Evaluation of cytarabine against Ewing sarcoma xenografts by the pediatric preclinical testing program

Houghton, Peter J.; Morton, Christopher L.; Kang, Min H.; Reynolds, C. Patrick; Billups, Catherine A.; Favours, Edward; Payne-Turner, Debbie; Tucker, Chandra L.; Smith, Malcolm A.

doi:10.1002/pbc.22355

Cited by 10 publications

(7 citation statements)

References 16 publications

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“…Conversely, cytarabine was shown to inhibit the therapeutic target in Ewing's sarcoma, with compelling preclinical activity both in vitro and in vivo , yet no activity was observed in a subsequent phase II trial . Despite the specificity of cytarabine toward EWS‐FLI1 , subsequent preclinical studies in an extended in vivo panel inferred a lack of activity in this cancer type . Although it has been suggested that more rigorous preclinical testing may have predicted this clinical outcome prior to trial initiation , there are no objective data to help guide preclinical researchers and trialists as to how much preclinical evidence is needed before a trial should be initiated, which preclinical studies best predict clinical success, or the translational relevance of current preclinical testing paradigms .…”

Section: Introductionmentioning

confidence: 99%

Predictors of Success of Phase II Pediatric Oncology Clinical Trials

et al. 2019

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Background There are limited data to predict which novel childhood cancer therapies are likely to be successful. To help rectify this, we sought to identify the factors that impact the success of phase II clinical trials for pediatric malignancies. Materials and Methods We examined the impact of 24 preclinical and trial design variables for their influence on 132 phase II pediatric oncology clinical trials. Success was determined by an objective assessment of patient response, with data analyzed using Fisher's exact test, Pearson's chi‐square test, and logistic regression models. Results Trials that evaluated patients with a single histological cancer type were more successful than those that assessed multiple different cancer types (68% vs. 47%, 27%, and 17% for 1, 2–3, 4–7, and 8+; p < .005). Trials on liquid or extracranial solid tumors were more successful than central nervous system or combined trials (70%, 60%, 38%, and 24%; p < .005), and trials of combination therapies were more successful than single agents (71% vs. 28%; p < .005). Trials that added therapies to standard treatment backbones were more successful than trials testing novel therapies alone or those that incorporated novel agents (p < .005), and trials initiated based on the results of adult studies were less likely to succeed (p < .05). For 61% of trials (80/132), we were unable to locate any relevant preclinical findings to support the trial. When preclinical studies were carried out (52/132), there was no evidence that the conduct of any preclinical experiments made the trial more likely to succeed (p < .005). Conclusion Phase II pediatric oncology clinical trials that examine a single cancer type and use combination therapies have the highest possibility of clinical success. Trials building upon a standard treatment regimen were also more successful. The conduct of preclinical experiments did not improve clinical success, emphasizing the need for a better understanding of the translational relevance of current preclinical testing paradigms. Implications for Practice To improve the clinical outcomes of phase II childhood cancer trials, this study identified factors impacting clinical success. These results have the potential to impact not only the design of future clinical trials but also the assessment of preclinical studies moving forward. This work found that trials on one histological cancer type and trials testing combination therapies had the highest possibility of success. Incorporation of novel therapies into standard treatment backbones led to higher success rates than testing novel therapies alone. This study found that most trials had no preclinical evidence to support initiation, and even when preclinical studies were available, they did not result in improved success.

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Section: Introductionmentioning

confidence: 99%

Predictors of Success of Phase II Pediatric Oncology Clinical Trials

et al. 2019

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“…For example, an mTOR inhibitor, MLN0128, was more active in solid tumor lines than in leukemia . Of note, the greatest differential sensitivity of the leukemic cell line panel over the solid tumor panel was for cytosine arabinoside (cytarabine), a drug used extensively in the treatment of childhood ALL …”

Section: Discussionmentioning

confidence: 99%

“…[8] Of note, the greatest differential sensitivity of the leukemic cell line panel over the solid tumor panel was for cytosine arabinoside (cytarabine), a drug used extensively in the treatment of childhood ALL. [9] In vivo, NSC 750854 was tested at a dose of 5 mg/kg administered IP daily for 5 days with the cycle repeated at day 15. This dose was selected based upon prior toxicity testing, and it is in the range of doses used previously against adult cancer models.…”

Section: Discussionmentioning

confidence: 99%

Initial Testing of NSC 750854, a Novel Purine Analog, Against Pediatric Tumor Models by the Pediatric Preclinical Testing Program

Görlick

Kolb

Keir

et al. 2015

Pediatr Blood Cancer

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Background NSC 750854 is a purine analog with an antitumor activity profile distinctive from that of other anticancer purines. It has shown significant activity against adult cancer preclinical models. Procedures NSC 750854 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro cell line panel at concentrations from 1.0 nM to 10 μM and against the PPTP in vivo xenograft panels administered intraperitoneally at a dose of 5 mg/kg, daily × 5 repeated at day 15. Results The median relative IC50 (rIC50) value for the PPTP cell lines was 32 nM, (range from 11 nM-124 nM), with consistent cytotoxicity across all cell lines. Acute lymphoblastic leukemia (ALL) cell lines were more sensitive to NSC 750854 than non-ALL cell lines. NSC 750854 induced significant differences in EFS distribution compared to control in 31 of 35 (89%) solid tumor xenografts. It induced tumor growth inhibition meeting criteria for intermediate or high EFS T/C activity in 17 of 32 (53%) evaluable solid tumor xenografts (most consistently in the rhabdomyosarcoma panel). Objective responses were observed in 15 of 37 (41%) solid tumor xenografts and in all 8 leukemia models with CR or MCR in 7 of 8. Conclusions NSC-750854 has a unique spectrum of antitumor activity compared with other agents tested by the PPTP as it induces regression in tumor models with limited sensitivity to most agents tested to date. Given the promising level of activity observed for NSC 750854 against PPTP preclinical models, further exploration of its mechanism of action is warranted.

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“…Cytarabine was found to be the most active agent tested in study 2, a result supporting its use in the patient. Interestingly, whilst cytarabine induces differentiation in RMS cell lines reducing in vivo tumorigencity [44], cytarabine has been found to be ineffective in both a Phase II clinical trial in patients with relapsed or refractory Ewing sarcoma [45], and by the Pediatric Preclinical Testing Program (PPTP) in sarcoma cell lines, including RMS and Ewing sarcoma PDX models [46]. Taken together, these results support the use of predictions based on gene expression of initial patient tumor harvest and propagated F0 PDX tumors, thus potentially minimizing the need to re-sample a patient's tumor following the development of resistance.…”

Section: Discussionmentioning

confidence: 99%