Publications by authors named "Andrew D J Pearson"

104 Publications

Pediatric Cancer Data Commons: Federating and Democratizing Data for Childhood Cancer Research.

JCO Clin Cancer Inform 2021 Sep;5:1034-1043

Department of Pediatrics, University of Chicago, Chicago, IL.

The international pediatric oncology community has a long history of research collaboration. In the United States, the 2019 launch of the Children's Cancer Data Initiative puts the focus on developing a rich and robust data ecosystem for pediatric oncology. In this spirit, we present here our experience in constructing the Pediatric Cancer Data Commons (PCDC) to highlight the significance of this effort in fighting pediatric cancer and improving outcomes and to provide essential information to those creating resources in other disease areas. The University of Chicago's PCDC team has worked with the international research community since 2015 to build data commons for children's cancers. We identified six critical features of successful data commons design and implementation: (1) establish the need for a data commons, (2) develop and deploy the technical infrastructure, (3) establish and implement governance, (4) make the data commons platform easy and intuitive for researchers, (5) socialize the data commons and create working knowledge and expertise in the research community, and (6) plan for longevity and sustainability. Data commons are critical to conducting research on large patient cohorts that will ultimately lead to improved outcomes for children with cancer. There is value in connecting high-quality clinical and phenotype data to external sources of data such as genomic, proteomics, and imaging data. Next steps for the PCDC include creating an informed and invested data-sharing culture, developing sustainable methods of data collection and sharing, standardizing genetic biomarker reporting, incorporating radiologic and molecular analysis data, and building models for electronic patient consent. The methods and processes described here can be extended to any clinical area and provide a blueprint for others wishing to develop similar resources.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/CCI.21.00075DOI Listing
September 2021

Second Paediatric Strategy Forum for anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies: ACCELERATE in collaboration with the European Medicines Agency with the participation of the Food and Drug Administration.

Eur J Cancer 2021 Sep 15;157:198-213. Epub 2021 Sep 15.

Hospital for Sick Children, Toronto, Canada.

The first (2017) and sixth (2021) multistakeholder Paediatric Strategy Forums focused on anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies. ALK is an important oncogene and target in several paediatric tumours (anaplastic large cell lymphoma [ALCL], inflammatory myofibroblastic tumour [IMT], neuroblastoma and hemispheric gliomas in infants and young children) with unmet therapeutic needs. ALK tyrosine kinase inhibitors have been demonstrated to be active both in ALK fusion-kinase positive ALCL and IMT. ALK alterations differ, with fusions occurring in ALCL, IMT and gliomas, and activating mutations and amplification in neuroblastoma. While there are many ALK inhibitors in development, the number of children diagnosed with ALK driven malignancies is very small. The objectives of this ALK Forum were to (i) Describe current knowledge of ALK biology in childhood cancers; (ii) Provide an overview of the development of ALK inhibitors for children; (iii) Identify the unmet needs taking into account planned or current ongoing trials; (iv) Conclude how second/third-generation inhibitors could be evaluated and prioritised; (v) Identify lessons learnt from the experience with ALK inhibitors to accelerate the paediatric development of other anti-cancer targeted agents in the new regulatory environments. There has been progress over the last four years, with more trials of ALK inhibitors opened in paediatrics and more regulatory submissions. In January 2021, the US Food and Drug Administration approved crizotinib for the treatment of paediatric and young adult patients with relapsed or refractory ALCL and there are paediatric investigation plans (PIPs) for brigatinib and for crizotinib in ALCL and IMT. In ALCL, the current goal is to investigate the inclusion of ALK inhibitors in front-line therapy with the aim of decreasing toxicity with higher/similar efficacy compared to present first-line therapies. For IMT, the focus is to develop a joint prospective trial with one product in children, adolescents and adults, taking advantage of the common biology across the age spectrum. As approximately 50% of IMTs are ALK-positive, molecular analysis is required to identify patients to be treated with an ALK inhibitor. For neuroblastoma, crizotinib has not shown robust anti-tumour activity. A focused and sequential development of ALK inhibitors with very good central nervous system (CNS) penetration in CNS tumours with ALK fusions should be undertaken. The Forum reinforced the strong need for global academic collaboration, very early involvement of regulators with studies seeking possible registration and early academia-multicompany engagement. Innovations in study design and conduct and the use of 'real-world data' supporting development in these rare sub-groups of patients for whom randomised clinical trials are not feasible are important initiatives. A focused and sequenced development strategy, where one product is evaluated first with other products being assessed sequentially, is applicable for ALK inhibitors and other medicinal products in children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2021.08.022DOI Listing
September 2021

Phase 1 dose-escalation and pharmacokinetic study of regorafenib in paediatric patients with recurrent or refractory solid malignancies.

Eur J Cancer 2021 Aug 20;153:142-152. Epub 2021 Jun 20.

Children & Young People's Unit, Paediatric and Adolescent Oncology Drug Development Team, The Royal Marsden NHS Foundation Trust and Division of Clinical Studies, Institute of Cancer Research, Sutton, UK.

Background: This phase 1 study evaluated safety, pharmacokinetics (PK), maximum tolerated dose (MTD), and antitumour activity of regorafenib in paediatric patients with solid tumours.

Patients And Methods: Patients (aged 6 months to <18 years) with recurrent/refractory solid tumours received oral regorafenib once daily for 3 weeks on/1 week off. The starting dose (60 mg/m) was derived from an adult physiology-based PK model and scaled to children; dose escalation was followed by safety expansion of the MTD cohort. Treatment-emergent adverse events (TEAEs) were evaluated using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Regorafenib PK was evaluated using a population PK model.

Results: Forty-one patients (median age 13 years) received regorafenib (four cohorts: 60-93 mg/m). Five of 23 evaluable patients experienced dose-limiting toxicities (Grade 4 thrombocytopenia, Grade 3 maculopapular rash, pyrexia, hypertension, and exfoliative dermatitis [each n = 1]). The MTD was defined as 82 mg/m. The most common Grade ≥3 drug-related TEAE was thrombocytopenia (10%). The incidence and severity of hypertension, diarrhoea, fatigue, hypothyroidism, and hand-foot skin reaction were lower than reported in adults. Regorafenib exposure increased with dose, with substantial overlap because of moderate-to-high interpatient variability. One patient with rhabdomyosarcoma experienced an unconfirmed partial response; 15 patients had stable disease, five for >16 weeks.

Conclusions: The recommended phase 2 dose of single-agent regorafenib in paediatric patients with solid malignancies is 82 mg/m. Regorafenib demonstrated acceptable tolerability and preliminary antitumour activity, supporting further investigation in paediatric patients.

Clinical Trial Number: NCT02085148.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2021.05.023DOI Listing
August 2021

Randomized Trial of Two Induction Therapy Regimens for High-Risk Neuroblastoma: HR-NBL1.5 International Society of Pediatric Oncology European Neuroblastoma Group Study.

J Clin Oncol 2021 Aug 21;39(23):2552-2563. Epub 2021 Jun 21.

Department of Paediatrics, St Anna Children's Hospital and Children's Cancer Research Institute, Medical University, Vienna, Austria.

Purpose: Induction therapy is a critical component of the therapy of high-risk neuroblastoma. We aimed to assess if the Memorial Sloan Kettering Cancer Center (MSKCC) N5 induction regimen (MSKCC-N5) would improve metastatic complete response (mCR) rate and 3-year event-free survival (EFS) compared with rapid COJEC (rCOJEC; cisplatin [C], vincristine [O], carboplatin [J], etoposide [E], and cyclophosphamide [C]).

Patients And Methods: Patients (age 1-20 years) with stage 4 neuroblastoma or stage 4/4s aged < 1 year with amplification were eligible for random assignment to rCOJEC or MSKCC-N5. Random assignment was stratified according to national group and metastatic sites. Following induction, therapy comprised primary tumor resection, high-dose busulfan and melphalan, radiotherapy to the primary tumor site, and isotretinoin with ch14.18/CHO (dinutuximab beta) antibody with or without interleukin-2 immunotherapy. The primary end points were mCR rate and 3-year EFS.

Results: A total of six hundred thirty patients were randomly assigned to receive rCOJEC (n = 313) or MSKCC-N5 (n = 317). Median age at diagnosis was 3.2 years (range, 1 month to 20 years), and 16 were younger than 1 year of age with amplification. mCR rate following rCOJEC induction (32%, 86/272 evaluable patients) was not significantly different from 35% (99/281) with MSKCC-N5 ( = .368), and 3-year EFS was 44% ± 3% for rCOJEC compared with 47% ± 3% for MSKCC-N5 ( = .527). Three-year overall survival was 60% ± 3% for rCOJEC compared with 65% ± 3% for MSKCC-N5 ( = .379). Toxic death rates with both regimens were 1%. However, nonhematologic CTC grade 3 and 4 toxicities were higher with MSKCC-N5: 68% (193/283) versus 48% (129/268) ( < .001); infection 35% versus 25% ( = .011); stomatitis 25% versus 3% ( < .001); nausea and vomiting 17% versus 7% ( < .001); and diarrhea 7% versus 3% ( = .011).

Conclusion: No difference in outcome was observed between rCOJEC and MSKCC-N5; however, acute toxicity was less with rCOJEC, and therefore rCOJEC is the preferred induction regimen for International Society of Pediatric Oncology European Neuroblastoma Group.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.03144DOI Listing
August 2021

A global approach to long-term follow-up of targeted and immune-based therapy in childhood and adolescence.

Pediatr Blood Cancer 2021 Jul 16;68(7):e29047. Epub 2021 Apr 16.

ACCELERATE Platform LTFU Working Group Co-Chair, ACCELERATE, Brussels, Belgium.

While considerable efforts and progress in our understanding of the long-term toxicities of surgery, radiation and chemotherapy in children with cancer have been made over the last 5 decades, there continues to be a wide gap in our knowledge of the long-term health impact of most novel targeted and immunotherapy agents. To address this gap, ACCELERATE, a multi-stakeholder collaboration of clinical and translational academics, regulators from the EMA and FDA, patient/family advocates and members spanning small biotechnology through to large pharmaceutical companies have initiated the development of an international long-term follow-up data registry to collect this important information prospectively. Providing critical safety data on the long-term use of these approved and investigational therapies in children will support the regulatory requirements and labeling information. It will also provide the necessary insight to help guide physicians and families on the appropriateness of a targeted or immune therapy for their child and inform survivorship planning.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.29047DOI Listing
July 2021

A nomogram of clinical and biologic factors to predict survival in children newly diagnosed with high-risk neuroblastoma: An International Neuroblastoma Risk Group project.

Pediatr Blood Cancer 2021 03 18;68(3):e28794. Epub 2020 Nov 18.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, Massachusetts.

Background: Long-term outcome remains poor for children with high-risk neuroblastoma (five-year overall survival [OS] ∼50%). Our objectives were to (a) identify prognostic biomarkers and apply them in a nomogram to identify the subgroup of ultra-high-risk patients at highest risk of disease progression/death, for whom novel frontline therapy is urgently needed; and (b) validate the nomogram in an independent cohort.

Methods: A total of 1820 high-risk patients (≥18 months old with metastatic neuroblastoma), diagnosed 1998-2015, from the International Neuroblastoma Risk Groups (INRG) Data Commons were analyzed in a retrospective cohort study. Using multivariable Cox regression of OS from diagnosis, a nomogram was created from prognostic biomarkers to predict three-year OS. External validation was performed using the SIOPEN HR-NBL1 trial cohort (n = 521), evidenced by receiver operating characteristic curves.

Results: The nomogram, including MYCN status (P < 0.0001), lactate dehydrogenase (LDH) (P = 0.0007), and presence of bone marrow metastases (P = 0.004), had robust performance and was validated. Applying the nomogram at diagnosis (a) gives prognosis of an individual patient and (b) identifies patients predicted to have poor outcome (three-year OS was 30% ± 5% for patients with a nomogram score of > 82 points; 58% ± 1% for those ≤82 points). Median follow-up time was 5.5 years (range, 0-14.1).

Conclusions: In high-risk neuroblastoma, a novel, publicly available nomogram using prognostic biomarkers (MYCN status, LDH, presence of bone marrow metastases; https://neuroblastoma.shinyapps.io/High-Risk-Neuroblastoma-Nomogram/) has the flexibility to apply a clinically suitable and context-specific cutoff to identify patients at highest risk of death. This will facilitate testing urgently needed new frontline treatment options to improve outcome for these children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.28794DOI Listing
March 2021

Reply to K. Beiske et al.

J Clin Oncol 2020 11 15;38(31):3720-3721. Epub 2020 Sep 15.

Elizabeth Sokol, MD, Department of Pediatrics and Lurie Children's Hospital, Northwestern University, Chicago, IL; Ami V. Desai, MD, MSCE, and Mark A. Applebaum, MD, Department of Pediatrics and Comer Children's Hospital, University of Chicago, Chicago, IL; Dominique Valteau-Couanet, MD, PhD, Institute Gustave Roussy, Villejuif, France; Julie R. Park, MD, Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA; Andrew D.J. Pearson, MD, Paediatric Drug Development, Children and Young People's Unit, Royal Marsden Hospital, London, UK; Gudrun Schleiermacher, MD, PhD, Department of Pediatric, Adolescents, and Young Adults Oncology and INSERM U830, Institut Curie, Paris, France; Meredith S. Irwin, MD, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; Michael Hogarty, MD, Department of Pediatrics, University of Pennsylvania, Philadelphia, PA; Arlene Naranjo, PhD, Department of Biostatistics, Children's Oncology Group Statistics and Data Center, University of Florida, Gainesville, FL; Samuel Volchenboum, MD, PhD, and Susan L. Cohn, MD, Department of Pediatrics and Comer Children's Hospital, University of Chicago, Chicago, IL; and Wendy B. London, PhD, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.20.02147DOI Listing
November 2020

Age Dependency of the Prognostic Impact of Tumor Genomics in Localized Resectable -Nonamplified Neuroblastomas. Report From the SIOPEN Biology Group on the LNESG Trials and a COG Validation Group.

J Clin Oncol 2020 11 9;38(31):3685-3697. Epub 2020 Sep 9.

Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA.

Purpose: For localized, resectable neuroblastoma without amplification, surgery only is recommended even if incomplete. However, it is not known whether the genomic background of these tumors may influence outcome.

Patients And Methods: Diagnostic samples were obtained from 317 tumors, International Neuroblastoma Staging System stages 1/2A/2B, from 3 cohorts: Localized Neuroblastoma European Study Group I/II and Children's Oncology Group. Genomic data were analyzed using multi- and pangenomic techniques and fluorescence in-situ hybridization in 2 age groups (cutoff age, 18 months) and were quality controlled by the International Society of Pediatric Oncology European Neuroblastoma (SIOPEN) Biology Group.

Results: Patients with stage 1 tumors had an excellent outcome (5-year event-free survival [EFS] ± standard deviation [SD], 95% ± 2%; 5-year overall survival [OS], 99% ± 1%). In contrast, patients with stage 2 tumors had a reduced EFS in both age groups (5-year EFS ± SD, 84% ± 3% in patients < 18 months of age and 75% ± 7% in patients ≥ 18 months of age). However, OS was significantly decreased only in the latter group (5-year OS ± SD in < 18months and ≥ 18months, 96% ± 2% and 81% ± 7%, respectively; = .001). In < 18months, relapses occurred independent of segmental chromosome aberrations (SCAs); only 1p loss decreased EFS (5-year EFS ± SD in patients 1p loss and no 1p loss, 62% ± 13% and 87% ± 3%, respectively; = .019) but not OS (5-year OS ± SD, 92% ± 8% and 97% ± 2%, respectively). In patients ≥ 18 months, only SCAs led to relapse and death, with 11q loss as the strongest marker (11q loss and no 11q loss: 5-year EFS ± SD, 48% ± 16% and 85% ± 7%, = .033; 5-year OS ± SD, 46% ± 22% and 92% ± 6%, = .038).

Conclusion: Genomic aberrations of resectable non-amplified stage 2 neuroblastomas have a distinct age-dependent prognostic impact. Chromosome 1p loss is a risk factor for relapse but not for diminished OS in patients < 18 months, SCAs (especially 11q loss) are risk factors for reduced EFS and OS in those > 18months. In older patients with SCA, a randomized trial of postoperative chemotherapy compared with observation alone may be indicated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.18.02132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605396PMC
November 2020

The RACE to accelerate drug development for children with cancer.

Lancet Child Adolesc Health 2020 10 18;4(10):714-716. Epub 2020 Aug 18.

ACCELERATE, Europe; Gustave Roussy Cancer Centre, Villejuif, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2352-4642(20)30247-9DOI Listing
October 2020

Paediatric Strategy Forum for medicinal product development for acute myeloid leukaemia in children and adolescents: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.

Eur J Cancer 2020 09 17;136:116-129. Epub 2020 Jul 17.

FORMA Therapeutics, USA.

Purpose: The current standard-of-care for front-line therapy for acute myeloid leukaemia (AML) results in short-term and long-term toxicity, but still approximately 40% of children relapse. Therefore, there is a major need to accelerate the evaluation of innovative medicines, yet drug development continues to be adult-focused. Furthermore, the large number of competing agents in rare patient populations requires coordinated prioritisation, within the global regulatory framework and cooperative group initiatives.

Methods: The fourth multi-stakeholder Paediatric Strategy Forum focused on AML in children and adolescents.

Results: CD123 is a high priority target and the paediatric development should be accelerated as a proof-of-concept. Efforts must be coordinated, however, as there are a limited number of studies that can be delivered. Studies of FLT3 inhibitors in agreed paediatric investigation plans present challenges to be completed because they require enrolment of a larger number of patients than actually exist. A consensus was developed by industry and academia of optimised clinical trials. For AML with rare mutations that are more frequent in adolescents than in children, adult trials should enrol adolescents and when scientifically justified, efficacy data could be extrapolated. Methodologies and definitions of minimal residual disease need to be standardised internationally and validated as a new response criterion. Industry supported, academic sponsored platform trials could identify products to be further developed. The Leukaemia and Lymphoma Society PedAL/EUpAL initiative has the potential to be a major advance in the field.

Conclusion: These initiatives continue to accelerate drug development for children with AML and ultimately improve clinical outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2020.04.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789799PMC
September 2020

Accelerating drug development for neuroblastoma: Summary of the Second Neuroblastoma Drug Development Strategy forum from Innovative Therapies for Children with Cancer and International Society of Paediatric Oncology Europe Neuroblastoma.

Eur J Cancer 2020 09 9;136:52-68. Epub 2020 Jul 9.

Department of Paediatric Haemaology/Oncology, Our Lady's Children's Hospital, Dublin, Ireland.

Only one class of targeted agents (anti-GD2 antibodies) has been incorporated into front-line therapy for neuroblastoma since the 1980s. The Neuroblastoma New Drug Development Strategy (NDDS) initiative commenced in 2012 to accelerate the development of new drugs for neuroblastoma. Advances have occurred, with eight of nine high-priority targets being evaluated in paediatric trials including anaplastic lymphoma kinase inhibitors being investigated in front-line, but significant challenges remain. This article reports the conclusions of the second NDDS forum, which expanded across the Atlantic to further develop the initiative. Pre-clinical and clinical data for 40 genetic targets and mechanisms of action were prioritised and drugs were identified for early-phase trials. Strategies to develop drugs targeting TERT, telomere maintenance, ATRX, alternative lengthening of telomeres (ALT), BRIP1 and RRM2 as well as direct targeting of MYCN are high priority and should be championed for drug discovery. Promising pre-clinical data suggest that targeting of ALT by ATM or PARP inhibition may be potential strategies. Drugs targeting CDK2/9, CDK7, ATR and telomere maintenance should enter paediatric clinical development rapidly. Optimising the response to anti-GD2 by combinations with chemotherapy, targeted agents and other immunological targets are crucial. Delivering this strategy in the face of small patient cohorts, genomically defined subpopulations and a large number of permutations of combination trials, demands even greater international collaboration. In conclusion, the NDDS provides an internationally agreed, biologically driven selection of prioritised genetic targets and drugs. Improvements in the strategy for conducting trials in neuroblastoma will accelerate bringing these new drugs more rapidly to front-line therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2020.05.010DOI Listing
September 2020

Influence of Surgical Excision on the Survival of Patients With Stage 4 High-Risk Neuroblastoma: A Report From the HR-NBL1/SIOPEN Study.

J Clin Oncol 2020 09 8;38(25):2902-2915. Epub 2020 Jul 8.

Paediatric Haematology/Oncology, Our Lady's Children's Hospital, Crumlin, Dublin, Republic of Ireland.

Purpose: To evaluate the impact of surgeon-assessed extent of primary tumor resection on local progression and survival in patients in the International Society of Pediatric Oncology Europe Neuroblastoma Group High-Risk Neuroblastoma 1 trial.

Patients And Methods: Patients recruited between 2002 and 2015 with stage 4 disease > 1 year or stage 4/4S with amplification < 1 year who had completed induction without progression, achieved response criteria for high-dose therapy (HDT), and had no resection before induction were included. Data were collected on the extent of primary tumor excision, severe operative complications, and outcome.

Results: A total of 1,531 patients were included (median observation time, 6.1 years). Surgeon-assessed extent of resection included complete macroscopic excision (CME) in 1,172 patients (77%) and incomplete macroscopic resection (IME) in 359 (23%). Surgical mortality was 7 (0.46%) of 1,531. Severe operative complications occurred in 142 patients (9.7%), and nephrectomy was performed in 124 (8.8%). Five-year event-free survival (EFS) ± SE (0.40 ± 0.01) and overall survival (OS; 0.45 ± 0.02) were significantly higher with CME compared with IME (5-year EFS, 0.33 ± 0.03; 5-year OS, 0.37 ± 0.03; < .001 and = .004). The cumulative incidence of local progression (CILP) was significantly lower after CME (0.17 ± 0.01) compared with IME (0.30 ± 0.02; < .001). With immunotherapy, outcomes were still superior with CME versus IME (5-year EFS, 0.47 ± 0.02 0.39 ± 0.04; = .038); CILP was 0.14 ± 0.01 after CME and 0.27 ± 0.03 after IME ( < .002). A hazard ratio of 1.3 for EFS associated with IME compared with CME was observed before and after the introduction of immunotherapy ( = .030 and = .038).

Conclusion: In patients with stage 4 high-risk neuroblastoma who have responded to induction therapy, CME of the primary tumor is associated with improved survival and local control after HDT, local radiotherapy (21 Gy), and immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.19.03117DOI Listing
September 2020

Noninvasive MRI Native T Mapping Detects Response to -targeted Therapies in the Th- Model of Neuroblastoma.

Cancer Res 2020 08 28;80(16):3424-3435. Epub 2020 Jun 28.

Division of Radiotherapy and Imaging, The Institute of Cancer Research, London and The Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom.

Noninvasive early indicators of treatment response are crucial to the successful delivery of precision medicine in children with cancer. Neuroblastoma is a common solid tumor of young children that arises from anomalies in neural crest development. Therapeutic approaches aiming to destabilize protein, such as small-molecule inhibitors of Aurora A and mTOR, are currently being evaluated in early phase clinical trials in children with high-risk -driven disease, with limited ability to evaluate conventional pharmacodynamic biomarkers of response. T mapping is an MRI scan that measures the proton spin-lattice relaxation time T. Using a multiparametric MRI-pathologic cross-correlative approach and computational pathology methodologies including a machine learning-based algorithm for the automatic detection and classification of neuroblasts, we show here that T mapping is sensitive to the rich histopathologic heterogeneity of neuroblastoma in the Th- transgenic model. Regions with high native T corresponded to regions dense in proliferative undifferentiated neuroblasts, whereas regions characterized by low T were rich in apoptotic or differentiating neuroblasts. Reductions in tumor-native T represented a sensitive biomarker of response to treatment-induced apoptosis with two -targeted small-molecule inhibitors, Aurora A kinase inhibitor alisertib (MLN8237) and mTOR inhibitor vistusertib (AZD2014). Overall, we demonstrate the potential of T mapping, a scan readily available on most clinical MRI scanners, to assess response to therapy and guide clinical trials for children with neuroblastoma. The study reinforces the potential role of MRI-based functional imaging in delivering precision medicine to children with neuroblastoma. SIGNIFICANCE: This study shows that MRI-based functional imaging can detect apoptotic responses to -targeted small-molecule inhibitors in a genetically engineered murine model of -driven neuroblastoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-20-0133DOI Listing
August 2020

The prognostic strength of serum LDH and serum ferritin in children with neuroblastoma: A report from the International Neuroblastoma Risk Group (INRG) project.

Pediatr Blood Cancer 2020 08 30;67(8):e28359. Epub 2020 May 30.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, Massachusetts.

Purpose: Age, MYCN status, stage, and histology have been used as neuroblastoma (NB) risk factors for decades. Serum lactate dehydrogenase (LDH) and serum ferritin are reproducible, easily obtained, and prognostic, though never used in risk stratification, except one German trial. We analyzed the prognostic strength of LDH and ferritin, overall, within high-risk NB, and by era, using the International Neuroblastoma Risk Group Data Commons.

Patients And Methods: Children with NB (1990-2016) were categorized into LDH (n = 8867) and ferritin (n = 8575) risk groups using EFS. Cox models compared the prognostic strength of LDH and ferritin to age, MYCN status, and INSS stage.

Results: Higher LDH conferred worse EFS, overall (5-year EFS) (100-899 IU/L: 76 ± 0.6%; 0-99 or 900-1399 IU/L: 60 ± 1.2%; ≥1400 IU/L: 36 ± 1.2%; P < .0001), and in high-risk NB post-2009 (3-year EFS) (117-381 IU/L: 67 ± 8.9%; 382-1334 IU/L: 58 ± 4.4%; 0-116 or ≥1335 IU/L: 46 ± 3.9%; P = .003). Higher ferritin conferred worse EFS, overall (5-year EFS) (1-29 ng/mL: 87 ± 0.9%; 0 or 30-89 ng/mL: 74 ± 0.8%; ≥90 ng/mL: 48 ± 0.9%; P < .0001), and in high-risk NB post-2009 (3-year EFS) (1-53 ng/mL: 71 ± 9.3%; 0 or 54-354 ng/mL: 55 ± 4.7%; ≥355 ng/mL: 34 ± 6.1%; P = .0008). In multivariable analyses adjusting for age, MYCN, and stage, LDH and ferritin maintained independent prognostic ability (P < .0001; adjusted HRs (95% CI): 1.7 (1.5-1.9), 2.3 (2.0-2.7), respectively).

Conclusions: LDH and ferritin are strongly prognostic in NB, overall and within high-risk NB patients treated post-2009 with modern therapy. LDH and ferritin show promise for (a) identifying ultra-high-risk; (b) refining risk stratification; and (c) clinical utility in low-/middle-income countries. Routine collection of LDH and ferritin should be reinitiated for evolving NB risk stratification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.28359DOI Listing
August 2020

Age, Diagnostic Category, Tumor Grade, and Mitosis-Karyorrhexis Index Are Independently Prognostic in Neuroblastoma: An INRG Project.

J Clin Oncol 2020 06 21;38(17):1906-1918. Epub 2020 Apr 21.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA.

Purpose: The Children's Oncology Group (COG) stratifies the treatment of patients with neuroblastoma on the basis of a combination of biomarkers that include age and tumor histology classified by age-linked International Neuroblastoma Pathology Classification (INPC) criteria. By definition, this leads to a duplication of the prognostic contribution of age. The individual histologic features underlying the INPC have prognostic strength and are incorporated in the International Neuroblastoma Risk Group classification schema. Here, we analyzed data in the International Neuroblastoma Risk Group Data Commons to validate the prognostic strength of the underlying INPC criteria and to determine whether a risk classification devoid of the confounding of age and INPC criteria will identify new prognostic subgroups.

Patients And Methods: Event-free survival of patients diagnosed between 1990 and 2002 (cohort 1; n = 10,104) and between 2003 and 2016 (cohort 2; n = 8,761) was analyzed. Recursive partitioning with univariate Cox models of event-free survival ("survival tree regression") was performed using (1) individual INPC criteria (age at diagnosis, histologic category, mitosis-karyorrhexis index (MKI), grade of differentiation) and (2) factors in (1) plus other COG-risk biomarkers (International Neuroblastoma Staging System [INSS] stage, status, ploidy).

Results: The independent prognostic ability of age, histologic category, MKI, and grade were validated. Four histologic prognostic groups were identified (< 18 months with low high MKI, and ≥ 18 months with differentiating undifferentiated/poorly differentiating tumors). Compared with survival trees generated with established COG risk criteria, an additional prognostic subgroup was identified and validated when individual histologic features were analyzed in lieu of INPC.

Conclusion: Replacing INPC with individual histologic features in the COG risk classification will eliminate confounding, facilitate international harmonization of risk classification, and provide a schema for more precise prognostication and refined therapeutic approaches.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.19.03285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280049PMC
June 2020

Quizartinib-resistant FLT3-ITD acute myeloid leukemia cells are sensitive to the FLT3-Aurora kinase inhibitor CCT241736.

Blood Adv 2020 04;4(7):1478-1491

Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, Sutton, United Kingdom.

Internal tandem duplication of FLT3 (FLT3-ITD) is one of the most common somatic mutations in acute myeloid leukemia (AML); it causes constitutive activation of FLT3 kinase and is associated with high relapse rates and poor survival. Small-molecule inhibition of FLT3 represents an attractive therapeutic strategy for this subtype of AML, although resistance from secondary FLT3 tyrosine kinase domain (FLT3-TKD) mutations is an emerging clinical problem. CCT241736 is an orally bioavailable, selective, and potent dual inhibitor of FLT3 and Aurora kinases. FLT3-ITD+ cells with secondary FLT3-TKD mutations have high in vitro relative resistance to the FLT3 inhibitors quizartinib and sorafenib, but not to CCT241736. The mechanism of action of CCT241736 results in significant in vivo efficacy, with inhibition of tumor growth observed in efficacy studies in FLT3-ITD and FLT3-ITD-TKD human tumor xenograft models. The efficacy of CCT241736 was also confirmed in primary samples from AML patients, including those with quizartinib-resistant disease, which induces apoptosis through inhibition of both FLT3 and Aurora kinases. The unique combination of CCT241736 properties based on robust potency, dual selectivity, and significant in vivo activity indicate that CCT241736 is a bona fide clinical drug candidate for FLT3-ITD and TKD AML patients with resistance to current drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2019000986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160287PMC
April 2020

Investigation of the Role of Dinutuximab Beta-Based Immunotherapy in the SIOPEN High-Risk Neuroblastoma 1 Trial (HR-NBL1).

Cancers (Basel) 2020 Jan 28;12(2). Epub 2020 Jan 28.

Department of Pediatric Hematology and Oncology, University Medicine Greifswald, 17489 Greifswald, Germany.

To explore the effects of immunotherapy in the International Society of Paediatric Oncology Europe Neuroblastoma Group SIOPEN high-risk neuroblastoma 1 trial (HR-NBL1 trial), two cohorts were studied: one prior to and one after the introduction of dinutuximab beta. All patients received standard induction and high-dose therapy (HDT) with autologous stem cell rescue (ASCR); the local control comprised surgery and radiotherapy to the primary tumour site, followed by isotretinoin. A landmark timepoint of 109 days, resulting from the median time between ASCR and initiation of immunotherapy, was used to define patients' eligibility in the pre-immunotherapy analysis cohort. Median follow-up was 5.8 years (inter-quartile range (IQR): 4.2-8.2 years) for 844 eligible patients balanced for risk factors, such as age, sex, stage 4, MYCN amplification and response prior to HDT. The five-year event-free and overall survival (95% confidence interval (CI) of 466 patients not receiving immunotherapy was 42% (38-47%) and 50% (46-55%) but was 57% (51-62%) and 64% (59-69%) for 378 patients receiving immunotherapy ( < 0.001). A multivariate analysis identified absence of immunotherapy (p = 0.0002, hazard ratio (HR) 1.573); type of HDT ( = 0.0029, HR 1.431); less than complete response prior to maintenance therapy ( = 0.0043, HR 1.494) and >1 metastatic compartment at diagnosis ( < 0.001, HR 2.665) as risk factors for relapse or progression. Results suggest an important role for dinutuximab beta-based immunotherapy within the treatment concepts applied in HR-NBL1/SIOPEN.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12020309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072500PMC
January 2020

ACCELERATE and European Medicines Agency Paediatric Strategy Forum for medicinal product development of checkpoint inhibitors for use in combination therapy in paediatric patients.

Eur J Cancer 2020 03 24;127:52-66. Epub 2020 Jan 24.

BMS, USA.

The third multistakeholder Paediatric Strategy Forum organised by ACCELERATE and the European Medicines Agency focused on immune checkpoint inhibitors for use in combination therapy in children and adolescents. As immune checkpoint inhibitors, both as monotherapy and in combinations have shown impressive success in some adult malignancies and early phase trials in children of single agent checkpoint inhibitors have now been completed, it seemed an appropriate time to consider opportunities for paediatric studies of checkpoint inhibitors used in combination. Among paediatric patients, early clinical studies of checkpoint inhibitors used as monotherapy have demonstrated a high rate of activity, including complete responses, in Hodgkin lymphoma and hypermutant paediatric tumours. Activity has been very limited, however, in more common malignancies of childhood and adolescence. Furthermore, apart from tumour mutational burden, no other predictive biomarker for monotherapy activity in paediatric tumours has been identified. Based on these observations, there is collective agreement that there is no scientific rationale for children to be enrolled in new monotherapy trials of additional checkpoint inhibitors with the same mechanism of action of agents already studied (e.g. anti-PD1, anti-PDL1 anti-CTLA-4) unless additional scientific knowledge supporting a different approach becomes available. This shared perspective, based on scientific evidence and supported by paediatric oncology cooperative groups, should inform companies on whether a paediatric development plan is justified. This could then be proposed to regulators through the available regulatory tools. Generally, an academic-industry consensus on the scientific merits of a proposal before submission of a paediatric investigational plan would be of great benefit to determine which studies have the highest probability of generating new insights. There is already a rationale for the evaluation of combinations of checkpoint inhibitors with other agents in paediatric Hodgkin lymphoma and hypermutated tumours in view of the activity shown as single agents. In paediatric tumours where no single agent activity has been observed in multiple clinical trials of anti-PD1, anti-PDL1 and anti-CTLA-4 agents as monotherapy, combinations of checkpoint inhibitors with other treatment modalities should be explored when a scientific rationale indicates that they could be efficacious in paediatric cancers and not because these combinations are being evaluated in adults. Immunotherapy in the form of engineered proteins (e.g. monoclonal antibodies and T cell engaging agents) and cellular products (e.g. CAR T cells) has great therapeutic potential for benefit in paediatric cancer. The major challenge for developing checkpoint inhibitors for paediatric cancers is the lack of neoantigens (based on mutations) and corresponding antigen-specific T cells. Progress critically depends on understanding the immune macroenvironment and microenvironment and the ability of the adaptive immune system to recognise paediatric cancers in the absence of high neoantigen burden. Future clinical studies of checkpoint inhibitors in children need to build upon strong biological hypotheses that take into account the distinctive immunobiology of childhood cancers in comparison to that of checkpoint inhibitor responsive adult cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2019.12.029DOI Listing
March 2020

A Phase I and Pharmacokinetic Study of Oral Dabrafenib in Children and Adolescent Patients with Recurrent or Refractory V600 Mutation-Positive Solid Tumors.

Clin Cancer Res 2019 12 10;25(24):7294-7302. Epub 2019 Sep 10.

The Hospital for Sick Children, University of Toronto, Department of Pediatrics, Toronto, Ontario.

Purpose: The 2-part, phase I/IIa, open-label study (NCT01677741) sought to determine the safety, tolerability, pharmacokinetics, and preliminary activity of dabrafenib in pediatric patients with advanced V600-mutated cancers.

Patients And Methods: This phase I dose-finding part treated patients ages 1 to <18 years with V600 mutation-positive tumors with oral dabrafenib 3 to 5.25 mg/kg/day to determine the RP2D based on safety and drug exposure target.

Results: Between May 2013 and November 2014, 27 patients [12 male; median age, 9 years (range, 1-17 years)] with V600-mutant solid tumors recurrent/refractory to treatment (low- or high-grade glioma, Langerhans cell histiocytosis, neuroblastoma, or thyroid cancer) were enrolled. The median treatment duration was 75.6 weeks (range, 5.6-148.7 weeks), with 63% treated for >52 weeks and 52% undergoing treatment at data cutoff date. The most common grade 3/4 adverse events suspected to be related to study drug were maculopapular rash and arthralgia (2 patients each). No dose-limiting toxicities were observed. Pharmacokinetic analyses showed a dose-dependent increase in AUC and achievement of adult exposure levels at the recommended phase II doses of 5.25 mg/kg/day (age <12 years) and 4.5 mg/kg/day (age ≥12 years) divided into 2 equal doses daily, not exceeding 300 mg daily.

Conclusions: In this first clinical trial in pediatric patients with pretreated V600-mutant tumors, dabrafenib was well tolerated while achieving target exposure levels; the average treatment duration was >1 year with many patients still on treatment. The phase II component is also closed and will be reported separately.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-17-3572DOI Listing
December 2019

MRI Imaging of the Hemodynamic Vasculature of Neuroblastoma Predicts Response to Antiangiogenic Treatment.

Cancer Res 2019 06 15;79(11):2978-2991. Epub 2019 Mar 15.

Division of Radiotherapy and Imaging, The Institute of Cancer Research, London and The Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom.

Childhood neuroblastoma is a hypervascular tumor of neural origin, for which antiangiogenic drugs are currently being evaluated; however, predictive biomarkers of treatment response, crucial for successful delivery of precision therapeutics, are lacking. We describe an MRI-pathologic cross-correlative approach using intrinsic susceptibility (IS) and susceptibility contrast (SC) MRI to noninvasively map the vascular phenotype in neuroblastoma Th-MYCN transgenic mice treated with the vascular endothelial growth factor receptor inhibitor cediranib. We showed that the transverse MRI relaxation rate * (second) and fractional blood volume (BV, %) were sensitive imaging biomarkers of hemorrhage and vascular density, respectively, and were also predictive biomarkers of response to cediranib. Comparison with MRI and pathology from patients with MYCN-amplified neuroblastoma confirmed the high degree to which the Th-MYCN model vascular phenotype recapitulated that of the clinical phenotype, thereby supporting further evaluation of IS- and SC-MRI in the clinic. This study reinforces the potential role of functional MRI in delivering precision medicine to children with neuroblastoma. SIGNIFICANCE: This study shows that functional MRI predicts response to vascular-targeted therapy in a genetically engineered murine model of neuroblastoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-18-3412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558276PMC
June 2019

ACCELERATE and European Medicine Agency Paediatric Strategy Forum for medicinal product development for mature B-cell malignancies in children.

Eur J Cancer 2019 03 14;110:74-85. Epub 2019 Feb 14.

Janssen Research & Development, NJ, USA.

Paediatric Strategy Forums have been created by the multistakeholder organisation, ACCELERATE, and the European Medicines Agency to facilitate dialogue between all relevant stakeholders and suggest strategies in critical areas of paediatric oncology drug development. As there are many medicines being developed for B-cell malignancies in adults but comparatively few in children with these malignancies, a Paediatric Strategy Forum was held to discuss the best approach to develop these products for children. It was concluded that as current frontline therapy is highly successful, despite associated acute toxicity, de-escalation of this or substitution of presently used drugs with new medicines can only be undertaken when there is an effective salvage regimen, which is currently not available. Therefore priority should be given to developing treatment for patients with relapsed and refractory mature B-cell lymphomas. The consensus of the clinicians attending the meeting was that CAR T-cells, T-cell engagers and antibody drug conjugates (excluding those with a vinca alkaloid-like drug) presently have the greatest probability of providing benefit in relapse in view of their mechanism of action. However, as producing autologous CAR T-cells currently takes at least 4 weeks, they are not products which could be quickly employed initially at relapse in rapidly progressing mature B-cell malignancies but only for the consolidation phase of the treatment. Global, industry-supported, academic-sponsored studies testing compounds from different pharmaceutical companies simultaneously should be considered in rare populations, and it was proposed that an international working group be formed to develop an overarching clinical trials strategy for these disease groups. Future Forums are planned for other relevant paediatric oncologic diseases with a high unmet medical need and relevant molecular targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2019.01.013DOI Listing
March 2019

Long-term analysis of children with metastatic neuroblastoma treated in the ENSG5 randomised clinical trial.

Pediatr Blood Cancer 2019 04 5;66(4):e27565. Epub 2018 Dec 5.

Children and Young People's Unit, The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom (retired).

Background: The European Neuroblastoma Study Group 5 (ENSG5) trial showed that time-intensive "rapid" induction chemotherapy (COJEC) was superior to "standard" 3-weekly chemotherapy for children with high-risk metastatic neuroblastoma. Long-term outcomes of the ENSG5 trial were analysed.

Procedure: Patients with metastatic neuroblastoma aged ≥12 months were randomly assigned to "standard" or "rapid" induction, receiving the same chemotherapy drugs and doses. Event-free survival (EFS) and overall survival (OS) were analysed and prognostic factors evaluated. Amongst patients surviving >5 years, a population of children with persistent metastatic disease after the end of treatment was identified and described.

Results: Ten-year EFS was 18.2% (95% confidence interval: 12.2-25.2) for the "standard" arm and 26.8% (19.5-34.7) for the "rapid" arm (hazard ratio [HR] 0.85, P = 0.28). Ten-year OS for the "standard" arm was 19.7% (13.4-26.8) and 28.3% (20.8-36.2) for the "rapid arm" (HR 0.83, P = 0.19). There was a trend for worse EFS and OS for patients having MYCN amplification (HR 1.37 and 1.40, respectively) and those with partial and mixed response to induction (HR 1.69 and 1.75 for EFS and 1.66 and 2.00 for OS, respectively). Among 69 patients who survived >5 years, six had persistent metastatic disease after the end of treatment.

Conclusion: The benefit of the "rapid" induction regimen seems to be maintained in the long term, although the small number of survivors could justify the lack of statistical significance. MYCN amplification and poor metastatic response to induction could be associated with worse outcomes. A small group of patients with persistent metastatic disease that survived long term has been described.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.27565DOI Listing
April 2019

Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): a multicentre, randomised, phase 3 trial.

Lancet Oncol 2018 12 12;19(12):1617-1629. Epub 2018 Nov 12.

Paediatric Haematology-Oncology Department, University Medicine Greifswald, Greifswald, Germany.

Background: Immunotherapy with the chimeric anti-GD2 monoclonal antibody dinutuximab, combined with alternating granulocyte-macrophage colony-stimulating factor and intravenous interleukin-2 (IL-2), improves survival in patients with high-risk neuroblastoma. We aimed to assess event-free survival after treatment with ch14.18/CHO (dinutuximab beta) and subcutaneous IL-2, compared with dinutuximab beta alone in children and young people with high-risk neuroblastoma.

Methods: We did an international, open-label, phase 3, randomised, controlled trial in patients with high-risk neuroblastoma at 104 institutions in 12 countries. Eligible patients were aged 1-20 years and had MYCN-amplified neuroblastoma with stages 2, 3, or 4S, or stage 4 neuroblastoma of any MYCN status, according to the International Neuroblastoma Staging System. Patients were eligible if they had been enrolled at diagnosis in the HR-NBL1/SIOPEN trial, had completed the multidrug induction regimen (cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide, with or without topotecan, vincristine, and doxorubicin), had achieved a disease response that fulfilled prespecified criteria, had received high-dose therapy (busulfan and melphalan or carboplatin, etoposide, and melphalan) and had received radiotherapy to the primary tumour site. In this component of the trial, patients were randomly assigned (1:1) to receive dinutuximab beta (20 mg/m per day as an 8 h infusion for 5 consecutive days) or dinutuximab beta plus subcutaneous IL-2 (6 × 10 IU/m per day on days 1-5 and days 8-12 of each cycle) with the minimisation method to balance randomisation for national groups and type of high-dose therapy. All participants received oral isotretinoin (160 mg/m per day for 2 weeks) before the first immunotherapy cycle and after each immunotherapy cycle, for six cycles. The primary endpoint was 3-year event-free survival, analysed by intention to treat. This trial was registered with ClinicalTrials.gov, number NCT01704716, and EudraCT, number 2006-001489-17, and recruitment to this randomisation is closed.

Findings: Between Oct 22, 2009, and Aug 12, 2013, 422 patients were eligible to participate in the immunotherapy randomisation, of whom 406 (96%) were randomly assigned to a treatment group (n=200 to dinutuximab beta and n=206 to dinutuximab beta with subcutaneous IL-2). Median follow-up was 4·7 years (IQR 3·9-5·3). Because of toxicity, 117 (62%) of 188 patients assigned to dinutuximab beta and subcutaneous IL-2 received their allocated treatment, by contrast with 160 (87%) of 183 patients who received dinutuximab beta alone (p<0·0001). 3-year event-free survival was 56% (95% CI 49-63) with dinutuximab beta (83 patients had an event) and 60% (53-66) with dinutuximab beta and subcutaneous IL-2 (80 patients had an event; p=0·76). Four patients died of toxicity (n=2 in each group); one patient in each group while receiving immunotherapy (n=1 congestive heart failure and pulmonary hypertension due to capillary leak syndrome; n=1 infection-related acute respiratory distress syndrome), and one patient in each group after five cycles of immunotherapy (n=1 fungal infection and multi-organ failure; n=1 pulmonary fibrosis). The most common grade 3-4 adverse events were hypersensitivity reactions (19 [10%] of 185 patients in the dinutuximab beta group vs 39 [20%] of 191 patients in the dinutuximab plus subcutaneous IL-2 group), capillary leak (five [4%] of 119 vs 19 [15%] of 125), fever (25 [14%] of 185 vs 76 [40%] of 190), infection (47 [25%] of 185 vs 64 [33%] of 191), immunotherapy-related pain (19 [16%] of 122 vs 32 [26%] of 124), and impaired general condition (30 [16%] of 185 vs 78 [41%] of 192).

Interpretation: There is no evidence that addition of subcutaneous IL-2 to immunotherapy with dinutuximab beta, given as an 8 h infusion, improved outcomes in patients with high-risk neuroblastoma who had responded to standard induction and consolidation treatment. Subcutaneous IL-2 with dinutuximab beta was associated with greater toxicity than dinutuximab beta alone. Dinutuximab beta and isotretinoin without subcutaneous IL-2 should thus be considered the standard of care until results of ongoing randomised trials using a modified schedule of dinutuximab beta and subcutaneous IL-2 are available.

Funding: European Commission 5th Frame Work Grant, St. Anna Kinderkrebsforschung, Fondation ARC pour la recherche sur le Cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(18)30578-3DOI Listing
December 2018

Outcome of children and adolescents with central nervous system tumors in phase I trials.

J Neurooncol 2018 Mar 13;137(1):83-92. Epub 2017 Dec 13.

Pediatric and Adolescent Drug Development, Children and Young People's Unit, The Royal Marsden NHS Foundation Trust - Paediatric Offices, Downs Road, Sutton, SM2 5PT, UK.

Central nervous system (CNS) tumors are a leading cause of death in pediatric oncology. New drugs are desperately needed to improve survival. We evaluated the outcome of children and adolescents with CNS tumors participating in phase I trials within the Innovative Therapies for Children with Cancer (ITCC) consortium. Patients with solid tumors aged < 18 years at enrollment in their first dose-finding trial between 2000 and 2014 at eight ITCC centers were included retrospectively. Survival was evaluated using univariate/multivariate analyses. Overall, 114 patients were included (109 evaluable for efficacy). Median age was 10.2 years (range 1.0-17.9). Main diagnoses included: medulloblastoma/primitive neuroectodermal tumors (32.5%) and high-grade gliomas (23.7%). Complete/partial responses (CR/PR) were reported in 7.3% patients and stable disease (SD) in 23.9%. Performance status of 90-100%, school/work attendance, normal ALT/AST and CR/PR/SD correlated with better overall survival (OS) in the univariate analysis. No variables assessable at screening/enrollment were associated with OS in the multivariate analysis. Five patients (4.5%) were discontinued from study due to toxicity. No toxic deaths occurred. Median OS was 11.9 months with CR/PR, 14.5 months with SD and 3.7 months with progressive disease (p < 0.001). The enrollment of children and adolescents with CNS tumors in phase I trials is feasible, safe and offers potential benefit for the patients. Sustained disease stabilization has a promising role as a marker of anti-tumor activity in children with CNS tumors participating in phase I trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11060-017-2698-zDOI Listing
March 2018

Revisiting the definition of dose-limiting toxicities in paediatric oncology phase I clinical trials: An analysis from the Innovative Therapies for Children with Cancer Consortium.

Eur J Cancer 2017 11 19;86:275-284. Epub 2017 Oct 19.

Gustave Roussy, Biostatistics and Epidemiology Unit, Villejuif, France; INSERM U1018, CESP, Univ. Paris-Sud, Univ. Paris-Saclay, Villejuif, France. Electronic address:

Background: Dose-escalation trials aim to identify the maximum tolerated dose and, importantly, the recommended phase II dose (RP2D) and rely on the occurrence of dose-limiting toxicities (DLTs) during the first treatment cycle. Molecularly targeted agents (MTAs) often follow continuous and prolonged administrations, displaying a distinct toxicity profile compared to conventional chemotherapeutics, and classical DLT criteria might not be appropriate to evaluate MTAs' toxicity. We investigated this issue in children.

Methods: The Innovative Therapies for Children with Cancer Consortium (ITCC) phase I trials of novel anticancer agents between 2004 and 2015 were analysed. Data from investigational product, trial design, items defining DLT/RP2D were extracted. A survey on dose-escalation process, DLTs and RP2D definition was conducted among the ITCC clinical trials committee members.

Results: Thirteen phase I trials with 15 dose-escalation cohorts were analysed. They explored 11 MTAs and 2 novel cytotoxics; 12 evaluated DLT during cycle 1. Definition of DLT was heterogeneous: Grade III-IV haematologic toxicities that were transient or asymptomatic and grade III-IV non-haematological toxicities manageable with adequate supportive care were often excluded, whereas some included dose intensity or grade II toxicities into DLT. None of the studies considered delayed toxicity into the RP2D definition.

Conclusion: DLTs should be homogeneously defined across trials, limiting the number of exceptions due to specific toxicities. Dose escalation should still be based on safety data from cycle 1, but delayed and overall toxicities, pharmacokinetic parameters and pharmacodynamic data should be considered to refine the final RP2D. The evaluation of long-term toxicity in the developing child cannot be adequately addressed in early trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2017.09.015DOI Listing
November 2017

In vitro nuclear magnetic resonance spectroscopy metabolic biomarkers for the combination of temozolomide with PI3K inhibition in paediatric glioblastoma cells.

PLoS One 2017 13;12(7):e0180263. Epub 2017 Jul 13.

Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom.

Recent experimental data showed that the PI3K pathway contributes to resistance to temozolomide (TMZ) in paediatric glioblastoma and that this effect is reversed by combination treatment of TMZ with a PI3K inhibitor. Our aim is to assess whether this combination results in metabolic changes that are detectable by nuclear magnetic resonance (NMR) spectroscopy, potentially providing metabolic biomarkers for PI3K inhibition and TMZ combination treatment. Using two genetically distinct paediatric glioblastoma cell lines, SF188 and KNS42, in vitro 1H-NMR analysis following treatment with the dual pan-Class I PI3K/mTOR inhibitor PI-103 resulted in a decrease in lactate and phosphocholine (PC) levels (P<0.02) relative to control. In contrast, treatment with TMZ caused an increase in glycerolphosphocholine (GPC) levels (P≤0.05). Combination of PI-103 with TMZ showed metabolic effects of both agents including a decrease in the levels of lactate and PC (P<0.02) while an increase in GPC (P<0.05). We also report a decrease in the protein expression levels of HK2, LDHA and CHKA providing likely mechanisms for the depletion of lactate and PC, respectively. Our results show that our in vitro NMR-detected changes in lactate and choline metabolites may have potential as non-invasive biomarkers for monitoring response to combination of PI3K/mTOR inhibitors with TMZ during clinical trials in children with glioblastoma, subject to further in vivo validation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180263PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509135PMC
September 2017

From class waivers to precision medicine in paediatric oncology.

Lancet Oncol 2017 07;18(7):e394-e404

Department of Clinical Research, Gustave Roussy, Paris-Sud University, Paris, France.

New drugs are crucially needed for children with cancer. The European Paediatric Regulation facilitates paediatric class waivers for drugs developed for diseases only occurring in adults. In this Review, we retrospectively searched oncology drugs that were class waivered between June, 2012, and June, 2015. 147 oncology class waivers were confirmed for 89 drugs. Mechanisms of action were then assessed as potential paediatric therapeutic targets by both a literature search and an expert review. 48 (54%) of the 89 class-waivered drugs had a mechanisms of action warranting paediatric development. Two (2%) class-waivered drugs were considered not relevant and 16 (18%) required further data. In light of these results, we propose five initiatives: an aggregated database of paediatric biological tumour drug targets; molecular profiling of all paediatric tumours at diagnosis and relapse; a joint academic-pharmaceutical industry preclinical platform to help analyse the activity of new drugs (Innovative Therapy for Children with Cancer Paediatric Preclinical Proof-of-Concept Platform); paediatric strategy forums; and the suppression of article 11b of the European Paediatric Regulation, which allows product-specific waivers on the grounds that the associated condition does not occur in children. These initiatives and a mechanism of action-based approach to drug development will accelerate the delivery of new therapeutic drugs for front-line therapy for those children who have unmet medical needs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(17)30442-4DOI Listing
July 2017

Early phase clinical trials of anticancer agents in children and adolescents - an ITCC perspective.

Nat Rev Clin Oncol 2017 Aug 16;14(8):497-507. Epub 2017 May 16.

Department of Clinical Research, Gustave Roussy, Paris-Sud University, Paris, France.

In the past decade, the landscape of drug development in oncology has evolved dramatically; however, this paradigm shift remains to be adopted in early phase clinical trial designs for studies of molecularly targeted agents and immunotherapeutic agents in paediatric malignancies. In drug development, prioritization of drugs on the basis of knowledge of tumour biology, molecular 'drivers' of disease and a drug's mechanism of action, and therapeutic unmet needs are key elements; these aspects are relevant to early phase paediatric trials, in which molecular profiling is strongly encouraged. Herein, we describe the strategy of the Innovative Therapies for Children with Cancer (ITCC) Consortium, which advocates for the adoption of trial designs that enable uninterrupted patient recruitment, the extrapolation from studies in adults when possible, and the inclusion of expansion cohorts. If a drug has neither serious dose-related toxicities nor a narrow therapeutic index, then studies should generally be started at the adult recommended phase II dose corrected for body surface area, and act as dose-confirmation studies. The use of adaptive trial designs will enable drugs with promising activity to progress rapidly to randomized studies and, therefore, will substantially accelerate drug development for children and adolescents with cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nrclinonc.2017.59DOI Listing
August 2017

A Phase I Study of the CDK4/6 Inhibitor Ribociclib (LEE011) in Pediatric Patients with Malignant Rhabdoid Tumors, Neuroblastoma, and Other Solid Tumors.

Clin Cancer Res 2017 May 21;23(10):2433-2441. Epub 2017 Apr 21.

Pediatric NeuroOncology, DanaFarber Cancer Institute, Boston, Massachusetts.

The cyclin-dependent kinase (CDK) 4/6 inhibitor, ribociclib (LEE011), displayed preclinical activity in neuroblastoma and malignant rhabdoid tumor (MRT) models. In this phase I study, the maximum tolerated dose (MTD) and recommended phase II dose (RP2D), safety, pharmacokinetics (PK), and preliminary activity of single-agent ribociclib were investigated in pediatric patients with neuroblastoma, MRT, or other cyclin D-CDK4/6-INK4-retinoblastoma pathway-altered tumors. Patients (aged 1-21 years) received escalating once-daily oral doses of ribociclib (3-weeks-on/1-week-off). Dose escalation was guided by a Bayesian logistic regression model with overdose control and real-time PK. Thirty-two patients (median age, 5.5 years) received ribociclib 280, 350, or 470 mg/m Three patients had dose-limiting toxicities of grade 3 fatigue (280 mg/m; = 1) or grade 4 thrombocytopenia (470 mg/m; = 2). Most common treatment-related adverse events (AE) were hematologic: neutropenia (72% all-grade/63% grade 3/4), leukopenia (63%/38%), anemia (44%/3%), thrombocytopenia (44%/28%), and lymphopenia (38%/19%), followed by vomiting (38%/0%), fatigue (25%/3%), nausea (25%/0%), and QTc prolongation (22%/0%). Ribociclib exposure was dose-dependent at 350 and 470 mg/m [equivalent to 600 (RP2D)-900 mg in adults], with high interpatient variability. Best overall response was stable disease (SD) in nine patients (seven with neuroblastoma, two with primary CNS MRT); five patients achieved SD for more than 6, 6, 8, 12, and 13 cycles, respectively. Ribociclib demonstrated acceptable safety and PK in pediatric patients. MTD (470 mg/m) and RP2D (350 mg/m) were equivalent to those in adults. Observations of prolonged SD support further investigation of ribociclib combined with other agents in neuroblastoma and MRT. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-16-2898DOI Listing
May 2017

Topotecan-Vincristine-Doxorubicin in Stage 4 High-Risk Neuroblastoma Patients Failing to Achieve a Complete Metastatic Response to Rapid COJEC: A SIOPEN Study.

Cancer Res Treat 2018 Jan 21;50(1):148-155. Epub 2017 Mar 21.

Paediatric Oncology, Istituto Giannina Gaslini, Genova, Italy.

Purpose: Metastatic response to induction therapy for high-risk neuroblastoma is a prognostic factor. In the International Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) HR-NBL-1 protocol, only patients with metastatic complete response (CR) or partial response (PR) with ≤ three abnormal skeletal areas on iodine 123-metaiodobenzylguanidine ([I]mIBG) scintigraphy and no bone marrow disease proceed to high dose therapy (HDT). In this study, topotecan-vincristine-doxorubicin (TVD) was evaluated in patients failing to achieve these criteria, with the aim of improving the metastatic response rate.

Materials And Methods: Patients with metastatic high-risk neuroblastoma who had not achieved the SIOPEN criteria for HDT after induction received two courses of topotecan 1.5 mg/m/day for 5 days, followed by a 48-hour infusion of vincristine, 2 mg/m, and doxorubicin, 45 mg/m.

Results: Sixty-three patients were eligible and evaluable. Following two courses of TVD, four (6.4%) patients had an overall CR, while 28 (44.4%) had a PR with a combined response rate of 50.8% (95% confidence interval [CI], 37.9 to 63.6). Of these, 23 patients achieved a metastatic CR or a PR with ≤ 3 mIBG skeletal areas and no bone marrow disease (36.5%; 95% CI, 24.7 to 49.6) and were eligible to receive HDT. Toxicity was mostly haematological, affecting 106 of the 126 courses (84.1%; 95% CI, 76.5 to 90.0), and dose reduction was necessary in six patients. Stomatitis was the second most common nonhematological toxicity, occurring in 20 patients (31.7%).

Conclusion: TVD was effective in improving the response rate of high-risk neuroblastoma patients after induction with COJEC enabling them to proceed to HDT. However, the long-term benefits of TVD needs to be determined in randomized clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4143/crt.2016.511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5784636PMC
January 2018
-->