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Page 4 of 10 Farlow et al. J Cancer Metastasis Treat 2019;5:18 I http://dx.doi.org/10.20517/2394-4722.2018.100
Table 1. Window trials of targeted therapies in head and neck squamous cell carcinoma
Toxicity/surgery
Ref. Agent(s) n* Inclusion criteria Duration Outcome(s) Biomarkers
delays
Day et al. [17] Rapamycin 16 (21 ) Stage II-IV OC/OP 21 days Tumor size (clinically, CT/ NS
‡
RECIST)
Machiels et al. [15] 1. Afatinib 25 Stage II-IV OC/OP 14 days 18 FDG-PET response TP53 genotype, G3 diarrhea, renal
2. No drug 5 (30) (EORTC, RECIST); DCE- hypoxia screen failure (n = 1),
MRI; DW-MRI surgery delay (n = 3)
Bauman et al. [14] 1. Erlotinib 14 Stage I-IV OC/OP/L 2-21 days Tumor size (CT) pMAPK, None
2. Desatinib 15 pSTAT3
3. Combination 14
4. Placebo 15 (56)
Uppaluri et al. [16] Trametinib 20 Stage II-IV OC 7-16 days Tumor size, SUV (PET/CT; NR G4 duodenal
(20) WHO); tumor stage perforation (n = 1),
G2 nausea (n = 1);
3 patients stopped
treatment
Ferris et al. [10] Cetuximab 40 (40) Stage III-IV OC/OP/ 21-28 days Tumor size (CT); EGFR-specific T NR
L/HP progression free survival cell counts
Gross et al. [13] 1. Erlotinib 19 Stage II-IVA OC/ 7-14 days Ki67 proliferation index pSrc G2 anxiety (n = 1
2. Erlotinib + 16 OP/L/HP stopped treatment),
Sulindac G2 mucositis (n = 1
†
3. Placebo 12 (39 ) decreased dosage)
Schmitz et al. [9] 1. Cetuximab 33 T1-T4 OC/OP/L/HP 21 days 18 FDG-PET response NS None
2. No drug 5 (SUV); tumor size (CT/
MRI); tumor cellularity
Thomas et al. [12] Erlotinib 35 T2-T4 OC/OP/L/ 18-29 days Tumor size (CT) p21 waf G3 pruritis and G2
HP rash (n = 6; n = 3
stopped treatment)
Studies listed by date published. ‡n = 21 and n = 37 listed as accrual number and actual enrollment on ClinicalTrials.gov, with n = 16
included in the published manuscript; †accrual number modified based on discontinuation of parent study; *sample sizes listed include
actual number of subjects, with the amount necessary for full accrual in parentheses if published. Biomarkers listed in the table include
biologic characteristics statistically associated with sensitivity or resistance to the tested therapy. Toxicities only include those attributed
to or possibly attributed to the drug being studied that are grade (G) 3 or higher or caused treatment dosage reduction or discontinuation.
Ref.: reference; HNSCC: head and neck squamous cell carcinoma; OC: oral cavity; OP: oropharynx; P: pharynx; HP: hypopharynx; L: larynx;
CT: computed tomography; FDG-PET: 18-fluorodeoxyglucose-positron emission tomography; SUV: standardized uptake value; DCE-MRI:
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dynamic contrast enhanced magnetic resonance imaging; DW-MRI: diffusion-weighted MRI; RECIST: response evaluation criteria in solid
tumors; EORTC: European Organization for Research and Treatment of Cancer; WHO: World Health Organization; NS: not significant; NR:
not reported
[15]
In another recent multicenter window study, Machiels et al. randomized 30 subjects to afatinib (an
irreversible second generation inhibitor of the EGFR-family of receptor tyrosine kinases) or no drug prior
to surgery. There were several afatinib-related adverse events, leading to discontinuation of the drug in one
patient and a delay of surgery by 24 days in one subject, as well as delayed surgery with continuation of
afatinib in two additional subjects. Radiologic response was seen in 16 of 23 evaluable subjects in the afatinib
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arm by FDG-PET and in 5 of 23 subjects by RECIST criteria. Tumor protein p53 (TP53) wild type allele and
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a hypoxia expression screen were associated with FDG-PET results but not responses by RECIST criteria.
OTHER TARGETED WINDOW TRIALS
[16]
Uppaluri et al hypothesized that MAPK/extracellular-signal-regulated kinase (ERK) pathway could be
[16]
targeted in oral cavity HNSCC. They performed a window trial of trametinib, an inhibitor of MAPK/
ERK kinase, that resulted in decreased tumor size by FDG avidity by PET/CT and tumor downstaging in
approximately half of the 17 evaluable subjects. There were, however, 3 subjects who discontinued the study,
including one who suffered a grade 4 duodenal perforation. While there was biochemical evidence of a
suppressed MAPK/ERK pathway in a third of evaluable patients, no clear correlation between biochemical
results and responsiveness to trametinib was drawn.
[17]
Recently, Day et al. undertook a single-armed window trial of rapamycin, an inhibitor of the mammalian
target of rapamycin pathway that is dysregulated in the majority of HNSCC. Their inclusion criteria differed