncology

PURPOSE To study response to chemotherapy and the outcome of children treated for a relapsed anaplastic large-cell lymphoma (ALCL) and to evaluate the role of bone marrow transplantation (BMT) in these patients. PATIENTS AND METHODS Clinical data concerning the 41 relapses that occurred in 119 patients with ALCL enrolled in 3 consecutive studies since 1975 were analysed. First-line treatment consisted of intensive chemotherapy according to the COPAD protocol for the first series of 12 patients treated between 1975 and 1989 and to the SFOP (French Society of Pediatric Oncology) HM protocols for the 30 patients treated between 1989 and 1997. Twenty-eight patients were treated with CV(B)A (CCNU, vinblastine, ara-C with or without bleomycin), and the others with miscellaneous protocols for recurrent disease. Fifteen patients underwent autologous BMT and 1 allogeneic BMT while in CR2. RESULTS Thirty-six of forty-one (88%) patients achieved CR2. With a median follow-up of 5 years, 12 patients died, 9 of their disease and 29 patients are alive in CR2 (20 patients), CR3 (5 patients), CR4 (2 patients), CR5 (1 patient) or CR6 (1 patient). Overall and disease-free survival are respectively 69% (53%-82%) and 44% (29%-61%) at three years. In univariate analysis, patients treated with ABMT while in CR2 did not appear to have a better outcome than the other. Remarkably, a long-lasting remission was obtained in 8 of 13 patients treated with weekly vinblastine for a relapse including 6 relapses occurring after ABMT. CONCLUSIONS Relapsed ALCL are highly chemosensitive but over 40% of the patients experience several relapses. Prolonged conventional chemotherapy based on vinblastine might, in some cases, be as efficient as short intensive treatment with ABMT.

Dose-finding approach for dose escalation with overdose control considering incomplete observations.

We propose a hybrid design, the time-to-event dose-escalation method with overdose control (TITE-EWOC), introducing the time-to-event approach, developed by Cheungit et al., in the EWOC method, developed by Babb et al. The aim of this new design is to decrease the dose-finding trial duration, without impairing the characteristics of the EWOC design, especially the overdose control ability. We conducted a simulation study, exploring four dose–toxicity relationships and three mean inter-patient arrival times. Performances of TITE-EWOC were compared with those of the EWOC method. This study shows that the trial duration can be greatly decreased with the TITE-EWOC, without impacting the proportion of overdosed patients or the number of dose-limiting toxicities by trial, for all explored dose–toxicity relationships, except for very short inter-patient arrival times. The ability of the method to find the true maximum tolerated dose remains unchanged.

Overexpression of Smad7 Blocks Primary Tumor Growth and Lung Metastasis Development in Osteosarcoma

Purpose: Osteosarcoma is the main malignant primary bone tumor in children and adolescents for whom the prognosis remains poor, especially when metastasis is present at diagnosis. Because transforming growth factor-β (TGFβ) has been shown to promote metastasis in many solid tumors, we investigated the effect of the natural TGFβ/Smad signaling inhibitor Smad7 and the TβRI inhibitor SD-208 on osteosarcoma behavior. Experimental Design: By using a mouse model of osteosarcoma induced by paratibial injection of cells, we assessed the impact of Smad7 overexpression or SD-208 on tumor growth, tumor microenvironment, bone remodeling, and metastasis development. Results: First, we demonstrated that TGFβ levels are higher in serum samples from patients with osteosarcoma compared with healthy volunteers and that TGFβ/Smad3 signaling pathway is activated in clinical samples. Second, we showed that Smad7 slows the growth of the primary tumor and increases mice survival. We furthermore demonstrated that Smad7 expression does not affect in vitro osteosarcoma cell proliferation but affects the microarchitectural parameters of bone. In addition, Smad7-osteosarcoma bone tumors expressed lower levels of osteolytic factors such as RANKL, suggesting that Smad7 overexpression affects the “vicious cycle” established between tumor cells and bone cells by its ability to decrease osteoclast activity. Finally, we showed that Smad7 overexpression in osteosarcoma cells and the treatment of mice with SD208 inhibit the development of lung metastasis. Conclusion: Taken together, these results demonstrate that the inhibition of the TGFβ/Smad signaling pathway may be a promising therapeutic strategy against tumor progression of osteosarcoma, specifically against the development of lung metastasis. Clin Cancer Res; 20(19); 5097–112. ©2014 AACR.

Dose-finding designs in pediatric phase I clinical trials: comparison by simulations in a realistic timeline framework.

OBJECTIVE Usual dose-finding methods in oncology are sequential. Accrual is suspended after each group of patients to assess toxicity before increasing the dose. An adapted Continual Reassessment Method (CRM) and Rolling 6 (R6) method, designed to avoid this suspension of accrual in pediatric oncology, are compared with the traditional 3+3 design. STUDY DESIGN AND SETTING The competing performances were evaluated in a simulation study integrating the temporal dimension, and a phase I trial was reanalyzed. We compared methods for various interpatient arrival times and dose-toxicity relations, in terms of distribution of final recommendations, number of skipped children and duration of trials. RESULTS R6 and CRM can be safely implemented to limit trial suspensions, especially when mean interpatient arrival time is short. CRM was found to be more efficient than algorithm-based methods (44% of good recommendations vs. 38%) but moderately increased the risk of overtreatment. The R6 design included more patients at suboptimal doses. The design with the shortest study duration depended on the number of dose to escalate before the target. CONCLUSION These new methods can reduce the number of skipped patients, but only provide limited gain in terms of ability to select the right dose. New designs are needed.

A new approach to integrate toxicity grade and repeated treatment cycles in the analysis and reporting of phase I dose-finding trials

BACKGROUND Safety assessment beyond the dose-limiting toxicity evaluation period provides relevant information to define the recommended phase II dose (RP2D) of a new treatment. We retrospectively analyzed three phase I trials to illustrate two indicators: per-cycle probability of graded toxicity and cumulative probability of severe toxicity over the treatment period. PATIENTS AND METHODS Data were collected from two continual reassessment method (CRM) trials (T1: aviscumine in solid tumors with short time on treatment; T2: erlotinib + radiotherapy in brainstem gliomas with longer time on treatment) and one 3 + 3 design (T3: liposomal doxorubicin + cyclophosphamide combination in ovarian carcinoma). The probability of severe and moderate or severe toxicity per cycle was estimated at each dose level with mixed proportional odds model. The cumulative probability of severe toxicity was also estimated with the time-to-event CRM. RESULTS Eighty-three patients were included in the three trials; 94, 96 and 72 treatment cycles were administered, in T1, T2 and T3, respectively. Moderate toxicities were at least twice as frequent as severe toxicities. An increased probability of toxicity over time was detected in T3 [P = 0.04; per-cycle probability of severe toxicity: 27% (cycle 1) to 59% (cycle 6) at the RP2D]. At the RP2D, 37% of patients experienced at least one severe toxicity over the first six cycles in T2, and 78% in T3. CONCLUSIONS Dedicated methods can be used to analyze toxicities from all cycles of treatment. They do not delay accrual and should be integrated in the analysis and reporting of phase I dose-finding trials.

1413OZOLEDRONATE DOES NOT REDUCE THE RISK OF TREATMENT FAILURE IN OSTEOSARCOMA: RESULTS OF THE FRENCH MULTICENTRE OS2006 RANDOMISED TRIAL

ABSTRACT Aim: Based on anti-tumour effect of zoledronate in vitro and in experimental models of rat osteosarcoma, we assessed whether zoledronate (Z) in combination with chemotherapy and surgery improved Event-Free Survival (EFS) in children and adult patients (pts) with osteosarcoma. Methods: Experimental treatment consisted of 10 Z-injections (4 pre and 6 postoperative), 4 mg/injection in adults, 0.05 mg/kg/injection in younger pts. Chemotherapy included methotrexate-etoposide-ifosfamide +/-adriamycine-cisplatin in children/adolescents, and doxorubicin-ifosfamide/doxorubicin-ifosfamide-cisplatinum in adults. Balanced randomisation between Z+arm and Z-arm was stratified by center, age, chemotherapy type and risk group (localised resectable disease versus unresectable primary and/or metastases). The study was planned as an open-label superiority trial, with 3 interim analyses (early stopping for efficacy or harm) disclosed to an independent safety monitoring board (DSMB). 470 pts (170 events) were required to achieve an 80%-power to detect a 13%-improvement of 3-year EFS (H1: 55% versus 68%, HR(event)=0.65) with zoledronate (2-sided alpha=0.05). Results: A second interim analysis was performed after 318 pts (82% with a localised and resectable tumour) have been recruited between April 2007 and February 2014: 158 Z- and 160 Z+. No significant increase in toxicity was found in Z+, except expected hypocalcemia grade 2-4 (p Conclusions: With current follow-up, the addition of zoledronate to chemotherapy did not reduce the risk of failure in osteosarcoma patients. Disclosure: All authors have declared no conflicts of interest.

SAE: An R package for early stopping rules in clinical trials

In the case of an unexpected high frequency of serious adverse events (SAE), statistical methods are needed to help in the decision making process as to continuation of accrual to the trial. This paper describes an R package, named SAE that implements a method recently developed by defining stopping rules after each observed SAE. The package function control for excessive toxicity either during the trial at the observation of each SAE (function SAE) or during the planning phase of a clinical trial (function DESIGN). This description and the package documentation are complementary to help the users to apply the method. The main difficulty in the implementation of the method is the choice of a priori parameters. Data from an ongoing clinical trial are presented as an example to improve the understanding and the use of the package.

Investigating the heterogeneity of alkylating agents' efficacy and toxicity between sexes: A systematic review and meta-analysis of randomized trials comparing cyclophosphamide and ifosfamide (MAIAGE study)

A marginal interaction between sex and the type of alkylating agent was observed for event‐free survival in the Euro‐EWING99‐R1 randomized controlled trial (RCT) comparing cyclophosphamide and ifosfamide in Ewing sarcoma. To further evaluate this interaction, we performed an individual patient data meta‐analysis of RCTs assessing cyclophosphamide versus ifosfamide in any type of cancer.

SFCE CO-06 - Allogreffe de cellules souches hématopoïétiques dans les lymphomes anaplasiques à grandes cellules ALK+ de l’enfant

L’allogreffe de cellules souches hematopoietiques (HSCT) est une des options pour le traitement des rechutes des lymphomes anaplasiques a grandes cellules (ALCL) de l’enfant. A ce jour, peu d’etudes ont evalue son efficacite et sa tolerance. 34 patients pediatriques ayant un ALCL ALK+ ont ete allogreffes entre 1993 et 2011. A la greffe, 28 patients (82,4%) etaient en remission complete (RC) et 6 (17.6%) avaient une maladie detectable. Le donneur etait familial chez 12 patients et pheno-identique chez 22 patients. Les conditionnements etaient principalement myelo-ablatifs (n=29). La prise de greffe a ete observee chez 32 patients. Avec un suivi median de 5,4 ans [1,1–2,5], les survies globale et sans evenement a 5 ans sont respectivement de 70%+/−8% and 58%+/−9%. Les incidences cumulees de rechute et de mortalite non liee a la rechute a 5 ans sont de 17% +/− 7% et de 25% +/− 8% respectivement. 4/6 patients ayant rechute ont obtenu une RC prolongee apres reinjection de lymphocytes du donneur (n=1) ou Vinblastine (n=3). Au total, 10 patients sont decedes dont 8 de toxicite. L’HSCT est une therapeutique efficace chez les patients porteurs d’un ALCL ALK+ en rechute. Cependant la toxicite importante pose la question de la place du Brentuximab et des inhibiteurs de ALK dans cette indication.

440TiPTHE HERBY STUDY: A PHASE 2 OPEN-LABEL, RANDOMIZED, MULTICENTER STUDY OF BEVACIZUMAB-BASED THERAPY IN PEDIATRIC PATIENTS WITH NEWLY DIAGNOSED HIGH-GRADE GLIOMA

ABSTRACT Background: Despite recent therapeutic advances, outcomes in pediatric high-grade glioma (HGG) remain poor. A phase 1 study (Glade-Bender et al., J Clin Oncol. 2008) indicated that bevacizumab (BEV) is well tolerated in children with refractory solid tumors and yielded pharmacokinetic data that support further studies of BEV in childhood cancer. Trial design: A total of 120 eligible patients aged 3 to 18 years with newly diagnosed, localized supratentorial or infratentorial cerebellar or peduncular, histologically confirmed World Health Organization grade 3 or 4 HGG (central independent histologic confirmation) will be randomized to 6 weeks of concomitant temozolomide (TMZ) and local radiotherapy, followed by a 4-week TMZ treatment break and 48 weeks of adjuvant TMZ ± BEV every other week. Children aged 6 months to 3 years with recurrent disease are eligible in a young patient cohort; at relapse, these patients will receive TMZ + BEV without radiotherapy. All patients/parents must provide written informed consent per the local institutional review boards. The primary end point is event-free survival, defined as the time to earliest occurrence of tumor progression/recurrence (by central independent assessment per Response Assessment in Neuro-Oncology criteria), secondary malignancy, or death. Secondary end points include overall survival, response rate, safety, feasibility, and tolerability. The usefulness of multimodal MRI will be explored with respect to the diagnosis of pseudoprogression and prognostication of tumor evolution. All randomized patients will be followed for ≥3 years. A futility analysis will be performed after the first 60 randomized patients have been followed for 1 year. The primary analysis will be performed after all patients have been followed for 1 year. Updated analyses will be performed 3 years after the last patient has been randomized. HERBY is being conducted at 87 clinical sites in 15 countries. The first patient was randomized in October 2011. Among 118 patients screened to date, 79 have been randomized, and 1 has been enrolled in the young patient cohort. Completion of the study is expected in 2016. Some content has been presented at ASCO 2012 (abs TPS9596), SNO 2013 (abs PC-007), and ISPN 2013 (abs P109). Disclosure: D. Hargrave: Advisory board: Roche; P. Varlet: Advisory board: Roche Other substantive relationships: Roche; T. Jaspan: Corporate sponsored research: Roche; C. Jones: Advisory board: Genentech Paediatric Oncology Advisory Board Corporate-sponsored research: Roche/Genentech - HERBY trial M. Massimino: Advisory board: Roche, present study; A.A. Azizi: Advisory board: Roche F. Saran: Advisory board: Roche; P. Morgan: Advisory board: Trial Steering Group for F Hoffmann‐La Roche sponsored HERBY study (BO25041) Corporate-sponsored research: Employing institution receives support for its role in the F Hoffmann‐La Roche sponsored HERBY study (BO25041); G. Zahlmann: Stock ownership: Roche employee program Corporate-sponsored research: Roche employee; M. Zheng: Stock ownership: Genentech/Roche; S. Fuerst-Recktenwald: Other substantive relationships: Roche employee C. Berger: Corporate sponsored research: Roche; E. Bouffet: Advisory board: Boehringer Ingelheim. All other authors have declared no conflicts of interest.