Tebentafusp in Patients with Metastatic Uveal Melanoma: A Real-Life Retrospective Multicenter Study.

BACKGROUND: Tebentafusp has recently been approved for the treatment of metastatic uveal melanoma (mUM) after proving to have survival benefits in a first-line setting. PATIENTS AND METHODS: This retrospective, multicenter study analyzed the outcomes and safety of tebentafusp therapy in 78 patients with mUM. RESULTS: Patients treated with tebentafusp had a median PFS of 3 months (95% CI 2.7 to 3.3) and a median OS of 22 months (95% CI 10.6 to 33.4). In contrast to a published Phase 3 study, our cohort had a higher rate of patients with elevated LDH (65.4% vs. 35.7%) and included patients with prior systemic and local ablative therapies. In patients treated with tebentafusp following ICI, there was a trend for a longer median OS (28 months, 95% CI 26.9 to 29.1) compared to the inverse treatment sequence (24 months, 95% CI 13.0 to 35.0, p = 0.257). The most common treatment-related adverse events were cytokine release syndrome in 71.2% and skin toxicity in 53.8% of patients. Tumor lysis syndrome occurred in one patient. CONCLUSIONS: Data from this real-life cohort showed a median PFS/OS similar to published Phase 3 trial data. Treatment with ICI followed by tebentafusp may result in longer PFS/OS compared to the inverse treatment sequence.

Radiation Dose Aspects of Hepatic Artery Infusion Chemotherapy in Uveal Melanoma Patients with Liver Metastases.

PURPOSE: In uveal melanoma patients, liver metastases can be treated by hepatic artery infusion chemotherapy (HAIC). During this procedure, melphalan or, less frequently, fotemustine is infused into the hepatic artery or the hepatic lobe arteries in regularly repeated interventions to achieve local tumor control. The aim of this study was to investigate the radiation exposure of HAIC. MATERIAL AND METHODS: In this retrospective study, dose data from 841 procedures in 140 patients (mean age 65.3 ± 9.9 years, 74 female) who underwent HAIC between 06/2017 and 10/2021 at one of three different angiography systems were analyzed. RESULTS: In the overall population, dose area product (DAP) (median (IQR)) was 1773 cGy·cm2 (884-3688). DAP was significantly higher in the first intervention, where a complete diagnostic workup of the vasculature was performed, than in follow-up interventions: 5765 cGy·cm2 (3160-8804) versus 1502 cGy·cm2 (807-2712) (p < 0.0001). DAP also increased significantly with the number of infusion positions (median, (IQR)): one position 1301 cGy·cm2 (633-2717), two positions 1985 cGy·cm2 (1118-4074), three positions 6407 cGy·cm2 (2616-11590) (p < 0.0001). CONCLUSION: In uveal melanoma patients with liver metastases undergoing HAIC, radiation exposure is significantly higher both at the first intervention compared to follow-up interventions, but also with increasing number of infusion positions.

Early detection of metastatic uveal melanoma by the analysis of tumor-specific mutations in cell-free plasma DNA.

BACKGROUND: Eye salvaging therapy of malignant melanomas of the uvea can preserve the eye in most cases, but still about half of patients die from metastatic disease. Previous analyses of cell-free DNA from plasma had shown detectable levels of tumor-specific GNAQ/GNA11 mutations in patients with the clinical diagnosis of progressive disease. However, data on the time span that elapses from the detection of ctDNA in plasma to the clinical detection of metastases (diagnostic lead time) are missing. METHODS: We examined 135 patients with uveal melanoma. Cell-free DNA was isolated from a total of 807 blood samples which were taken over a period of up to 41 months and analyzed for the presence of GNAQ/GNA11 mutations by deep amplicon sequencing. RESULTS: Twenty-one of the 135 patients developed metastases or recurrence. A ctDNA signal was identified in the plasma of 17 of the 21 patients. In 10 patients, this ctDNA signal preceded the clinical diagnosis of metastasis by 2-10 months. In 10 other patients, a ctDNA signal was only detected in samples obtained shortly before or after radiotherapy. The presence of a ctDNA signal in 16 of the remaining 125 patients was linked to clinical manifestation of metastases (n = 14) or tumor recurrence (n = 2) with a sensitivity and specificity of 80% and 96%, respectively. CONCLUSION: Detection of ctDNA in plasma can provide a diagnostic lead time over the clinical diagnosis of metastases or tumor recurrence. Longer lead times are to be expected if intervals between sampling are shortened.

Predictive impact of the inflammation-based indices in uveal melanoma liver metastases treated with transarterial hepatic chemoperfusion.

BACKGROUND: The aim of the study was to evaluate pretreatment inflammatory markers as prognostic factors in patients with unresectable uveal melanoma liver metastases treated with transarterial hepatic chemoperfusion. PATIENTS AND METHODS: 54 patients (44% male, median age: 61 years) were retrospectively assessed. A median of 3 (range: 1-11) treatment sessions were performed with melphalan (92%) or fotemustin (8%). Inflammatory indices were calculated as follows: neutrophils/nl to lymphocytes/nl ratio (NLR), systemic immune-inflammation index ([platelets/nl × neutrophils/nl]/[lymphocytes/nl]; SII), and platelets/nl to lymphocytes/nl ratio (PLR). The cut-off for dichotomization purposes was set at the median (inflammatory indices, hepatic tumor burden) or the upper level of normal. Kaplan Meier analysis was performed for median overall survival (OS) in months, and Cox proportional hazard model for uni(UVA) and multivariate (MVA) hazard ratio (HR, 95%CI) analyses were performed. RESULTS: Median OS of the study cohort was 7.7 (6.3-10.9) months. In UVA OS was prolonged for low C reactive protein (CRP) (13.5 vs. 5.2; p = 0.0005), low SII (10.8 vs. 5.6; p = 0.0005), low NLR (11.1 vs. 6.3; p = 0.0045), low aspartate aminotransferase (AST) (11.5 vs. 5.6; p = 0.015), alanine aminotransferases (ALT) (11.5 vs. 5.6; p = 0.01), and tumor burden ≦ 50% (8.2 vs. 4.8; p = 0.007). MVA confirmed low CRP (HR: 0.29, 0.11-0.7; p = 0.005), low SII (HR: 0.19, 0.11-0.7; p = 0.008), and low ALT (HR: 0.13, 0.02-0.63; p = 0.011) as independent predictors for prolonged OS. Patients with ≦ 1, 2, 3 elevated significant MVA-factors survived a median of 14.9, 7.7, and 3.9 months, respectively (p = 0.0001). CONCLUSIONS: Pretreatment inflammatory markers (CRP, SII) and AST were independent prognostic survival markers in patients with uveal melanoma liver metastases treated with transarterial hepatic chemoperfusion. A combination of factors may help to identify patients potentially benefitting from treatment.

Lactate Dehydrogenase Prior to Transarterial Hepatic Chemoperfusion Predicts Survival and Time to Progression in Patients with Uveal Melanoma Liver Metastases.

PURPOSE: To assess serum lactate dehydrogenase (LDH) as a pretreatment prognostic factor in patients with uveal melanoma liver metastases treated with transarterial hepatic chemoperfusion (THC). MATERIALS AND METHODS: 56 patients (48 % male, median age: 63.5 years) underwent a median of 4 THC sessions. Kaplan-Meier for median overall survival (OS) and time to hepatic progression (TTP; 95 %CI) in months and Cox proportional hazards model for uni- (UVA) & multivariate analyses (MVA) for hazard ratio (HR) evaluation were calculated. RESULTS: The median OS was 9.4 months. The pretreatment LDH value before 1st THC was the strongest OS predictor with 19.8 months for normal (≦ 280 units per liter (U/L)), 9.7 for intermediate (> 280-< 1000 U/L), and 3.84 months for high (≧ 1000 U/L) LDH. LDH significantly predicted a median TTP with 8 months, 4 months, and 1 month for normal, intermediate, and high LDH, respectively. UVA revealed intermediate (16.5) and high (77.3) LDH, bilirubin > the upper limit of normal (ULN) (2.89), alkaline phosphatase > 1.5 ULN (6.8), leukocytes > ULN (4.2), gamma-glutamyl transferase (GGT) > ULN (7), extrahepatic metastases (1.8) and liver lesions ≥ 5 cm (3.6) as significant predictors for worse OS. MVA confirmed intermediate (5) and high (27.1) LDH, bilirubin (5.7), GGT (2.9), and tumor size ≥ 5 cm (3.7) as significant independent predictors for worse OS. Patients with decreasing vs. increasing LDH > 10 % between 1st and 2nd THC (median: 38 days) survived longer (14.6 vs. 4.3 months) and progressed later (7 months vs. 1 month). CONCLUSION: Elevated pretreatment serum LDH is an essential and robust OS and TTP predictor, potentially allowing for the identification of patients benefiting most from transarterial hepatic chemoperfusion. KEY POINTS: · Pretherapeutic LDH is the most reliable prognosticator for OS and TTP. · Therapy-related LDH decrease > 10 % between 1st and 2nd THC had prolonged OS and TTP. · Lower Values of LDH, bilirubin, gamma-glutamyl transferase, and tumor size are independent pretherapeutic predictors for longer OS. · Extrahepatic metastases do not have an independent influence on overall survival. CITATION FORMAT: · Ludwig J, Haubold J, Heusner T et al. Lactate Dehydrogenase Prior to Transarterial Hepatic Chemoperfusion Predicts Survival and Time to Progression in Patients with Uveal Melanoma Liver Metastases. Fortschr Röntgenstr 2021; 193: 683 - 691.

Improved survival in metastatic breast cancer: results from a 20-year study involving 1033 women treated at a single comprehensive cancer center.

PURPOSE: Diagnosis and treatment of breast cancer have changed profoundly over the past 25 years. The outcome improved dramatically and was well quantified for early stage breast cancer (EBC). However, progress in the treatment of metastatic disease has been less convincingly demonstrated. We have studied survival data of patients with metastatic breast cancer (MBC) from a large academic cancer center over a period of 20 years. METHODS: Data from 1033 consecutive MBC patients who were treated at the Department of Medical Oncology of the West German Cancer Center from January 1990 to December 2009 were retrospectively analyzed for overall survival (OS) and risk factors. Patients were grouped in 5-year cohorts, and survival parameters of each cohort were compared before and after adjustment for risk factors. RESULTS: Overall survival of patients with MBC treated at specialized center has significantly improved from 1990 to 2010 (hazard ratio 0.7, 95%CI 0.58-0.84). The increments in OS have become less profound over time (median OS 1990-1994: 24.2 months, 1995-1999: 29.6 months, 2000-2004: 36.5 months, 2005-2009: 37.8 months). CONCLUSION: Survival of patients with MBC has improved between 1990 and 2004, but less from 2005 to 2009. Either this suggests an unnoticed shift in the patient population, or a lesser impact of therapeutic innovations introduced in the most recent period.

Rogaratinib in patients with advanced cancers selected by FGFR mRNA expression: a phase 1 dose-escalation and dose-expansion study.

BACKGROUND: The clinical activity of fibroblast growth factor receptor (FGFR) inhibitors seems restricted to cancers harbouring rare FGFR genetic aberrations. In preclinical studies, high tumour FGFR mRNA expression predicted response to rogaratinib, an oral pan-FGFR inhibitor. We aimed to assess the safety, maximum tolerated dose, recommended phase 2 dose, pharmacokinetics, and preliminary clinical activity of rogaratinib. METHODS: We did a phase 1 dose-escalation and dose-expansion study of rogaratinib in adults with advanced cancers at 22 sites in Germany, Switzerland, South Korea, Singapore, Spain, and France. Eligible patients were aged 18 years or older, and were ineligible for standard therapy, with an Eastern Cooperative Oncology Group performance status of 0-2, a life expectancy of at least 3 months, and at least one measurable or evaluable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. During dose escalation, rogaratinib was administered orally twice daily at 50-800 mg in continuous 21-day cycles using a model-based dose-response analysis (continuous reassessment method). In the dose-expansion phase, all patients provided an archival formalin-fixed paraffin-embedded (FFPE) tumour biopsy or consented to a new biopsy at screening for the analysis of FGFR1-3 mRNA expression. In the dose-expansion phase, rogaratinib was given at the recommended dose for expansion to patients in four cohorts: urothelial carcinoma, head and neck squamous-cell cancer (HNSCC), non-small-cell lung cancer (NSCLC), and other solid tumour types. Primary endpoints were safety and tolerability, determination of maximum tolerated dose including dose-limiting toxicities and determination of recommended phase 2 dose, and pharmacokinetics of rogaratinib. Safety analyses were reported in all patients who received at least one dose of rogaratinib. Patients who completed cycle 1 or discontinued during cycle 1 due to an adverse event or dose-limiting toxicity were included in the evaluation of recommended phase 2 dose. Efficacy analyses were reported for all patients who received at least one dose of study drug and who had available post-baseline efficacy data. This ongoing study is registered with ClinicalTrials.gov, number NCT01976741, and is fully recruited. FINDINGS: Between Dec 30, 2013, and July 5, 2017, 866 patients were screened for FGFR mRNA expression, of whom 126 patients were treated (23 FGFR mRNA-unselected patients in the dose-escalation phase and 103 patients with FGFR mRNA-overexpressing tumours [52 patients with urothelial carcinoma, eight patients with HNSCC, 20 patients with NSCLC, and 23 patients with other tumour types] in the dose-expansion phase). No dose-limiting toxicities were reported and the maximum tolerated dose was not reached; 800 mg twice daily was established as the recommended phase 2 dose and was selected for the dose-expansion phase. The most common adverse events of any grade were hyperphosphataemia (in 77 [61%] of 126 patients), diarrhoea (in 65 [52%]), and decreased appetite (in 48 [38%]); and the most common grade 3-4 adverse events were fatigue (in 11 [9%] of 126 patients) and asymptomatic increased lipase (in 10 [8%]). Serious treatment-related adverse events were reported in five patients (decreased appetite and diarrhoea in one patient with urothelial carcinoma, and acute kidney injury [NSCLC], hypoglycaemia [other solid tumours], retinopathy [urothelial carcinoma], and vomiting [urothelial carcinoma] in one patient each); no treatment-related deaths occurred. Median follow-up after cessation of treatment was 32 days (IQR 25-36 days). In the expansion cohorts, 15 (15%; 95% CI 8·6-23·5) out of 100 evaluable patients achieved an objective response, with responses recorded in all four expansion cohorts (12 in the urothelial carcinoma cohort and one in each of the other three cohorts), and in ten (67%) of 15 FGFR mRNA-overexpressing tumours without apparent FGFR genetic aberration. INTERPRETATION: Rogaratinib was well tolerated and clinically active against several types of cancer. Selection by FGFR mRNA expression could be a useful additional biomarker to identify a broader patient population who could be eligible for FGFR inhibitor treatment. FUNDING: Bayer AG.

A phase I dose-escalation study of IMAB362 (Zolbetuximab) in patients with advanced gastric and gastro-oesophageal junction cancer.

INTRODUCTION: IMAB362 (Zolbetuximab) is a chimeric monoclonal antibody that binds to Claudin-18.2, a target antigen specific to cancer cells. In vitro, IMAB362 mediates cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity; thus, IMAB362 may serve as a potent, targeted immunotherapeutic agent. METHODS: This first-in-human phase I study enroled adult patients (N = 15) with advanced gastric or gastro-oesophageal junction cancer into five sequential single dose-escalation cohorts (33, 100, 300, 600, and 1000 mg/m2) following a 3 + 3 design. Safety/tolerability, including determination of maximum tolerated dose and recommended phase II dose, were the primary objectives; secondary objectives included assessment of the IMAB362 pharmacokinetic profile, immunogenicity, and antitumour activity (assessed by Response Evaluation Criteria in Solid Tumors v1.0). RESULTS: IMAB362 was generally well tolerated at all doses, with gastrointestinal toxicities being the most commonly observed treatment-related adverse events. As dose-limiting toxicity was not observed within 4 weeks of treatment, a maximum tolerated dose was not established. The pharmacokinetic profile of IMAB362 appeared to be proportional across the dose range; and mean half-life ranged from 13 to 24 d. While most patients showed progressive disease at weeks 4-5 after a single intravenous IMAB362 infusion, one patient in the 600 mg/m2 dose group achieved and maintained stable disease for approximately 2 months postinfusion. CONCLUSIONS: Findings from this study demonstrate that IMAB362 is generally well tolerated and support further evaluation in patients with gastric/gastro-oesophageal junction cancer. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov, Identifier NCT00909025.

A phase I study of BI 811283, an Aurora B kinase inhibitor, in patients with advanced solid tumors.

PURPOSE: This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and antitumor activity of the Aurora B kinase inhibitor BI 811283 in patients with advanced solid tumors. METHODS: BI 811283 was administered via 24-h infusion on Days 1 and 15 of a 4-week cycle (schedule A) or Day 1 of a 3-week cycle (schedule B) in a modified 3 + 3 dose-escalation design. Pharmacodynamic assessments included immunohistochemistry for phosphorylated histone H3 (pHH3) on skin biopsies to determine Aurora B kinase inhibition and plasma concentrations of caspase-cleaved CK-18 (apoptosis marker). RESULTS: A total of 121 patients were treated. The MTDs of BI 811283 were 125 mg (schedule A) and 230 mg (schedule B). Dose-limiting toxicities were primarily hematological (febrile neutropenia and grade 4 neutropenia); the most common drug-related adverse effects included neutropenia, fatigue, leukopenia, nausea, alopecia, diarrhea, and decreased appetite. A trend toward a decrease in pHH3 was observed, with increasing BI 811283 doses, indicating target engagement; there was no consistent trend regarding caspase-cleaved CK-18 levels. No objective response was observed although 19 patients in each schedule achieved clinical benefit (stable disease). CONCLUSIONS: BI 811283 demonstrated a generally manageable safety profile and disease stabilization in some patients. TRIAL REGISTRATION: EudraCT No: 2007-000191-17, ClinicalTrials.gov Identifier: NCT00701324.

A single-center experience in radioembolization as salvage therapy of hepatic metastases of uveal melanoma.

BACKGROUND: Overall survival (OS) of patients with hepatic metastases of uveal melanoma is strongly linked with hepatic tumor control. Due to the lack of an effective systemic chemotherapy, locoregional therapies like radioembolization should play an increasingly important role. PURPOSE: To report complications and response rates of radioembolization as salvage therapy for hepatic uveal melanoma metastases. MATERIAL AND METHODS: Between October 2006 and January 2014, eight patients (age, 59.1 ± 15.3 years; 5 men) with histologically proven uveal melanoma and hepatic metastases received radioembolization with glass microspheres at a single center. All patients had been heavily pretreated with multiple systemic/locoregional therapies resulting in a long median interval between diagnosis of hepatic metastases and radioembolization (17.1 months; range, 6.4-23.2 months). Follow-up consisted of clinical assessment, laboratory tests and tri-phasic computed tomography (CT) before and 1, 3, 6, 9, and 12 months after radioembolization. Response to therapy was evaluated by CT using RECIST version 1.1 and by survival time. Safety (laboratory and clinical toxicity) was rated according to Common Terminology Criteria for Adverse Events 4.03. Using Kaplan-Meier analysis time to progression of hepatic metastases (hTTP) and OS were calculated. RESULTS: One month after radioembolization 50% of patients presented with stable and 50% with progressive disease. Median hTTP and OS after radioembolization were 4.3 weeks (range, 3.4-28.6 weeks) and 12.3 weeks (range, 3.7-62.6 weeks), respectively. Median OS after diagnosis of hepatic metastases was 19.9 months (range, 7.3-31.4 months). Radioembolization was tolerated well in all patients without toxicity higher than grade 2. CONCLUSION: Radioembolization is a safe salvage therapy even in heavily pretreated hepatic metastases of uveal melanoma.

Phase I clinical study of the toll-like receptor 9 agonist MGN1703 in patients with metastatic solid tumours.

PURPOSE: This study was initiated to evaluate safety, toxicity, pharmacokinetics, and pharmacodynamics of treatment with MGN1703, a novel synthetic DNA-based toll-like receptor 9 (TLR9)-immunomodulator. METHODS: The study consisted of an escalating single dose regimen followed by a multiple dose part. Dose levels of 0.25, 2, 10, 30, and 60 mg of MGN1703 were administered subcutaneously over 6 weeks twice weekly. Patients with at least stable disease (SD) could participate in the extension phase of the study for six further weeks. Effects on the immune status were monitored. RESULTS: 28 patients with metastatic solid tumours were included. Fatigue and activated partial thromboplastin time (aPTT) prolongation were the only two cases of drug-related grade 3 Common Terminology Criteria adverse events (CTCAE). The most frequently reported drug-related adverse events were of CTC Grade ⩽2. There was no relationship between toxicity and dose and no patient was withdrawn from the study due to drug-related AE. No drug-related serious AE (SAE) were reported. Six out of 24 patients had SD after 6 weeks of treatment and three of those remained in SD after a total of 12 weeks. Four patients were further treated in a compassionate use programme showing long-term disease stabilisation for up to 18 months. Immune assessment of cell compartments showed a non-significant increase of TLR9 expressing naïve B cells during therapy. CONCLUSION: Twice weekly subcutaneous applications of MGN1703 in a dose of up to 60 mg are safe and well tolerated without dose-limiting toxicities. MGN1703 shows immune activation and anti-tumour efficacy in heavily pretreated patients. The recommended dose of 60 mg twice weekly is currently used in a phase II trial in small cell lung cancer and a phase III trial in colorectal cancer patients.

First-in-human phase I study of PRS-050 (Angiocal), an Anticalin targeting and antagonizing VEGF-A, in patients with advanced solid tumors.

BACKGROUND: To report the nonrandomized first-in-human phase I trial of PRS-050, a novel, rationally engineered Anticalin based on human tear lipocalin that targets and antagonizes vascular endothelial growth factor A (VEGF-A). METHODS: Patients with advanced solid tumors received PRS-050 at 0.1 mg/kg to 10 mg/kg by IV in successive dosing cohorts according to the 3+3 escalation scheme. The primary end point was safety. RESULTS: Twenty-six patients were enrolled; 25 were evaluable. Two patients experienced dose-limiting toxicity, comprising grade (G) 3 hypertension and G3 pyrexia, respectively. The maximum tolerated dose was not reached. Most commonly reported treatment-emergent adverse events (AEs) included chills (52%; G3, 4%), fatigue (52%; G3, 4%), hypertension (44%; G3, 16%), and nausea (40%, all G1/2). No anti-PRS-050 antibodies following multiple administration of the drug were detected. PRS-050 showed dose-proportional pharmacokinetics (PK), with a terminal half-life of approximately 6 days. Free VEGF-A was detectable at baseline in 9/25 patients, becoming rapidly undetectable after PRS-050 infusion for up to 3 weeks. VEGF-A/PRS-050 complex was detectable for up to 3 weeks at all dose levels, including in patients without detectable baseline-free VEGF-A. We also detected a significant reduction in circulating matrix metalloproteinase 2, suggesting this end point could be a pharmacodynamic (PD) marker of the drug's activity. CONCLUSIONS: PRS-050, a novel Anticalin with high affinity for VEGF-A, was well-tolerated when administered at the highest dose tested, 10 mg/kg. Based on target engagement and PK/PD data, the recommended phase II dose is 5 mg/kg every 2 weeks administered as a 120-minute infusion. TRIAL REGISTRATION: ClinicalTrials.gov NCT01141257 http://clinicaltrials.gov/ct2/show/NCT01141257.

Preemptive tumor profiling for biomarker-stratified early clinical drug development in metastatic breast cancer patients.

Biomarker-stratified cancer pharmacotherapy was pioneered in the care of breast cancer patients. The utility of agents modulating hormone receptors, synthesis of steroid hormones, or HER2-targeting agents has been greatly enhanced by the detection of predictive biomarkers in diagnostic tumor samples. Based on deeper understanding of breast cancer biology multiple drug candidates have been developed to modulate additional molecular targets which may associate with specific biomarker profiles. Accordingly, exploratory biomarkers are increasingly incorporated in early clinical trials, thus demanding a new process of patient selection. Here, we describe the implementation of preemptive, multiplexed biomarker profiling linked to standard diagnostic algorithms for metastatic breast cancer patients treated at the West German Cancer Center. Profiling for experimental biomarkers was prospectively offered to patients with metastatic breast cancer who met generic clinical trial inclusion criteria. Formalin-fixed, paraffin-embedded tumor samples were retrieved and studied for potentially "actionable" biomarkers related to active clinical trials by immunohistochemistry, amplicon sequencing, and in situ hybridization. The clinical course of those "profiled" patients was closely monitored to offer trial participation whenever applicable. Here, we report results from the first 131 patients enrolled in this program. PIK3CA mutations (23 %) and amplifications (2 %), loss of PTEN expression (13 %), and FGFR1 amplifications (8 %) were detected next to established biomarkers such as estrogen (67 %) and progesterone receptor expression (52 %), and HER2 overexpression or amplification (23 %). So far 16 "profiled" patients (12 %) have been enrolled in biomarker-stratified early clinical trials. Preemptive profiling of investigational biomarkers can be integrated into the diagnostic algorithm of a large Comprehensive Cancer Center. Extensive administrative efforts are required to successfully enroll "profiled" patients with metastatic breast cancer in early clinical trials stratified by exploratory biomarkers.

Feasibility of preemptive biomarker profiling for personalised early clinical drug development at a Comprehensive Cancer Center.

PURPOSE: Multiple investigational drugs are currently explored in cancer patient populations defined by specific biomarkers. This demands a new process of patient selection for clinical trials. PATIENTS AND METHODS: Starting January 1, 2012, preemptive biomarker profiling was offered at the West German Cancer Center to all patients with advanced non-small-cell lung (NSCLC) or colorectal cancer (CRC), who met generic study inclusion criteria. Tumour specimens were subjected to prespecified profiling algorithms to detect 'actionable biomarkers' by amplicon sequencing, in situ hybridisation and immunohistochemistry. The clinical course was closely monitored to offer trial participation whenever applicable. RESULTS: Within 12 months, 267 patients (188 NSCLC, 79 CRC) were profiled. Estimated additional cost for biomarker profiling was 219615.51 EUR excluding histopathology workup and administration. The most prevalent biomarkers in pulmonary adenocarcinoma were KRAS mutations (29%), loss of PTEN expression (18%), EGFR mutations (9%), HER2 amplification (5%) and BRAF mutations (3%), while the prevalence of ALK translocations and PIK3CA mutations was extremely low. In pulmonary squamous cell carcinoma FGFR1 amplifications were found in 15%, PTEN expression was lost in 20% and DDR2 was mutated in a single case. KRAS mutations (41%) predominated in CRC, followed by loss of PTEN expression (16%), PIK3CA (5%) and BRAF (5%) mutations. So far 13 patients (5%) have entered biomarker-stratified clinical trials. Therapeutic decisions for approved drugs were guided in another 45 patients (17%). CONCLUSION: Preemptive biomarker profiling can be implemented into the diagnostic algorithm of a large Comprehensive Cancer Center. Substantial investments in diagnostics and administration are required.

A Phase I study of pazopanib in combination with gemcitabine in patients with advanced solid tumors.

PURPOSE: Pazopanib plus gemcitabine combination therapy was explored in patients with advanced solid tumors. METHODS: In a modified 3 + 3 enrollment scheme, oral once-daily pazopanib was administered with intravenous gemcitabine (Days 1 and 8, 21-day cycles). Three protocol-specified dose levels were tested: pazopanib 400 mg plus gemcitabine 1,000 mg/m(2), pazopanib 800 mg plus gemcitabine 1,000 mg/m(2), and pazopanib 800 mg plus gemcitabine 1,250 mg/m(2). Maximum-tolerated dose was based on dose-limiting toxicities during treatment Cycle 1. In the expansion phase, six additional patients were enrolled at the highest tolerable dose level. RESULTS: Twenty-two patients were enrolled. At the highest dose level tested (pazopanib 800 plus gemcitabine 1,250), patients received >80% of their planned dose and the regimen was deemed safe and tolerable. The most common treatment-related adverse events included fatigue, neutropenia, nausea, and decreased appetite. Neutropenia and thrombocytopenia were the most common events leading to dose modifications. Pharmacokinetic interaction between pazopanib and gemcitabine was not observed. One objective partial response at the highest dose was observed in a patient with metastatic melanoma. Prolonged disease stabilization (>12 cycles) was reported in three patients (metastatic melanoma, cholangiocarcinoma, and colorectal carcinoma). CONCLUSION: Combination pazopanib plus gemcitabine therapy is tolerable, with an adverse event profile reflective of that associated with the individual agents. There was no apparent pharmacokinetic interaction with pazopanib plus gemcitabine co-administration, although patient numbers were limited. Further investigation of combined pazopanib plus gemcitabine is warranted.

Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: a review of four phase I trials in patients with advanced refractory solid tumors.

Sorafenib is an oral multikinase inhibitor that inhibits Raf serine/threonine kinases and receptor tyrosine kinases involved in tumor growth and angiogenesis. It has demonstrated preclinical and clinical activity in several tumor types. Sorafenib 400 mg twice daily (bid) has been approved in several countries worldwide for the treatment of renal cell carcinoma. This review summarizes key safety, pharmacokinetic, and efficacy data from four phase I, single-agent, dose-escalation studies with sorafenib in patients with advanced refractory solid tumors (n = 173). These trials followed different treatment regimens (7 days on/7 days off, n = 19; 21 days on/7 days off, n = 44; 28 days on/7 days off, n = 41; or continuous dosing, n = 69) to establish the optimum dosing schedule. Sorafenib was generally well tolerated; most adverse events were mild to moderate in severity up to the defined maximum-tolerated dose of 400 mg twice daily (bid). The most frequently reported drug-related adverse events at any grade included fatigue (40%), anorexia (35%), diarrhea (34%), rash/desquamation (27%), and hand-foot skin reaction (25%). Sorafenib demonstrated preliminary antitumor activity, particularly among patients with renal cell carcinoma or hepatocellular carcinoma: overall, two of 137 evaluable patients achieved partial responses and 38 (28%) had stable disease. Although there was high interpatient variability in plasma pharmacokinetics across these studies, this was not associated with an increased incidence or severity of toxicity. Preliminary studies suggest that phosphorylated extracellular signal-related kinase in tumor cells or peripheral blood lymphocytes may be a useful biomarker for measuring and, ultimately, predicting the effects of sorafenib. Based on these findings, continuous daily 400 mg bid sorafenib was chosen as the optimal regimen for phase II/III studies. Trials are ongoing in renal cell carcinoma, hepatocellular carcinoma, melanoma, and non-small cell lung cancer.

Results of a phase I trial of sorafenib (BAY 43-9006) in combination with oxaliplatin in patients with refractory solid tumors, including colorectal cancer.

BACKGROUND: Sorafenib (BAY 43-9006), a multiple kinase inhibitor, has been shown to inhibit tumor growth and tumor angiogenesis by targeting Raf kinase, vascular endothelial growth factor receptor, and platelet-derived growth factor receptor. In phase I studies, sorafenib demonstrated single-agent activity in patients with advanced solid tumors and was successfully combined with oxaliplatin in preclinical studies. This phase I study investigated the safety, pharmacokinetics, and efficacy of sorafenib in combination with oxaliplatin. PATIENTS AND METHODS: Twenty-seven patients with refractory solid tumors were enrolled in the initial dose-escalation part (cohorts 1, 2A, and 2B) and 10 additional patients with oxaliplatin-refractory colorectal cancer were subsequently enrolled in an extension part (cohort 3). Oxaliplatin 130 mg/m2 was given on day 1 of a 3-week cycle and oral sorafenib was administered continuously from day 4 of cycle 1 at 200 mg twice daily (cohort 1) or 400 mg twice daily (cohorts 2A, 2B, and 3). RESULTS: Adverse events were generally mild to moderate and the maximum tolerated dose was not reached. Common adverse events were diarrhea (52% of patients in the dose-escalation part and 20% in the extension part), sensory neuropathy (44% and 20%), and dermatologic toxicities (41% and 80%). No pharmacokinetic interaction between sorafenib and oxaliplatin was detectable. Two patients with gastric cancer had a partial response. Forty-three percent of patients in cohorts 1 and 2A/B and 78% of patients in cohort 3 exhibited stable disease for >or=10 weeks. CONCLUSION: Continuous oral sorafenib 400 mg twice daily was safely combined with oxaliplatin without detectable drug interactions and showed preliminary antitumor activity in this phase I study. This dose is recommended for phase II studies.

Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors.

PURPOSE: BAY 43-9006 is a novel dual-action Raf kinase and vascular endothelial growth factor receptor inhibitor that inhibits tumor cell proliferation and angiogenesis. This study established the safety and pharmacokinetics of BAY 43-9006 in 69 patients with advanced refractory solid tumors. PATIENTS AND METHODS: BAY 43-9006 (50 to 800 mg) was administered once or twice daily on a varying weekly schedule. Pharmacokinetic sampling was performed in all patients; preliminary tumor response was also assessed. The effect of BAY 43-9006 on phorbol myristate acetate-stimulated ERK phosphorylation in peripheral blood lymphocytes was studied using flow cytometry. RESULTS: Mild to moderate diarrhea was the most common (55%) treatment-related adverse event. The maximum-tolerated dose was 400 mg bid continuous. Dose-limiting toxicities were grade 3 diarrhea and fatigue at 800 mg bid, and grade 3 skin toxicity at 600 mg bid. BAY 43-9006 pharmacokinetics were highly variable for single and multiple dosing, and toxicity did not appear to be dose dependent. Significant decreases of phorbol myristate acetate-stimulated ERK phosphorylation (P < .01) were identified at doses >/= 200 mg bid continuous. Forty-five patients were assessable for efficacy; one patient had a partial response (hepatocellular carcinoma at 400 mg bid continuous), 25 patients had stable disease, with eight lasting > 6 months and five for >12 months. Eighteen patients had progressive disease, and tumor response could not be evaluated in one patient. CONCLUSION: Oral BAY 43-9006 was well tolerated and appeared to provide some clinical benefits. Based on the results of this study, BAY 43-9006 at 400 mg bid continuous is recommended for ongoing and future studies.

Phase I clinical and pharmacokinetic study of BBR 3576, a novel aza-anthrapyrazole, administered i.v. every 4 weeks in patients with advanced solid tumors: a phase I study group trial of the Central European Society of Anticancer-Drug Research (CESAR).

BBR 3576 is a novel aza-anthrapyrazole with limited potential for cardiotoxicity in preclinical models. This phase I clinical and pharmacokinetic study was performed to determine the maximum tolerated dose, the dose-limiting toxicity (DLT) and the pharmacokinetic profile of BBR 3576 administered i.v. as a 1-h infusion repeated every 4 weeks. In total, 27 patients were treated at doses starting from 1 to 150 mg/m2. The dose levels 1, 2, 4, 8, 16, 32, 64, 90, 125 and 150 mg/m2 were investigated in one, three, one, three, two, one, three, four, three and six patients, respectively. The DLT was a grade 3 stomatitis at 150 mg/m2. At this dose level as well as at 125 mg/m2, neutropenia grade 3 and 4 were frequently seen, but not reaching the criteria for DLT. Time to neutrophil nadir was about 2 weeks and recovery took place within 1 week. Other bone marrow toxicities were mild; lymphopenia was also observed. No significant drug-induced cardiotoxicity was observed. The plasma concentration versus time curves of BBR 3576 showed a biexponential profile with a linear kinetic behavior. A very large volume of distribution, a high plasma clearance and long elimination half-lives were calculated. Renal unchanged drug excretion was less than 10% and therefore a minor excretion route. No objective antitumor responses were found. On the basis of this study, the recommended dose for phase II studies is 150 mg/m2, although the maximum tolerated dose as per protocol definition was not reached. This trial showed that BBR 3576 has a manageable toxicity profile on a 4-week schedule. Phase II studies have started in patients with solid tumors, as suggested by preclinical data in different in vivo model systems.