A pilot study of the pan-class I PI3K inhibitor buparlisib in combination with cetuximab in patients with recurrent or metastatic head and neck cancer.

BACKGROUND: This study assessed the maximum tolerated dose (MTD) of the PI3K inhibitor buparlisib given concurrently with cetuximab in recurrent and metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). METHODS: Twelve patients with R/M HNSCC were enrolled. Patients were given oral buparlisib starting day 7 and daily thereafter. The dose of buparlisib was escalated in a 3 + 3 design followed by a dose expansion cohort of 6 patients. The MTD of buparlisib per protocol was 100 mg daily with cetuximab given intravenously every 14 days starting day 0. RESULTS: Ten patients had ≥2 previous treatment regimens (11 with prior cetuximab). There were no dose limiting toxicities observed during dose escalation. One patient achieved a partial response and 4 achieved stable disease. CONCLUSION: Based on this pilot study, buparlisib at 100 mg daily plus cetuximab proved to be well-tolerated. Patients previously treated with cetuximab monotherapy showed benefit from this combination.

Final Results of a Randomized Phase 2 Trial Investigating the Addition of Cetuximab to Induction Chemotherapy and Accelerated or Hyperfractionated Chemoradiation for Locoregionally Advanced Head and Neck Cancer.

PURPOSE: The role of cetuximab in the treatment of locoregionally advanced head and neck squamous cell cancer (LA-HNSCC) remains poorly defined. In this phase 2 randomized study, we investigated the addition of cetuximab to both induction chemotherapy (IC) and hyperfractionated or accelerated chemoradiation. METHODS AND MATERIALS: Patients with LA-HNSCC were randomized to receive 2 cycles of weekly IC (cetuximab, paclitaxel, carboplatin) and either Cetux-FHX (concurrent cetuximab, 5-fluorouracil, hydroxyurea, and 1.5 Gy twice-daily radiation therapy every other week to 75 Gy) or Cetux-PX (cetuximab, cisplatin, and accelerated radiation therapy with delayed concomitant boost to 72 Gy in 42 fractions). The primary endpoint was progression-free survival (PFS), with superiority compared with historical control achieved if either arm had 2-year PFS ≥70%. RESULTS: 110 patients were randomly assigned to either Cetux-FHX (n=57) or Cetux-PX (n=53). The overall response rate to IC was 91%. Severe toxicity on IC was limited to rash (23% grade ≥3) and myelosuppression (38% grade ≥3 neutropenia). The 2-year rates of PFS for both Cetux-FHX (82.5%) and Cetux-PX (84.9%) were significantly higher than for historical control (P<.001). The 2-year overall survival (OS) was 91.2% for Cetux-FHX and 94.3% for Cetux-PX. With a median follow-up time of 72 months, there were no significant differences in PFS (P=.35) or OS (P=.15) between the treatment arms. The late outcomes for the entire cohort included 5-year PFS, OS, locoregional failure, and distant metastasis rates of 74.1%, 80.3%, 15.7%, and 7.4%, respectively. The 5-year PFS and OS were 84.4% and 91.3%, respectively, among human papillomavirus (HPV)-positive patients and 65.9% and 72.5%, respectively, among HPV-negative patients. CONCLUSIONS: The addition of cetuximab to IC and chemoradiation was tolerable and produced long-term control of LA-HNSCC, particularly among poor-prognosis HPV-negative patients. Further investigation of cetuximab may be warranted in the neoadjuvant setting and with non-platinum-based chemoradiation.

Phase II study of gefitinib adaptive dose escalation to skin toxicity in recurrent or metastatic squamous cell carcinoma of the head and neck.

BACKGROUND: Gefitinib has activity in patients with advanced squamous cell carcinoma of the head and neck (SCCHN) and skin toxicity has been postulated to be a predictor of response and improved outcome. METHODS: This open-label, multi-institution, phase II study evaluated the activity of gefitinib at individually escalated doses up to 750 mg to achieve the skin toxicity grade ≥2. RESULTS: Forty four patients were enrolled. Only twenty-three (52%) experienced skin rash grade ≥2. Of 44 patients, partial responses were noted in 3 (7%), stable disease in 8 (18%) and progressive disease in 33 patients. Median progression-free survival was 1.9 months (95% CI 1.6-2.2) and median overall survival was 5.1 months (95% CI 2.4-7.8). Grade of skin rash was not associated with response rate (p=0.169) nor tumor control rate (p=0.284); however, higher gefitinib trough levels were associated with disease control. Of the 11 tissue samples analyzed for EGFR gene copy by FISH, 7 were EGFR FISH positive, but this was not associated with improved tumor control or survival. CONCLUSIONS: Gefitinib has clinical activity as monotherapy in SCCHN. Dose escalation of gefitinib is feasible and may increase skin toxicity, but our data do not support increased activity.

Epidermal growth factor receptor inhibitor gefitinib added to chemoradiotherapy in locally advanced head and neck cancer.

PURPOSE: Assess efficacy and toxicity of gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, added to, and in maintenance after, concurrent chemoradiotherapy (CCRT) in locally advanced head and neck cancer (LA-HNC) and correlate outcomes with EGFR gene copy number alterations. PATIENTS AND METHODS: Patients with stage III to IV LA-HNC received two cycles of carboplatin/paclitaxel induction chemotherapy (IC) followed by split-course CCRT with fluorouracil, hydroxyurea, twice daily radiotherapy (FHX), and gefitinib (250 mg daily) followed by continued gefitinib for 2 years total. The primary end point was complete response (CR) rate after CCRT. EGFR gene copy number was assessed by fluorescent in situ hybridization. RESULTS: Sixty-nine patients (66 with stage IV disease, 37 with oropharynx primary tumors, and 67 with performance status 0 to 1) were enrolled with a median age of 55 years. Predominant grade 3 or 4 toxicities during IC and CCRT were neutropenia (n = 20) and in-field mucositis (n = 59) and dermatitis (n = 23), respectively. CR rate after CCRT was 90%. After median follow-up of 3.5 years, 4-year overall, progression-free, and disease-specific survival rates were 74%, 72%, and 89%, respectively. To date, one patient has developed a second primary tumor in the aerodigestive tract. In 31 patients with available tissue, high EGFR gene copy number was associated with worse overall survival (P = .02). CONCLUSION: Gefitinib can be administered with FHX and as maintenance therapy for at least 2 years, demonstrating CR and survival rates that compare favorably with prior experience. High EGFR gene copy number may be associated with poor outcome in patients with LA-HNC treated with this regimen.

Phase II study of sunitinib malate in head and neck squamous cell carcinoma.

BACKGROUND: Sunitinib is an orally administered multitargeted tyrosine kinase inhibitor of RET, VEGFR, PDGFR, and c-KIT. We conducted a phase II trial to evaluate the tolerability and efficacy of sunitinib in metastatic and/or recurrent SCCHN patients. METHODS: Patients who had received no more than two prior chemotherapy regimens were eligible and, depending on ECOG performance status (PS), were entered into either Cohort A (PS 0-1) or Cohort B (PS 2). Sunitinib was administered in 6-week cycles at 50 mg daily for 4 weeks followed by 2 weeks off. Primary endpoint for Cohort A was objective tumor response. A Simon two-stage design required twelve patients to be enrolled in the first stage and if 1 or fewer responses were observed, further study of this cohort would be terminated due to lack of treatment efficacy. Primary endpoint of Cohort B was to determine the feasibility of sunitinib in patients with ECOG performance status 2. RESULTS: Twenty-two patients were accrued (Cohort A - 15 patients, Cohort B - 7 patients). Median age in cohort A and B was 56 and 61 years, respectively. Grade 3 hematologic toxicities encountered were lymphopenia (18%), neutropenia (14%) and thrombocytopenia (5%). There was only one incidence of grade 4 hematologic toxicity which was thrombocytopenia. Fatigue and anorexia were the most common non-hematologic toxicities. Grade 3 fatigue occurred in 23% of patients. The only grade 4 non-hematologic toxicity was one incidence of gastrointestinal hemorrhage. Non-fatal hemorrhagic complications occurred in 8 patients: epistaxis (3 patients), pulmonary hemorrhage (2 patients), gastrointestinal hemorrhage (2 patients) and tumor hemorrhage (1 patient). Four patients were not evaluable for tumor response (Cohort A - 3patients, Cohort B - 1 pt). One partial response was observed in the entire study. Dose reduction was required in 5 patients (Cohort A - 3 patients for grd 3 fatigue, grd 3 mucositis and recurrent grd 3 neutropenia; Cohort B - 2 patients for grd 3 fatigue and grd 3 nausea). Median time to progression for cohort A and B were 8.4 and 10.5 weeks, respectively. Median overall survival for cohort A and B was 21 and 19 weeks, respectively. CONCLUSIONS: Sunitinib had low single agent activity in SCCHN necessitating early closure of cohort A at interim analysis. Sunitinib was well tolerated in PS 2 patients. Further evaluation of single agent sunitinib in head and neck is not supported by the results of this trial.

Erlotinib and bevacizumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck: a phase I/II study.

BACKGROUND: Epidermal growth factor receptor (EGFR) is a validated target in squamous-cell carcinoma of the head and neck, but in patients with recurrent or metastatic disease, EGFR targeting agents have displayed modest efficacy. Vascular endothelial growth factor (VEGF)-mediated angiogenesis has been implicated as a mechanism of resistance to anti-EGFR therapy. In this multi-institutional phase I/II study we combined an EGFR inhibitor, erlotinib, with an anti-VEGF antibody, bevacizumab. METHODS: Between April 15, 2003, and Jan 27, 2005, patients with recurrent or metastatic squamous-cell carcinoma of the head and neck were enrolled from seven centres in the USA and were given erlotinib (150 mg daily) and bevacizumab in escalating dose cohorts. The primary objectives in the phase I and II sections, respectively, were to establish the maximum tolerated dose and dose-limiting toxicity of bevacizumab when administered with erlotinib and to establish the proportion of objective responses and time to disease progression. Pretreatment serum and tissues were collected and analysed by enzyme-linked immunosorbent assay and immunofluorescence quantitative laser analysis, respectively. This study was registered with ClinicalTrials.gov, number NCT00055913. FINDINGS: In the phase I section of the trial, ten patients were enrolled in three successive cohorts with no dose-limiting toxic effects noted. 46 patients were enrolled in the phase II section of the trial (including three patients from the phase I section) on the highest dose of bevacizumab (15 mg/kg every 3 weeks). Two additional patients were accrued beyond the protocol-stipulated 46, leaving a total of 48 patients for the phase II assessment. The most common toxic effects of any grade were rash and diarrhoea (41 and 16 of 48 patients, respectively). Three patients had serious bleeding events of grade 3 or higher. Seven patients had a response, with four showing a complete response allowing rejection of the null hypothesis. Median time of overall survival and progression-free survival (PFS) were 7.1 months (95% CI 5.7-9.0) and 4.1 months (2.8-4.4), respectively. Higher ratios of tumour-cell phosphorylated VEGF receptor-2 (pVEGFR2) over total VEGFR2 and endothelial-cell pEGFR over total EGFR in pretreatment biopsies were associated with complete response (0.704 vs 0.386, p=0.036 and 0.949 vs 0.332, p=0.036, respectively) and tumour shrinkage (p=0.007 and p=0.008, respectively) in a subset of 11 patients with available tissue. INTERPRETATION: The combination of erlotinib and bevacizumab is well tolerated in recurrent or metastatic squamous-cell carcinoma of the head and neck. A few patients seem to derive a sustained benefit and complete responses were associated with expression of putative targets in pretreatment tumour tissue.

Phase I study of bevacizumab added to fluorouracil- and hydroxyurea-based concomitant chemoradiotherapy for poor-prognosis head and neck cancer.

PURPOSE: We conducted a phase I dose escalation study to determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of bevacizumab, when added to the standard FHX (fluorouracil [FU], hydroxyurea [HU], radiation) chemoradiotherapy platform in poor-prognosis head and neck cancer (HNC) patients. PATIENTS AND METHODS: Patients with recurrent, previously radiated or poor-prognosis, treatment-naive HNC were eligible. Treatment was repeated every 14 days for seven cycles: Bevacizumab was escalated 2.5 to 10 mg/kg, FU 600 to 800 mg/m(2) (120 hours continuous infusion), and hydroxyurea from 500 to 1,000 mg (twice daily for 5 days), starting day 1. At the MTD, the cohort was expanded. RESULTS: Forty-three patients were treated. DLT was reached at level 3 (bevacizumab 5 mg/kg, FU 800 mg/m(2), HU 1,000 mg) with two grade 3 transaminase elevations and one grade 4 neutropenia, attributed to the combination of chemotherapy with bevacizumab. For level 4, chemotherapy doses were reduced (FU 600 mg/(2), HU 500 mg), and bevacizumab escalation continued to 10 mg/kg. Treatment of six assessable patients resulted in one venous thrombosis; this dose level was expanded to 26 patients. Late complications included five patients with fistula formation (11.6%) and four with ulceration/tissue necrosis (9.3%). Serious toxicities (hemorrhage/thrombosis/death) were comparable to prior reirradiation reports. Median overall survival for reirradiated patients with recurrent, nonmetastatic disease was 10.3 months [95% CI, 5.6 to 13.5]; 2-year cumulative incidence of death resulting from disease was 51.7% (95% CI, 31.7 to 68.5). CONCLUSION: Bevacizumab can be integrated with FHX chemoradiotherapy at a dose of 10 mg/m(2) every 2 weeks with decreased chemotherapy doses because of neutropenia. The regimen shows antitumor activity. Observed fistula formation/tissue necrosis may be bevacizumab related, and further investigation should proceed with careful monitoring.

A phase I trial of docetaxel based induction and concomitant chemotherapy in patients with locally advanced head and neck cancer.

The purpose of this study was to determine the maximum tolerated dose (MTD) of docetaxel based induction and concomitant chemoradiotherapy (CRT) after using the FHX platform (5 = 5-FU, H = hydroxyurea, X = Radiation). Patients with Stage III/IV locally advanced HNSCC were enrolled. Induction chemotherapy (carboplatin/docetaxel) was followed by 5 cycles of concomitant docetaxel based CRT. No DLTs were observed in dose levels 1/2 for induction and CRT. Dose level 2 was expanded. The overall survival CR rate after CRT was 79 percent. Median overall (OS) has not been reached and 2-year OS is 80.7 percent. The recommended Phase II dose of docetaxel with FHX CRT is 25 mg/m(2) and 35 mg/m(2) in combination with carboplatin induction (AUC = 6).

Efficacy and safety of caspofungin for the empiric management of fever in neutropenic children.

This retrospective review evaluates the response to caspofungin when given to children with febrile neutropenia and describes adverse effects attributable to caspofungin, including risk of hepatotoxicity during concomitant therapy with cyclosporine. Sixty-seven courses of caspofungin administered to 56 patients (1-17 years) were surveyed; 53 (79%) courses resulted in an overall favorable response. Ten children (15% of courses) experienced an adverse drug-related event that was probably or possibly attributable to caspofungin. Rash and hypokalemia were the most commonly identified adverse effects. One of 19 children receiving caspofungin and cyclosporine concurrently developed hepatotoxicity possibly related to caspofungin.

Pharmacokinetic modelling of a once-daily dosing regimen for intravenous tobramycin in paediatric cystic fibrosis patients.

OBJECTIVES: This study was designed to determine an optimal dose range for the once-daily dosing (ODD) of tobramycin in the treatment of an acute pulmonary exacerbation in paediatric cystic fibrosis (CF) patients. In addition, we aimed to assess whether certain patient characteristics affect tobramycin pharmacokinetics and, therefore, dosing. METHODS: Patient characteristics and pharmacokinetic parameters of patients receiving tobramycin three times daily from 1 January 1992 to 31 October 2005 were analysed using univariate analysis and multiple linear regression to determine statistically significant relationships and to derive dosing models. The binary partitioning method was used to derive critical values to determine stratification within the chosen dosing model. RESULTS: Using multiple linear regression, age and sex were significantly associated with the volume of distribution divided by the body weight (V/kg). By the binary partitioning method, the critical value for age was 13.75 years. CONCLUSIONS: Age and sex were used to derive an ODD regimen for tobramycin in paediatric CF. Using a target peak concentration range of 25-35 mg/L, the initial dose for female CF patients at least 14 years of age was calculated to be 7 mg/kg/day given intravenously as a single daily dose. All other CF patients would receive an initial dose of 9 mg/kg/day given intravenously as a single daily dose. These dosing guidelines will require prospective evaluation for safety and efficacy.

Meta-analysis of randomized controlled trials of prophylactic granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor after autologous and allogeneic stem cell transplantation.

PURPOSE: The primary objective of our meta-analysis was to determine whether prophylactic hematopoietic colony-stimulating factors (CSFs) after hematopoietic autologous and allogeneic stem-cell transplantation (SCT) reduced documented infections. Our secondary objectives were to determine whether prophylactic CSFs affected other outcomes including parenteral antibiotic therapy duration, infection-related mortality, graft-versus-host disease (GVHD), or treatment-related mortality. METHODS: We included studies if there was random assignment between CSFs and placebo/no therapy and CSFs were given after SCT and before recovery of neutrophils. From 3,778 reviewed study articles, 34 were included based on predefined inclusion criteria. All analyses were conducted using a random effects model. RESULTS: CSFs reduced the risk of documented infections (relative risk [RR] 0.87; 95% CI, 0.76 to 1.00; P = .05) and duration of parenteral antibiotics (weighted mean difference, -1.39 days, 95% CI, -2.56 to -0.22; P = .02) but did not reduce infection-related mortality (RR, 0.76; 95% CI, 0.41 to 1.44; P = .4). CSFs did not increase grade 2 to 4 acute GVHD (RR, 1.03; 95% CI, 0.81 to 1.31; P = .8) or treatment-related mortality (RR, 1.00; 95% CI, 0.78 to 1.29; P = .98). CONCLUSION: CSFs were associated with a small reduction in the risk of documented infections but did not affect infection or treatment-related mortality.

Intensity-modulated radiation therapy in advanced head and neck patients treated with intensive chemoradiotherapy: preliminary experience and future directions.

We review our recent experience with intensity-modulated radiation therapy (IMRT) and conventional three-dimensional radiation therapy (C3DRT) in advanced head and neck cancer. Sixty-nine patients with Stage IV head and neck cancer (and stage III base of tongue and hypopharynx) enrolled in a Phase II study of definitive chemoradiation; 20 received all or part of their radiation with IMRT. Image-guided set-up, using video subtraction techniques, was used in all patients. Six weekly doses of induction carboplatin (AUC=2) and paclitaxel (135 mg/m2) were followed by alternating weekly chemoradiation to 75 Gy with 1.5 Gy BID fractions, concurrent with paclitaxel (100 mg/m2/week), 5-fluorouracil (600 mg/m2/d) and hydroxyurea (500 mg PO BID). Two consecutive cohorts enrolled, differing in radiation scheme: 75 Gy to gross disease in both, 60 or 54 Gy to first echelon lymphatics and 45 or 39 Gy to second echelon lymphatics. With a median follow-up of 47 months, 3-year overall survival is 68.5% and 3-year locoregional control is 94.0%, with no significant differences between those treated with C3DRT versus IMRT, nor between the two radiation dosing schemes. Actuarial overall survival without tracheostomy or laryngectomy, or without a gastrostomy tube was also similar. Acute mucositis, dermatitis and pain were similar with C3DRT and IMRT. Preliminary data suggests IMRT is well tolerated, and does not compromise locoregional control, indicating that IMRT adequately covers the clinical volume at risk. Building on the present clinical experience, future directions include more directed efforts at reducing toxicity, with better planning software and planning techniques.

Phase II trial of gefitinib 250 mg daily in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck.

PURPOSE: An objective response rate of 11% was reported in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) treated with 500 mg daily gefitinib although the recommended dose in lung cancer is 250 mg. This study evaluated the efficacy and toxicity of 250 mg daily gefitinib in patients with recurrent and/or metastatic SCCHN. EXPERIMENTAL DESIGN: Phase II trial with objective response rate as the primary end point. Measurements of quality of life and levels of serum vascular endothelial growth factor and transforming growth factor-alpha were assessed before and during therapy. RESULTS: In 70 patients, 1 (1.4%) partial response was observed. Median progression-free survival and overall survival were 1.8 and 5.5 months, respectively. Quality of life scores improved transiently during the first weeks of therapy before returning to baseline. Median vascular endothelial growth factor and transforming growth factor-alpha levels were above the normal range but were not predictive of outcome. Four patients experienced grade 3 drug-related adverse events. Rash of any grade was observed in 64% of subjects. Correlation between disease control (partial response + stable disease), progression-free survival, and overall survival and grade of cutaneous toxicity was observed (P = 0.001, 0.001, and 0.008 respectively). CONCLUSIONS: Gefitinib monotherapy at 250 mg in recurrent and/or metastatic SCCHN seems to have less activity than was previously observed for 500 mg daily. A dose-response relationship may exist for this agent in SCCHN and grade of cutaneous toxicity attributable to gefitinib is a clinical predictor of better outcome.