Research Spotlight

Reardon, D. A., A. Desjardins, J. J. Vredenburgh, D. M. O’Rourke, D. D. Tran, K. L. Fink, L. B. Nabors, G. Li, D. A. Bota, R. V. Lukas, L. S. Ashby, J. P. Duic, M. M. Mrugala, S. Cruickshank, L. Vitale, Y. He, J. A. Green, M. J. Yellin, C. D. Turner, T. Keler, T. A. Davis and J. H. Sampson (2020). “Rindopepimut with Bevacizumab for Patients with Relapsed EGFRvIII-Expressing Glioblastoma (ReACT): Results of a Double-Blind Randomized Phase II Trial.” Clin Cancer Res 26(7): 1586-1594.

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PURPOSE: Rindopepimut is a vaccine targeting the tumor-specific EGF driver mutation, EGFRvIII. The ReACT study investigated whether the addition of rindopepimut to standard bevacizumab improved outcome for patients with relapsed, EGFRvIII-positive glioblastoma. PATIENTS AND METHODS: In this double-blind, randomized, phase II study (NCT01498328) conducted at 26 hospitals in the United States, bevacizumab-naive patients with recurrent EGFRvIII-positive glioblastoma were randomized to receive rindopepimut or a control injection of keyhole limpet hemocyanin, each concurrent with bevacizumab. The primary endpoint was 6-month progression-free survival (PFS6) by central review with a one-sided significance of 0.2. RESULTS: Between May 2012 and 2014, 73 patients were randomized (36 rindopepimut, 37 control). Rindopepimut toxicity included transient, low-grade local reactions. As primary endpoint, PFS6 was 28% (10/36) for rindopepimut compared with 16% (6/37) for control (P = 0.12, one-sided). Secondary and exploratory endpoints also favored the rindopepimut group including a statistically significant survival advantage [HR, 0.53; 95% confidence interval (CI), 0.32-0.88; two-sided log-rank P = 0.01], a higher ORR [30% (9/30) vs. 18% (6/34; P = 0.38)], median duration of response [7.8 months (95% CI, 3.5-22.2) vs. 5.6 (95% CI, 3.7-7.4)], and ability to discontinue steroids for >/=6 months [33% (6/18) vs. 0% (0/19)]. Eighty percent of rindopepimut-treated patients achieved robust anti-EGFRvIII titers (>/=1:12,800), which were associated with prolonged survival (HR = 0.17; 95% CI, 0.07-0.45; P < 0.0001). CONCLUSIONS: Our randomized trial supports the potential for targeted immunotherapy among patients with GBM, but the therapeutic benefit requires validation due to the small sample size and potential heterogeneity of bevacizumab response among recurrent patients with GBM.See related commentary by Wick and Wagener, p. 1535.

Raoof, T. J., D. Hooper, A. Moore, M. Zaiac, T. Sullivan, L. Kircik, E. Lain, J. Jankicevic and I. Stuart (2020). “Efficacy and safety of a novel topical minocycline foam for the treatment of moderate to severe acne vulgaris: A phase 3 study.” J Am Acad Dermatol 82(4): 832-837.

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BACKGROUND: FMX101 4% topical minocycline foam has been shown to be an effective and safe treatment for acne vulgaris (AV). OBJECTIVE: To further evaluate the efficacy and safety of FMX101 4% in treating moderate to severe acne vulgaris. METHODS: A 12-week, multicenter, randomized (1:1), double-blind, vehicle-controlled study was conducted. Coprimary end points were the absolute change in inflammatory lesion count from baseline and the rate of treatment success (Investigator’s Global Assessment score of 0 or 1 with a >/=2-grade improvement). RESULTS: There were 1488 participants in the intent-to-treat population. The FMX101 4% group had significantly greater reductions in the number of inflammatory lesions from baseline (P < .0001) and a greater rate of treatment success based on Investigator's Global Assessment (P < .0001) versus the foam vehicle group at week 12. FMX101 4% was generally safe and well tolerated. LIMITATIONS: The efficacy and safety of FMX101 4% were not characterized in participants with mild AV. CONCLUSION: FMX101 4% topical minocycline.

Puduvalli, V. K., J. Wu, Y. Yuan, T. S. Armstrong, E. Vera, J. Wu, J. Xu, P. Giglio, H. Colman, T. Walbert, J. Raizer, M. D. Groves, D. Tran, F. Iwamoto, N. Avgeropoulos, N. Paleologos, K. Fink, D. Peereboom, M. Chamberlain, R. Merrell, M. Penas Prado, W. K. A. Yung and M. R. Gilbert (2020). “A Bayesian Adaptive Randomized Phase II Multicenter Trial of Bevacizumab with or without Vorinostat in Adults with Recurrent Glioblastoma.” Neuro Oncol Mar 13. pii: noaa062. [Epub ahead of print].

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BACKGROUND: Bevacizumab has promising activity against recurrent glioblastoma (GBM). However, acquired resistance to this agent results in tumor recurrence. We hypothesized that vorinostat, a histone deacetylase (HDAC) inhibitor with antiangiogenic effects, would prevent acquired resistance to bevacizumab. METHODS: This multicenter phase II trial used a Bayesian adaptive design to randomize patients with recurrent GBM to bevacizumab alone or bevacizumab plus vorinostat with the primary endpoint of progression-free survival (PFS) and secondary end points of overall survival (OS) and clinical outcomes assessment (MDASI-BT). Eligible patients were adults (>/=18 yrs) with histologically confirmed GBM recurrent after prior radiation therapy, with adequate organ function, KPS>/=60, and no prior bevacizumab or HDAC inhibitors. RESULTS: Ninety patients (bevacizumab+vorinostat:49, bevacizumab:41) were enrolled of whom 74 were evaluable for PFS (bevacizumab+vorinostat:44, bevacizumab:30). Median PFS (3.7 vs 3.9 months, p=0.94, HR 0.63 [95% CI 0.38, 1.06, p=0.08]), median OS (7.8 vs 9.3 months, p=0.64, HR 0.93 [95% CI 0.5, 1.6, p=0.79]) and clinical benefit were similar between the two arms. Toxicity (>/=grade 3) in 85 evaluable patients included hypertension (n=37), neurological changes (n=2), anorexia (n=2), infections (n=9), wound dehiscence (n=2), DVT/PE (n=2), and colonic perforation (n=1). CONCLUSIONS: Bevacizumab combined with vorinostat did not yield improvement in PFS, OS or clinical benefit compared with bevacizumab alone nor a clinical benefit in adults with recurrent GBM. This trial is the first to test a Bayesian adaptive design with adaptive randomization and Bayesian continuous monitoring in patients with primary brain tumor and demonstrates the feasibility of using complex Bayesian adaptive design in a multicenter setting.

Pineda, R., D. Prince, J. Reynolds, M. Grabill and J. Smith (2020). “Preterm infant feeding performance at term equivalent age differs from that of full-term infants.” J Perinatol 40(4): 646-654.

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OBJECTIVE: To identify differences in feeding skill performance among preterm infants at term equivalent age compared with full-term infants. STUDY DESIGN: Ninety-two infants (44 preterm infants born

Philipp, S., A. Menter, A. F. Nikkels, K. Barber, I. Landells, L. F. Eichenfield, M. Song, B. Randazzo, S. Li, M. C. Hsu, Y. Zhu, S. DePrimo and A. S. Paller (2020). “Ustekinumab for the treatment of moderate-to-severe plaque psoriasis in pediatric patients (>/=6 to <12 years of age): efficacy, safety, pharmacokinetic, and biomarker results from the open-label CADMUS Jr study." Br J Dermatol Mar 16. [Epub ahead of print].

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BACKGROUND: Limited options are available for treatment of pediatric psoriasis. OBJECTIVES: To evaluate the efficacy and safety of ustekinumab in pediatric psoriasis patients (>/=6 to <12 years of age). METHODS: CADMUS Junior (Jr), a phase 3, open-label, single-arm, multicenter study, evaluated ustekinumab in pediatric patients with moderate-to-severe plaque psoriasis. Patients received weight-based dosing of ustekinumab (<60kg: 0.75mg/kg; >/=60to100kg: 90mg) administered by subcutaneous injection at weeks 0/4, then every-12-weeks through week 40. Study endpoints (all at week 12) included the proportions of patients achieving a Physician’s Global Assessment score of cleared/minimal (PGA 0/1) and >/=75%/90% improvement in Psoriasis Area and Severity Index (PASI 75/90) and change in Children’s Dermatology Life Quality Index (CDLQI). Serum ustekinumab concentrations, anti-drug antibodies (ADA), and cytokine levels were measured through week 52. Safety was evaluated through week 56. RESULTS: A total of 44 patients (median age, 9.5 years) received at least one dose of ustekinumab. Three patients discontinued study agent through week 40. At week 12, 77.3% of patients achieved PGA 0/1, 84.1% achieved PASI 75, and 63.6% achieved PASI 90 response; mean change in CDLQI was -6.3. Trough serum ustekinumab concentrations reached steady state at weeks 28-52. The incidence of ADA was 9.5% (n=4). Mean serum concentrations of IL-17A/F and IL-22 were significantly reduced at weeks 12/52. Overall, 34 patients (77.3%) had at least one adverse event and 3 (6.8%) had a serious adverse event. CONCLUSIONS: Ustekinumab effectively treated moderate-to-severe psoriasis in pediatric patients, and no new safety concerns were identified.