Molecular-guided therapy for the treatment of patients with relapsed and refractory childhood cancers: a Beat Childhood Cancer Research Consortium trial.

BACKGROUND: Children with relapsed central nervous system (CNS tumors), neuroblastoma, sarcomas, and other rare solid tumors face poor outcomes. This prospective clinical trial examined the feasibility of combining genomic and transcriptomic profiling of tumor samples with a molecular tumor board (MTB) approach to make real­time treatment decisions for children with relapsed/refractory solid tumors. METHODS: Subjects were divided into three strata: stratum 1-relapsed/refractory neuroblastoma; stratum 2-relapsed/refractory CNS tumors; and stratum 3-relapsed/refractory rare solid tumors. Tumor samples were sent for tumor/normal whole-exome (WES) and tumor whole-transcriptome (WTS) sequencing, and the genomic data were used in a multi-institutional MTB to make real­time treatment decisions. The MTB recommended plan allowed for a combination of up to 4 agents. Feasibility was measured by time to completion of genomic sequencing, MTB review and initiation of treatment. Response was assessed after every two cycles using Response Evaluation Criteria in Solid Tumors (RECIST). Patient clinical benefit was calculated by the sum of the CR, PR, SD, and NED subjects divided by the sum of complete response (CR), partial response (PR), stable disease (SD), no evidence of disease (NED), and progressive disease (PD) subjects. Grade 3 and higher related and unexpected adverse events (AEs) were tabulated for safety evaluation. RESULTS: A total of 186 eligible patients were enrolled with 144 evaluable for safety and 124 evaluable for response. The average number of days from biopsy to initiation of the MTB-recommended combination therapy was 38 days. Patient benefit was exhibited in 65% of all subjects, 67% of neuroblastoma subjects, 73% of CNS tumor subjects, and 60% of rare tumor subjects. There was little associated toxicity above that expected for the MGT drugs used during this trial, suggestive of the safety of utilizing this method of selecting combination targeted therapy. CONCLUSIONS: This trial demonstrated the feasibility, safety, and efficacy of a comprehensive sequencing model to guide personalized therapy for patients with any relapsed/refractory solid malignancy. Personalized therapy was well tolerated, and the clinical benefit rate of 65% in these heavily pretreated populations suggests that this treatment strategy could be an effective option for relapsed and refractory pediatric cancers. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02162732. Prospectively registered on June 11, 2014.

A phase II trial of nifurtimox combined with topotecan and cyclophosphamide for refractory or relapsed neuroblastoma and medulloblastoma.

Children with relapsed/refractory (R/R) neuroblastoma (NB) and medulloblastoma (MB) have poor outcomes. We evaluated the efficacy of nifurtimox (Nfx) in a clinical trial for children with R/R NB and MB. Subjects were divided into three strata: first relapse NB, multiply R/R NB, and R/R MB. All patients received Nfx (30 mg/kg/day divided TID daily), Topotecan (0.75 mg/m2 /dose, days 1-5) and Cyclophosphamide (250 mg/m2 /dose, days 1-5) every 3 weeks. Response was assessed after every two courses using International Neuroblastoma Response Criteria and Response Evaluation Criteria in Solid Tumors (RECIST) criteria. One hundred and twelve eligible patients were enrolled with 110 evaluable for safety and 76 evaluable for response. In stratum 1, there was a 53.9% response rate (CR + PR), and a 69.3% total benefit rate (CR + PR + SD), with an average time on therapy of 165.2 days. In stratum 2, there was a 16.3% response rate, and a 72.1% total benefit rate, and an average time on study of 158.4 days. In stratum 3, there was a 20% response rate and a 65% total benefit rate, an average time on therapy of 105.0 days. The most common side effects included bone marrow suppression and reversible neurologic complications. The combination of Nfx, topotecan and cyclophosphamide was tolerated, and the objective response rate plus SD of 69.8% in these heavily pretreated populations suggests that this combination is an effective option for patients with R/R NB and MB. Although few objective responses were observed, the high percentage of stabilization of disease and prolonged response rate in patients with multiply relapsed disease shows this combination therapy warrants further testing.

A pilot study of genomic-guided induction therapy followed by immunotherapy with difluoromethylornithine maintenance for high-risk neuroblastoma.

BACKGROUND: Survival for patients with high-risk neuroblastoma (HRNB) remains poor despite aggressive multimodal therapies. AIMS: To study the feasibility and safety of incorporating a genomic-based targeted agent to induction therapy for HRNB as well as the feasibility and safety of adding difluoromethylornithine (DFMO) to anti-GD2 immunotherapy. METHODS: Twenty newly diagnosed HRNB patients were treated on this multicenter pilot trial. Molecular tumor boards selected one of six targeted agents based on tumor-normal whole exome sequencing and tumor RNA-sequencing results. Treatment followed standard upfront HRNB chemotherapy with the addition of the selected targeted agent to cycles 3-6 of induction. Following consolidation, DFMO (750 mg/m2 twice daily) was added to maintenance with dinutuximab and isotretinoin, followed by continuation of DFMO alone for 2 years. DNA methylation analysis was performed retrospectively and compared to RNA expression. RESULTS: Of the 20 subjects enrolled, 19 started targeted therapy during cycle 3 and 1 started during cycle 5. Eighty-five percent of subjects met feasibility criteria (receiving 75% of targeted agent doses). Addition of targeted agents did not result in toxicities requiring dose reduction of chemotherapy or permanent discontinuation of targeted agent. Following standard consolidation, 15 subjects continued onto immunotherapy with DFMO. This combination was well-tolerated and resulted in no unexpected adverse events related to DFMO. CONCLUSION: This study demonstrates the safety and feasibility of adding targeted agents to standard induction therapy and adding DFMO to immunotherapy for HRNB. This treatment regimen has been expanded to a Phase II trial to evaluate efficacy.

A Phase 1 Trial of TPI 287 as a Single Agent and in Combination With Temozolomide in Patients with Refractory or Recurrent Neuroblastoma or Medulloblastoma.

BACKGROUND: The primary aim of this Phase I study was to determine the maximum tolerated dose (MTD) of TPI 287 and the safety and tolerability of TPI 287 alone and in combination with temozolomide (TMZ) in pediatric patients with refractory or recurrent neuroblastoma or medulloblastoma. The secondary aims were to evaluate the pharmacokinetics of TPI 287 and the treatment responses. PROCEDURE: Eighteen patients were enrolled to a phase I dose escalation trial of weekly intravenous infusion of TPI 287 for two 28-day cycles with toxicity monitoring to determine the MTD, followed by two cycles of TPI 287 in combination with TMZ. Samples were collected to determine the pharmacokinetic parameters C(max), AUC(0-24), t(1/2), CL, and Vd on day 1 of cycles 1 (TPI 287 alone) and 3 (TPI 287 + TMZ) following TPI 287 infusion. Treatment response was evaluated by radiographic (CT or MRI) and radionuclide (MIBG) imaging for neuroblastoma. RESULTS: We determined the MTD of TPI 287 alone and in combination with temozolomide to be 125 mg/m(2). The non-dose-limiting toxicities at this dose were mainly anorexia and pain. The dose-limiting toxicities (DLTs) of two patients at 135 mg/m(2) were grade 3 hemorrhagic cystitis and grade 3 sensory neuropathy. CONCLUSIONS: Overall, TPI 287 was well tolerated by pediatric patients with refractory and relapsed neuroblastoma and medulloblastoma at a dose of 125 mg/m(2) IV on days 1, 8, and 15 of a 28 day cycle.

Feasibility of implementing molecular-guided therapy for the treatment of patients with relapsed or refractory neuroblastoma.

The primary objective of the study was to evaluate the feasibility and safety of a process which would utilize genome-wide expression data from tumor biopsies to support individualized treatment decisions. Current treatment options for recurrent neuroblastoma are limited and ineffective, with a survival rate of <10%. Molecular profiling may provide data which will enable the practitioner to select the most appropriate therapeutic option for individual patients, thus improving outcomes. Sixteen patients with neuroblastoma were enrolled of which fourteen were eligible for this study. Feasibility was defined as completion of tumor biopsy, pathological evaluation, RNA quality control, gene expression profiling, bioinformatics analysis, generation of a drug prediction report, molecular tumor board yielding a treatment plan, independent medical monitor review, and treatment initiation within a 21 day period. All eligible biopsies passed histopathology and RNA quality control. Expression profiling by microarray and RNA sequencing were mutually validated. The average time from biopsy to report generation was 5.9 days and from biopsy to initiation of treatment was 12.4 days. No serious adverse events were observed and all adverse events were expected. Clinical benefit was seen in 64% of patients as stabilization of disease for at least one cycle of therapy or partial response. The overall response rate was 7% and the progression free survival was 59 days. This study demonstrates the feasibility and safety of performing real-time genomic profiling to guide treatment decision making for pediatric neuroblastoma patients.

Poor predictability of prenatal ultrasonography for a nonfunctional kidney.

We present 2 cases in which the diagnosis of a unilateral nonfunctioning kidney was not anticipated. The first case appeared to be simple, antenatally diagnosed, unilateral hydronephrosis with adequate parenchyma. However, at 3 months postnatally, it was found to be nonfunctional, most likely secondary to early high-grade obstruction. The second case presented prenatally as a left hydronephrotic kidney with parenchymal cysts, and the right kidney showed only mild parenchymal cystic changes. By 6 months, however, the right kidney was nonfunctional. These cases emphasize the need for coordinated prenatal and postnatal care. The sonographic appearance of renal dysplasia is variable (in size, number of cysts, and degree of hydronephrosis), depending on the point at which it is evaluated during the disease course. Subtle signs of dysplasia, such as increased echogenicity, may be the only warning sign of a nonfunctioning kidney, for which one should have a high index of suspicion.