Phase I/II Study of the WEE1 Inhibitor Adavosertib (AZD1775) in Combination with Carboplatin in Children with Advanced Malignancies: Arm C of the AcSé-ESMART Trial.

PURPOSE: AcSé-ESMART Arm C aimed to define the recommended dose and activity of the WEE1 inhibitor adavosertib in combination with carboplatin in children and young adults with molecularly enriched recurrent/refractory malignancies. PATIENTS AND METHODS: Adavosertib was administered orally, twice every day on Days 1 to 3 and carboplatin intravenously on Day 1 of a 21-day cycle, starting at 100 mg/m2/dose and AUC 5, respectively. Patients were enriched for molecular alterations in cell cycle and/or homologous recombination (HR). RESULTS: Twenty patients (median age: 14.0 years; range: 3.4-23.5) were included; 18 received 69 treatment cycles. Dose-limiting toxicities were prolonged grade 4 neutropenia and grade 3/4 thrombocytopenia requiring transfusions, leading to two de-escalations to adavosertib 75 mg/m2/dose and carboplatin AUC 4; no recommended phase II dose was defined. Main treatment-related toxicities were hematologic and gastrointestinal. Adavosertib exposure in children was equivalent to that in adults; both doses achieved the cell kill target. Overall response rate was 11% (95% confidence interval, 0.0-25.6) with partial responses in 2 patients with neuroblastoma. One patient with medulloblastoma experienced unconfirmed partial response and 5 patients had stable disease beyond four cycles. Seven of these eight patients with clinical benefit had alterations in HR, replication stress, and/or RAS pathway genes with or without TP53 alterations, whereas TP53 pathway alterations alone (8/10) or no relevant alterations (2/10) were present in the 10 patients without benefit. CONCLUSIONS: Adavosertib-carboplatin combination exhibited significant hematologic toxicity. Activity signals and identified potential biomarkers suggest further studies with less hematotoxic DNA-damaging therapy in molecularly enriched pediatric cancers.

A PD-1/PD-L1 Proximity Assay as a Theranostic Marker for PD-1 Blockade in Patients with Metastatic Melanoma.

PURPOSE: Less than 50% of patients with melanoma respond to anti-programmed cell death protein 1 (anti-PD-1), and this treatment can induce severe toxicity. Predictive markers are thus needed to improve the benefit/risk ratio of immune checkpoint inhibitors (ICI). Baseline tumor parameters such as programmed death ligand 1 (PD-L1) expression, CD8+ T-cell infiltration, mutational burden, and various transcriptomic signatures are associated with response to ICI, but their predictive values are not sufficient. Interaction between PD-1 and its main ligand, PD-L1, appears as a valuable target of anti-PD-1 therapy. Thus, instead of looking at PD-L1 expression only, we evaluated the predictive value of the proximity between PD-1 and its neighboring PD-L1 molecules in terms of response to anti-PD-1 therapy. EXPERIMENTAL DESIGN: PD-1/PD-L1 proximity was assessed by proximity ligation assay (PLA) on 137 samples from two cohorts (exploratory n = 66 and validation n = 71) of samples from patients with melanoma treated with anti-PD-1±anti-CTLA-4. Additional predictive biomarkers, such as PD-L1 expression (MELscore), CD8+ cells density, and NanoString RNA signature, were also evaluated. RESULTS: A PD-1/PD-L1 PLA model was developed to predict tumor response in an exploratory cohort and further evaluated in an independent validation cohort. This score showed higher predictive ability (AUC = 0.85 and 0.79 in the two cohorts, respectively) for PD-1/PD-L1 PLA as compared with other parameters (AUC = 0.71-0.77). Progression-free and overall survival were significantly longer in patients with high PLA values (P = 0.00019 and P < 0.0001, respectively). CONCLUSIONS: The proximity between PD-1 and PD-L1, easily assessed by this PLA on one formalin-fixed paraffin-embedded section, appears as a new biomarker of anti-PD-1 efficacy.

First-in-child phase I/II study of the dual mTORC1/2 inhibitor vistusertib (AZD2014) as monotherapy and in combination with topotecan-temozolomide in children with advanced malignancies: arms E and F of the AcSé-ESMART trial.

AIM: Arms E and F of the AcSé-ESMART phase I/II platform trial aimed to define the recommended dose and preliminary activity of the dual mTORC1/2 inhibitor vistusertib as monotherapy and with topotecan-temozolomide in a molecularly enriched population of paediatric patients with relapsed/refractory malignancies. In addition, we evaluated genetic phosphatidylinositol 3-kinase (PI3K)/AKT/ mammalian (or mechanistic) target of rapamycin (mTOR) pathway alterations across the Molecular Profiling for Paediatric and Young Adult Cancer Treatment Stratification (MAPPYACTS) trial (NCT02613962). EXPERIMENTAL DESIGN AND RESULTS: Four patients were treated in arm E and 10 in arm F with a median age of 14.3 years. Main diagnoses were glioma and sarcoma. Dose escalation was performed as per the continuous reassessment method, expansion in an Ensign design. The vistusertib single agent administered at 75 mg/m2 twice a day (BID) on 2 days/week and vistusertib 30 mg/m2 BID on 3 days/week combined with temozolomide 100 mg/m2/day and topotecan 0.50 mg/m2/day on the first 5 days of each 4-week cycle were safe. Treatment was well tolerated with the main toxicity being haematological. Pharmacokinetics indicates equivalent exposure in children compared with adults. Neither tumour response nor prolonged stabilisation was observed, including in the 12 patients whose tumours exhibited PI3K/AKT/mTOR pathway alterations. Advanced profiling across relapsed/refractory paediatric cancers of the MAPPYACTS cohort shows genetic alterations associated with this pathway in 28.0% of patients, with 10.5% carrying mutations in the core pathway genes. CONCLUSIONS: Vistusertib was well tolerated in paediatric patients. Study arms were terminated because of the absence of tumour responses and insufficient target engagement of vistusertib observed in adult trials. Targeting the PI3K/AKT/mTOR pathway remains a therapeutic avenue to be explored in paediatric patients. CLINICAL TRIAL IDENTIFIER: NCT2813135.

Phase I or II Study of Ribociclib in Combination With Topotecan-Temozolomide or Everolimus in Children With Advanced Malignancies: Arms A and B of the AcSé-ESMART Trial.

PURPOSE: AcSé-ESMART is a proof-of-concept, phase I or II, platform trial, designed to explore targeted agents in a molecularly enriched cancer population. Arms A and B aimed to define the recommended phase II dose and activity of the CDK4/6 inhibitor ribociclib with topotecan and temozolomide (TOTEM) or everolimus, respectively, in children with recurrent or refractory malignancies. PATIENTS AND METHODS: Ribociclib was administered orally once daily for 16 days after TOTEM for 5 days (arm A) or for 21 days with everolimus orally once daily continuously in a 28-day cycle (arm B). Dose escalation followed the continuous reassessment method, and activity assessment the Ensign design. Arms were enriched on the basis of molecular alterations in the cell cycle or PI3K/AKT/mTOR pathways. RESULTS: Thirty-two patients were included, 14 in arm A and 18 in arm B, and 31 were treated. Fourteen patients had sarcomas (43.8%), and 13 brain tumors (40.6%). Main toxicities were leukopenia, neutropenia, and lymphopenia. The recommended phase II dose was ribociclib 260 mg/m2 once a day, temozolomide 100 mg/m2 once a day, and topotecan 0.5 mg/m2 once a day (arm A) and ribociclib 175 mg/m2 once a day and everolimus 2.5 mg/m2 once a day (arm B). Pharmacokinetic analyses confirmed the drug-drug interaction of ribociclib on everolimus exposure. Two patients (14.3%) had stable disease as best response in arm A, and seven (41.2%) in arm B, including one patient with T-acute lymphoblastic leukemia with significant blast count reduction. Alterations considered for enrichment were present in 25 patients (81%) and in eight of nine patients with stable disease; the leukemia exhibited CDKN2A/B and PTEN deficiency. CONCLUSION: Ribociclib in combination with TOTEM or everolimus was well-tolerated. The observed activity signals initiated a follow-up study of the ribociclib-everolimus combination in a population enriched with molecular alterations within both pathways.

Phase II and biomarker study of programmed cell death protein 1 inhibitor nivolumab and metronomic cyclophosphamide in paediatric relapsed/refractory solid tumours: Arm G of AcSé-ESMART, a trial of the European Innovative Therapies for Children With Cancer Consortium.

PURPOSE: AcSé-ESMART is a European multicentre, proof-of-concept multiarm phase I/II platform trial in paediatric patients with relapsed/refractory cancer. Arm G assessed the activity and safety of nivolumab in combination with metronomic cyclophosphamide +/- irradiation. EXPERIMENTAL DESIGN: Following a Phase II Simon two-stage design, nivolumab was administered intravenously at 3 mg/kg every 2 weeks of a 28-day cycle, oral cyclophosphamide at 25 mg/m2 twice a day, 1 week on/1 week off. The primary endpoint was objective response rate. Irradiation/radioablation of primary tumour or metastasis could be administered as per physician's choice. Biomarker evaluation was performed by tumour immunohistochemistry, whole exome and RNA sequencing, and immunophenotyping of peripheral blood by flow cytometry. RESULTS: Thirteen patients were treated with a median age of 15 years (range: 5.5-19.4). The main histologies were high-grade glioma, neuroblastoma, and desmoplastic small round cell tumour (DSRCT). The safety profile was similar to those of single-agent nivolumab, albeit haematologic toxicity, mainly lymphocytopenia, was commonly reported with the addition of cyclophosphamide +/- irradiation. Two patients with DSRCT and ependymoma presented unconfirmed partial response and prolonged disease stabilisation. Low mutational load with modest intratumour CD3+ T-cell infiltration and immunosuppressive tumour microenvironment were observed in the tumour samples. Under combined treatment, no positive modulation of circulating T cells was displayed, while derived neutrophil-to-lymphocyte ratio increased. CONCLUSIONS: Nivolumab in combination with cyclophosphamide was well tolerated but had limited activity in this paediatric setting. Metronomic cyclophosphamide did not modulate systemic immune response that could compensate limited T-cell infiltration and the immunosuppressive tumour microenvironment. CLINICALTRIALS. GOV IDENTIFIER: NCT2813135.

Sarcome-13/OS2016 trial protocol: a multicentre, randomised, open-label, phase II trial of mifamurtide combined with postoperative chemotherapy for patients with newly diagnosed high-risk osteosarcoma.

INTRODUCTION: The controversial results on the mifamurtide efficacy associated with chemotherapy, issued from the American INT-0133-study, in localised osteosarcomas, and the underpowered analysis performed separately in metastatic patients, should be clarified to homogenise international use of this promising drug. The European Commission has granted a marketing authorisation to mifamurtide combined with postoperative chemotherapy in localised osteosarcomas but not in metastatic patients, while the Food and Drug Administration (FDA) has denied this authorisation. METHODS AND ANALYSIS: Sarcome-13/OS2016 trial is a multicentre randomised open-label phase II trial evaluating the survival benefit of mifamurtide administered during 36 weeks in combination with postoperative chemotherapy versus chemotherapy alone, in patients >2 and ≤50 years with newly diagnosed high-risk localised or metastatic osteosarcoma. The main objective is to evaluate the impact on event-free survival (EFS) of mifamurtide on intention-to-treat population. The secondary objectives are to evaluate the impact of mifamurtide on overall survival, to evaluate the feasibility and toxicity of the planned treatment, to correlate biology/immunology with the mifamurtide efficacy/toxicity. With a total of 126 enrolled patients and 51 events, the power is 80% if mifamurtide is associated with an 18% improvement of the 3-year EFS (52%vs70%, equivalent to an HR=0.55), with a one-sided logrank test alpha=10%. As relevant historical data are available (aggregate treatment effect from the INT-0133 trial and individual data from the control group of the Sarcome-09/OS2006 trial), a Bayesian analysis is also planned. ETHICS AND DISSEMINATION: This study was approved by the 'Comité de Protection des Personnes Ile de France I' (12/06/2018), complies with the Declaration of Helsinki and French laws and regulations, and follows the International Conference on Harmonisation E6 Guideline for Good Clinical Practice. The trial results, even if they are inconclusive, as well as biological ancillary studies will be presented at appropriate international congresses and published in international peer-review journals. TRIAL REGISTRATION NUMBER: EudraCT 2017-001165-24, NCT03643133.

Incorporating individual historical controls and aggregate treatment effect estimates into a Bayesian survival trial: a simulation study.

BACKGROUND: Performing well-powered randomised controlled trials (RCTs) of new treatments for rare diseases is often infeasible. However, with the increasing availability of historical data, incorporating existing information into trials with small sample sizes is appealing in order to increase the power. Bayesian approaches enable one to incorporate historical data into a trial's analysis through a prior distribution. METHODS: Motivated by a RCT intended to evaluate the impact on event-free survival of mifamurtide in patients with osteosarcoma, we performed a simulation study to evaluate the impact on trial operating characteristics of incorporating historical individual control data and aggregate treatment effect estimates. We used power priors derived from historical individual control data for baseline parameters of Weibull and piecewise exponential models, while we used a mixture prior to summarise aggregate information obtained on the relative treatment effect. The impact of prior-data conflicts, both with respect to the parameters and survival models, was evaluated for a set of pre-specified weights assigned to the historical information in the prior distributions. RESULTS: The operating characteristics varied according to the weights assigned to each source of historical information, the variance of the informative and vague component of the mixture prior and the level of commensurability between the historical and new data. When historical and new controls follow different survival distributions, we did not observe any advantage of choosing a piecewise exponential model compared to a Weibull model for the new trial analysis. However, we think that it remains appealing given the uncertainty that will often surround the shape of the survival distribution of the new data. CONCLUSION: In the setting of Sarcome-13 trial, and other similar studies in rare diseases, the gains in power and accuracy made possible by incorporating different types of historical information commensurate with the new trial data have to be balanced against the risk of biased estimates and a possible loss in power if data are not commensurate. The weights allocated to the historical data have to be carefully chosen based on this trade-off. Further simulation studies investigating methods for incorporating historical data are required to generalise the findings.

Real world prospective experience of axitinib in metastatic renal cell carcinoma in a large comprehensive cancer centre.

BACKGROUND: Axitinib has shown activity in metastatic renal cell carcinoma (mRCC) in a large phase III clinical trial and was approved in patients who failed first-line therapy. This drug has been available in France since November 2012. The objective is to report efficacy and safety of axitinib in mRCC outside of clinical trials. METHODS: A prospective evaluation of mRCC patients treated by axitinib in second or further next-line therapy at Gustave Roussy was conducted from 2012 to 2015. Objective response rate (ORR), progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS) and toxicities were analysed. The correlation between clinical markers and ORR, PFS, TTF and OS were explored. RESULTS: One-hundred and sixty patients with mRCC, received axitinib in second (40%) or further next-line therapy (60%). International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group classification was good, intermediate and poor in 13%, 54% and 32%, respectively. Dose titration (DT) to 7 mg twice a day (bid) was performed in 38% and to 10 mg bid in 19% of the patients. Hypertension was the most common adverse event, (grade (G)3: 39%; G4: 2%). ORR occurred in 32% (n = 33, only partial response). Median PFS, TTF and OS were 8.3, 5.8 and 16.4 months, respectively. IMDC risk group and DT at 2 weeks are associated to ORR while grade 3 hypertension is marginally associated. IMDC risk group and grade 3 hypertension are significantly associated with better PFS, TTF and OS while DT at 2 weeks is associated to PFS and TTF. CONCLUSION: Efficacy of axitinib in routine practice is similar to that previously reported, not only in second- but also in further next-lines of therapy.

Bayesian survival analysis in clinical trials: What methods are used in practice?

Background Bayesian statistics are an appealing alternative to the traditional frequentist approach to designing, analysing, and reporting of clinical trials, especially in rare diseases. Time-to-event endpoints are widely used in many medical fields. There are additional complexities to designing Bayesian survival trials which arise from the need to specify a model for the survival distribution. The objective of this article was to critically review the use and reporting of Bayesian methods in survival trials. Methods A systematic review of clinical trials using Bayesian survival analyses was performed through PubMed and Web of Science databases. This was complemented by a full text search of the online repositories of pre-selected journals. Cost-effectiveness, dose-finding studies, meta-analyses, and methodological papers using clinical trials were excluded. Results In total, 28 articles met the inclusion criteria, 25 were original reports of clinical trials and 3 were re-analyses of a clinical trial. Most trials were in oncology (n = 25), were randomised controlled (n = 21) phase III trials (n = 13), and half considered a rare disease (n = 13). Bayesian approaches were used for monitoring in 14 trials and for the final analysis only in 14 trials. In the latter case, Bayesian survival analyses were used for the primary analysis in four cases, for the secondary analysis in seven cases, and for the trial re-analysis in three cases. Overall, 12 articles reported fitting Bayesian regression models (semi-parametric, n = 3; parametric, n = 9). Prior distributions were often incompletely reported: 20 articles did not define the prior distribution used for the parameter of interest. Over half of the trials used only non-informative priors for monitoring and the final analysis (n = 12) when it was specified. Indeed, no articles fitting Bayesian regression models placed informative priors on the parameter of interest. The prior for the treatment effect was based on historical data in only four trials. Decision rules were pre-defined in eight cases when trials used Bayesian monitoring, and in only one case when trials adopted a Bayesian approach to the final analysis. Conclusion Few trials implemented a Bayesian survival analysis and few incorporated external data into priors. There is scope to improve the quality of reporting of Bayesian methods in survival trials. Extension of the Consolidated Standards of Reporting Trials statement for reporting Bayesian clinical trials is recommended.