Phase II study of 131 I-metaiodobenzylguanidine with 5 days of topotecan for refractory or relapsed neuroblastoma: Results of the French study MIITOP.

PURPOSE: We report the results of the French multicentric phase II study MIITOP (NCT00960739), which evaluated tandem infusions of 131 I-metaiodobenzylguanidine (mIBG) and topotecan in children with relapsed/refractory metastatic neuroblastoma (NBL). METHODS: Patients received 131 I-mIBG on day 1, with intravenous topotecan daily on days 1-5. A second activity of 131 I-mIBG was given on day 21 to deliver a whole-body radiation dose of 4 Gy, combined with a second course of topotecan on days 21-25. Peripheral blood stem cells were infused on day 31. RESULTS: Thirty patients were enrolled from November 2008 to June 2015. Median age at diagnosis was 5.5 years (2-20). Twenty-one had very high-risk NBL (VHR-NBL), that is, stage 4 NBL at diagnosis or at relapse, with insufficient response (i.e., less than a partial response of metastases and more than three mIBG spots) after induction chemotherapy; nine had progressive metastatic relapse. Median Curie score at inclusion was 6 (1-26). Median number of prior lines of treatment was 3 (1-7). Objective response rate was 13% (95% confidence interval [CI]: 4-31) for the whole population, 19% for VHR-NBL, and 0% for progressive relapses. Immediate tolerance was good, with nonhematologic toxicity limited to grade-2 nausea/vomiting in eight patients. Two-year event-free survival was 17% (95% CI: 6-32). Among the 16 patients with VHR-NBL who had not received prior myeloablative busulfan-melphalan consolidation, 13 had at least stable disease after MIITOP; 11 subsequently received busulfan-melphalan; four of them were alive (median follow-up: 7 years). CONCLUSION: MIITOP showed acceptable tolerability in this heavily pretreated population and encouraging survival rates in VHR-NBL when followed by busulfan-melphalan.

METRO-PD1: Phase 1 study of nivolumab in combination with metronomic chemotherapy in children and adolescents with relapsing/refractory solid tumors.

BACKGROUND: This multicenter Phase I study (NCT03585465) evaluated nivolumab in combination with 3 metronomic chemotherapy (MC) regimens in children with refractory/relapsing solid tumors. OBJECTIVES: To evaluate the feasibility and safety of the three regimens METHODS: Patients aged < 18 years were enrolled. Nivolumab was combined with cyclophosphamide and vinblastine (arm A), capecitabine (arm B), or cyclophosphamide, vinblastine and capecitabine (arm C). Arm A and B were allocated sequentially. Arm C opened only if A and B were deemed safe. Dose-limiting toxicities (DLTs) were evaluated over the first two cycles. Patients were evaluable if they received > 2 cycles and > 70% of the planned dose. POPULATION: Sixteen patients were enrolled, 3 in arm A, 6 in arm B, and 7 in arm C. Median age was 11.5 years (range, 5-19). Patients previously received a median of 3.5 (range, 1-4) lines of systemic treatment, 14 patients had surgery and 11 had radiotherapy. RESULTS: Median number of cycles was 2 (1-24), median treatment duration was 56 days (18-714). In arm C, median number of cycles was 4 with median treatment duration of 95 days. No DLT was observed. Grade 3 adverse events (AE) and serious AE were observed in 8 patients (50%) and 1 patient (6%), respectively, over the first 2 cycles. No grade 4 AE occurred. The 6-month PFS and OS were 12% and 44%, respectively, in the whole population. Prolonged stable disease was observed in a high-grade glioma and an atypical teratoid rhabdoid tumor. CONCLUSION: Arm C appears safe. A randomized phase II trial evaluating the addition of nivolumab to the triple MC is ongoing.

Dose-finding designs using a novel quasi-continuous endpoint for multiple toxicities.

The aim of a phase I oncology trial is to identify a dose with an acceptable safety profile. Most phase I designs use the dose-limiting toxicity, a binary endpoint, to assess the unacceptable level of toxicity. The dose-limiting toxicity might be incomplete for investigating molecularly targeted therapies as much useful toxicity information is discarded. In this work, we propose a quasi-continuous toxicity score, the total toxicity profile (TTP), to measure quantitatively and comprehensively the overall severity of multiple toxicities. We define the TTP as the Euclidean norm of the weights of toxicities experienced by a patient, where the weights reflect the relative clinical importance of each grade and toxicity type. We propose a dose-finding design, the quasi-likelihood continual reassessment method (CRM), incorporating the TTP score into the CRM, with a logistic model for the dose-toxicity relationship in a frequentist framework. Using simulations, we compared our design with three existing designs for quasi-continuous toxicity score (the Bayesian quasi-CRM with an empiric model and two nonparametric designs), all using the TTP score, under eight different scenarios. All designs using the TTP score to identify the recommended dose had good performance characteristics for most scenarios, with good overdosing control. For a sample size of 36, the percentage of correct selection for the quasi-likelihood CRM ranged from 80% to 90%, with similar results for the quasi-CRM design. These designs with TTP score present an appealing alternative to the conventional dose-finding designs, especially in the context of molecularly targeted agents.

Phase I Study of a Combination of Fluvastatin and Celecoxib in Children with Relapsing/Refractory Low-Grade or High-Grade Glioma (FLUVABREX).

Preclinical data support the activity of celecoxib and fluvastatin in high-grade (HGG) and low-grade gliomas (LGG). A phase I trial (NCT02115074) was designed to evaluate the safety of this combination in children with refractory/relapsed HGG and LGG using four dose levels of fluvastatin with a fixed daily dose of celecoxib. A Continual Reassessment Method was used for fluvastatin dose escalation. Dose-limiting toxicities (DLT) were determined on the first treatment cycle. Twenty patients were included. Ten LGG and ten HGG patients received a median of 3.5 treatment cycles. Two DLTs were reported: one grade 3 maculopapular rash (4 mg/kg dose level) and one grade 4 increase of Creatine Phospho-Kinase (6 mg/kg dose level). We identified the dose of 6 mg/kg/day as the recommended phase II dose (RP2D) of fluvastatin with celecoxib. Four patients with LGG continued treatment beyond 12 cycles because of stable disease, including one patient who received 23 treatment cycles. In children with refractory/relapsed glioma, the RP2D of fluvastatin with celecoxib is 6 mg/kg/day. The long-term stable diseases observed in LGG suggest a possible role of the combination in a maintenance setting, given its good tolerance and low cost for children living in low- and middle-income countries.

Prophylactic Radical Fimbriectomy with Delayed Oophorectomy in Women with a High Risk of Developing an Ovarian Carcinoma: Results of a Prospective National Pilot Study.

Risk-reducing salpingo-oophorectomy is the gold standard for the prophylaxis of ovarian cancer in high-risk women. Due to significant adverse effects, 20-30% of women delay or refuse early oophorectomy. This prospective pilot study (NCT01608074) aimed to assess the efficacy of radical fimbriectomy followed by a delayed oophorectomy in preventing ovarian and pelvic invasive cancer (the primary endpoint) and to evaluate the safety of both procedures. The key eligibility criteria were pre-menopausal women ≥35 years with a high risk of ovarian cancer who refused a risk-reducing salpingo-oophorectomy. All the surgical specimens were subjected to the SEE-FIM protocol. From January 2012 to October 2014, 121 patients underwent RF, with 51 in an ambulatory setting. Occult neoplasia was found in two cases, with one tubal high-grade serous ovarian carcinoma. Two patients experienced grade 1 intraoperative complications. No early or delayed grade ≥3 post-operative complications occurred. After 7.3 years of median follow-up, no cases of pelvic invasive cancer have been noted. Three of the fifty-two patients developed de novo breast cancer. One BRCA1-mutated woman delivered twins safely. Twenty-five patients underwent menopause, including fifteen who had received chemotherapy for breast cancer, and twenty-three underwent menopause before the delayed oophorectomy, while two did not undergo a delayed oophorectomy at all. Overall, 46 women underwent a delayed oophorectomy. No abnormalities were found in any delayed oophorectomy specimens. Radical fimbriectomy followed by delayed oophorectomy appears to be a safe and well-tolerated risk-reducing approach, which avoids early menopause for patients with a high risk of breast and ovarian cancer.

Taking the long view: how to design a series of Phase III trials to maximize cumulative therapeutic benefit.

BACKGROUND: Traditional clinical trial designs strive to definitively establish the superiority of an experimental treatment, which results in risk-adverse criteria and large sample sizes. Increasingly, common cancers are recognized as consisting of small subsets with specific aberrations for targeted therapy, making large trials infeasible. PURPOSE: To compare the performance of different trial design strategies over a long-term research horizon. METHODS: We simulated a series of two-treatment superiority trials over 15 years using different design parameters. Trial parameters examined included the number of positive trials to establish superiority (one-trial vs. two-trial rule), α level (2.5%-50%), and the number of trials in the 15-year period, K (thus, trial sample size). The design parameters were evaluated for different disease scenarios, accrual rates, and distributions of treatment effect. Metrics used included the overall survival gain at a 15-year horizon measured by the hazard ratio (HR), year 15 versus year 0. We also computed the expected total survival benefit and the risk of selecting as new standard of care at year 15 a treatment inferior to the initial control treatment, P(detrimental effect). RESULTS: Expected survival benefits over the 15-year horizon were maximized when more (smaller) trials were conducted than recommended under traditional criteria, using the criterion of one positive trial (vs. two), and relaxing the α value from 2.5% to 20%. Reducing the sample size and relaxing the α value also increased the likelihood of selecting an inferior treatment at the end. The impact of α and K on the survival benefit depended on the specific disease scenario and accrual rate: greater gains for relaxing α in diseases with good outcome and/or low accrual rates and greater gains for increasing K for diseases with poor outcomes. Trials with smaller sample size did not perform well when using stringent (standard) level of evidence. For each disease scenario and accrual rate studied, the optimal design, defined as the design that the maximized expected total survival benefit while constraining P(detrimental effect) < 2.5%, specified α = 20% or 10%, and a sample size considerably smaller than that recommended by the traditional designs. The results were consistent under different assumed distributions for treatment effect. LIMITATIONS: The simulations assumed no toxicity issues and did not consider interim analyses. CONCLUSIONS: It is worthwhile to consider a design paradigm that seeks to maximize the expected survival benefit across a series of trials, over a longer research horizon. In today's environment of constrained, biomarker-selected populations, our results indicate that smaller sample sizes and larger α values lead to greater long-term survival gains compared to traditional large trials designed to meet stringent criteria with a low efficacy bar.

Assessing Prognostic and Predictive Biomarkers of Regorafenib Response in Patients with Advanced Soft Tissue Sarcoma: REGOSARC Study.

: Regorafenib significantly prolonged progression-free survival (PFS) in pretreated patients with advanced non-adipocytic sarcoma (HR = 0.46; p < 0.001) in a placebo-controlled, randomized, phase-II trial (NCT01900743). Thus, here, we assessed the prevalence of 57 biomarkers and their prognostic and predictive values for PFS and overall survival (OS). We analyzed 134/182 patients included in this trial, treated with regorafenib (n = 71, 53%) or placebo (n = 63, 47%). Mutational analyses were performed via full coding sequence analysis for 10 genes, and mutation hotspot panel for 50 genes (four genes in common). H19 was studied with RNA in-situ hybridization. The prognostic and predictive biomarkers' values were studied only for biomarkers found positive/mutated in at least 10 patients. Overall, 25 out of 57 studied biomarkers, including five out of seven genes involved in angiogenesis, were found mutated/positive in at least one patient, of which 23 biomarkers had low prevalence (fewer than eight out of 134 patients), contrasting with H19 (n = 24, 18%), and TP53 (n = 35, 26%). However, in multivariable models of PFS and OS, including treatment effects and interactions, no significant prognostic or predictive values of the tested biomarkers were observed. Though several promising biomarkers were found to be positive/mutated, none of them were identified as viable predictive and prognostic biomarkers.

Equal access to innovative therapies and precision cancer care.

Patients with cancers of differing histologies that express certain biomarkers are likely to benefit from treatment with targeted therapies. However, targets can be present in malignancies other than those indicated by a drug's label, and as a result, affected patients will have no access to those potentially useful drugs. To tackle this issue, the French National Cancer Institute developed the AcSé Programme in 2013. This programme is designed to make treatment decisions or recommendations on the basis of the presence of relevant biomarkers for malignancies with no targeted therapies available and also aims to improve safety, and evaluate the efficacy of targeted drugs used outside of their approved indications. Patients across France have access to molecular testing in 28 molecular genetics centres and to targeted therapies within phase II trials provided no other trials exist in which they could reasonably be included. Trials include patients below the age of 18 if safe dosing data are available. As of January 2016, 183 French clinical sites and over 7,000 patients are participating in AcSé led trials. Proof of concept is being demonstrated through trials designed to investigate the effectiveness of crizotinib and vemurafenib in a wide variety of cancers.