Joel Kaplan

A Phase I Trial of DFMO Targeting Polyamine Addiction in Patients with Relapsed/Refractory Neuroblastoma

Background Neuroblastoma (NB) is the most common cancer in infancy and most frequent cause of death from extracranial solid tumors in children. Ornithine decarboxylase (ODC) expression is an independent indicator of poor prognosis in NB patients. This study investigated safety, response, pharmacokinetics, genetic and metabolic factors associated with ODC in a clinical trial of the ODC inhibitor difluoromethylornithine (DFMO) ± etoposide for patients with relapsed or refractory NB. Methods and Findings Twenty-one patients participated in a phase I study of daily oral DFMO alone for three weeks, followed by additional three-week cycles of DFMO plus daily oral etoposide. No dose limiting toxicities (DLTs) were identified in patients taking doses of DFMO between 500-1500 mg/m2 orally twice a day. DFMO pharmacokinetics, single nucleotide polymorphisms (SNPs) in the ODC gene and urinary levels of substrates for the tissue polyamine exporter were measured. Urinary polyamine levels varied among patients at baseline. Patients with the minor T-allele at rs2302616 of the ODC gene had higher baseline levels (p=0.02) of, and larger decreases in, total urinary polyamines during the first cycle of DFMO therapy (p=0.003) and had median progression free survival (PFS) that was over three times longer, compared to patients with the major G allele at this locus although this last result was not statistically significant (p=0.07). Six of 18 evaluable patients were progression free during the trial period with three patients continuing progression free at 663, 1559 and 1573 days after initiating treatment. Median progression-free survival was less among patients having increased urinary polyamines, especially diacetylspermine, although this result was not statistically significant (p=0.056). Conclusions DFMO doses of 500-1500mg/m2/day are safe and well tolerated in children with relapsed NB. Children with the minor T allele at rs2302616 of the ODC gene with relapsed or refractory NB had higher levels of urinary polyamine markers and responded better to therapy containing DFMO, compared to those with the major G allele at this locus. These findings suggest that this patient subset may display dependence on polyamines and be uniquely susceptible to therapies targeting this pathway. Trial Registration Clinicaltrials.gov NCT#01059071

Allogeneic stem cell transplantation in a patient with relapsed Ewing sarcoma

Ewing sarcoma (ES) can express tumor antigens which can be recognized by T cells, making allogeneic stem cell transplant (SCT) a potential option for those patients with refractory disease. A 6‐year old with multifocal ES developed a recurrence of pulmonary metastases and underwent an allogeneic bone marrow transplant from her human leukocyte antigen (HLA) 10/10 matched mother. During a taper of her immunosuppression, she developed grade 1 skin and oral graft versus host disease (GVHD). CT scans performed 9 months post‐transplant revealed a marked decrease in the size of her pulmonary lesions compared to scans 2 months post‐transplant. This case highlights the possibility of treating patients with refractory metastatic ES with allogeneic SCT. Pediatr Blood Cancer 2008;51:142–144.

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.

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

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.

Abstract LB-160: A feasibility trial using molecular-guided therapy for the treatment of patients with refractory or recurrent neuroblastoma.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background: Neuroblastoma is the most common extracranial solid tumor in children, and treatment options for recurrent neuroblastoma are limited. Using molecular profiling to target the molecular vulnerabilities of individual patient tumors with existing therapeutic agents may result in a rational, data-driven approach to treatment with potential to improve clinical outcomes. Methods: This was a multicenter study through the Neuroblastoma and Medulloblastoma Translational Research Consortium. The primary objective of this study was to evaluate the feasibility of supporting real-time treatment decisions through predictive modeling of genome-wide mRNA gene expression data from neuroblastoma tumor biopsies. Feasibility was defined as completion of tumor biopsy, histopathological evaluation, RNA extraction and quality control, gene expression profiling within a CLIA-certified laboratory, bioinformatic analysis, generation of a drug prediction report, molecular tumor board review yielding a formulated treatment plan, independent medical monitor review, treatment initiation within a 2-week period and completion of one cycle of therapy. The secondary objectives included a reproducibility study of patient biopsies, safety and response to therapy. Research validation in cell culture models of patient tumors was performed. Results: Fourteen patients with multiply relapsed neuroblastoma were enrolled between July 2011 and November 2012. All biopsies passed histopathology and RNA quality control. Generation of gene expression data and its analysis (3-8 days), reports which linked this data into medically actionable drug candidates (0-3 days), molecular tumor board (1-6 days) and independent medical monitor review (1 -4 days) were all completed in real-time. The average time was 12.4 days from biopsy to initiation of treatment. There were no unexpected serious adverse events on study and patients tolerated therapy well. Clinical benefit was seen 50% of patients. Triplicate biopsies showed reproducible sets of drugs and the comparatively large differences in drug lists between patients show that the drug lists are tailored to patients. Comparison of RNA expression profiles with RNA sequencing from each patient showed strong correlation. Conclusion: This study shows that it is feasible to create therapeutic treatment plans based on genomic profiling in real time and that patients are able to be treated safely on a tumor board derived molecular guided therapy using existing medications. Incorporation of further genomic studies to evaluate additional molecular profiling techniques in order to make more informed individual therapeutic treatment plans will be evaluated in future studies. Citation Format: Giselle L. Sholler, Genevieve Bergendahl, Alyssa VanderWerff, William Ferguson, William Roberts, Don Eslin, Jacqueline Kraveka, Joel Kaplan, Deanna Mitchell, Nehal Parikh, Kathleen Neville, Takamaru Ashikaga, Jeffrey Bond, Gina Hanna, Melinda Merchant, Matt Huentelman, Jason Corneveaux, Jeffrey Trent. A feasibility trial using molecular-guided therapy for the treatment of patients with refractory or recurrent neuroblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-160. doi:10.1158/1538-7445.AM2013-LB-160

Abstract LB-179: Phase I trial of relapsed neuroblastoma with DFMO alone and in combination with etoposide.

Background: Neuroblastoma (NB) is the most common extracranial solid tumor in children. There is no curative treatment for children with relapsed NB, and the 5-year survival rate is Citation Format: Giselle L. Sholler, Eugene W. Gerner, Genevieve Bergendahl, Bonnie J. LaFleur, Alyssa VanderWerff, Takamaru Ashikaga, William Ferguson, William Roberts, Don Eslin, Joel Kaplan, Jacqueline M. Kraveka, Deanna Mitchell, Kathleen Neville, Randal Wada, Nehal Parikh, Leonard Sender, Timothy Higgins, Andre Bachmann. Phase I trial of relapsed neuroblastoma with DFMO alone and in combination with etoposide. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-179. doi:10.1158/1538-7445.AM2013-LB-179

Abstract 3942: A pilot trial testing the feasibility of using molecular-guided therapy in patients with refractory or recurrent neuroblastoma

Background: Neuroblastoma is the most common extracranial solid tumor in children. The prognosis for infants with neuroblastoma is good, while only 30% of children diagnosed after 12-15 months of age survive despite aggressive multimodal therapies. There are currently few treatment options from which pediatric oncologists can select with any degree of confidence to improve the management of multiply recurrent neuroblastoma patients. The identification of agents through genomic profiling that target specific molecular pathways associated with the development and/or progression of neoplastic diseases holds promise. Improved approaches that identify effective existing agents in a rational, data-driven fashion may result in a survival benefit in the clinical setting, while avoiding the toxicity associated with agents that are unlikely to be beneficial. Method: The primary objective of this pilot study was to evaluate the feasibility of using predictive modeling based on genome-wide mRNA expression profiles of neuroblastoma tumor biopsies to make real-time treatment decisions. Feasibility was defined as the completion of the following in a two week time period: tumor biopsy, quality RNA extraction, mRNA U133 2+ Affymetrix gene chip hybridization, analysis utilizing a series of predictive methodologies, report generation, tumor board review with formulated treatment plan, and medical monitor review. Results: There were 5 patients enrolled between April-June 2010 with multiply relapsed or refractory neuroblastoma. Patients had received between 2-13 previous relapsed therapies and were between 2-6.5 years post diagnosis. All patients had soft tissue disease which was able to be biopsied. All biopsies were adequate by pathology evaluation (>75% viable tumor) and RNA quality (>6.5 RIN). Gene chips were completed in 3-7 days, report generation was 1-5 days, tumor board was 1-3 days, medical monitor sign off was 1 day. The total time was 10-12 days for all patients. The tumor board was able to create individualized therapy regimens for all patients. Correlative biology specimens were obtained and grown in culture. Mice xenografts of 2/5 patients were established. Cultures and xenografts were used for validation studies of predicted drug sensitivity. Conclusion: It is feasible to obtain real-time genomic profiling for molecularly guided therapy for use in treatment decision making. This warrants further testing in a Phase I study. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3942. doi:10.1158/1538-7445.AM2011-3942