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Background: Preclinical studies showed that capmatinib reversibly inhibits cytochrome P450 (CYP) 3A4 and CYP1A2 in a time-dependent manner. In this study, we evaluated the effect of capmatinib on the exposure of sensitive substrates of CYP3A (midazolam) and CYP1A2 (caffeine) in patients with mesenchymal-epithelial transition (MET)-dysregulated solid tumours. Besides pharmacokinetics, we assessed treatment response and safety., Methods: This open-label, multicentre, single-sequence study consisted of a molecular prescreening period, a screening/baseline period of ≤28 days and a drug-drug interaction (DDI) phase of 12 days. On day 1 of the DDI phase, 37 patients received a single oral dose of midazolam 2.5 mg and caffeine 100 mg as a two-drug cocktail. Capmatinib 400 mg bid was administered from day 4 on a continuous dosing schedule. On day 9 of the DDI phase, patients were re-exposed to midazolam and caffeine. After the DDI phase, patients received capmatinib on continuous 21-day cycles until disease progression at the discretion of the investigator., Results: A 22% (90% confidence interval [CI] 7-38%) increase in the midazolam maximum plasma concentration (C max ) was noted when administered with capmatinib, but this was deemed not clinically meaningful. Co-administration with capmatinib resulted in 134% (90% CI 108-163%) and 122% (90% CI 95-153%) increases in the caffeine area under the plasma concentration-time curve from time zero to infinity (AUC inf ) and area under the plasma concentration-time curve from time zero to the last measurable point (AUC last ), respectively, with no change in C max . Adverse events were consistent with the known capmatinib safety profile. No new safety signals were reported in this study., Conclusion: The data from this study demonstrated that capmatinib is a moderate CYP1A2 inhibitor. Capmatinib administration did not cause any clinically relevant changes in midazolam exposure., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Purpose: Ceritinib is an ALK receptor tyrosine kinase inhibitor approved as first- and second-line treatment in adult patients with ALK + metastatic non-small cell lung cancer (NSCLC). The study investigated the drug-drug interaction (DDI) potential of ceritinib when coadministered with midazolam and warfarin as probe substrates for CYP3A and CYP2C9 activity, respectively., Methods: This was a phase I, multicenter, open-label, single sequence, crossover DDI study in 33 adult patients with ALK + NSCLC or other advanced tumors. A single dose of a cocktail consisting of midazolam and warfarin was administered with and without concomitant administration of ceritinib. The primary objective was to evaluate the pharmacokinetics of midazolam and warfarin. Secondary objectives included pharmacokinetics, safety, tolerability, overall response rate (ORR), and duration of response (DOR) of ceritinib 750 mg once daily., Results: Ceritinib inhibited CYP3A-mediated metabolism of midazolam, resulting in a markedly increased AUC (geometric mean ratio [90% confidence interval]) by 5.4-fold (4.6, 6.3). Ceritinib also led to an increase in the AUC of S-warfarin by 54% (36%, 75%). The pharmacokinetics and safety profile of ceritinib in this study are consistent with previous reports and no new safety signals were reported. Among the 19 patients with NSCLC, efficacy (ORR: 42.1% and DCR: 63.2%) was similar to that reported previously in studies of pretreated patients with ALK + NSCLC., Conclusion: Ceritinib is a strong CYP3A inhibitor and a weak CYP2C9 inhibitor. These findings should be reflected as actionable clinical recommendations in the prescribing information for ceritinib with regards to concomitant medications whose pharmacokinetics may be altered by ceritinib.

Genomic screening of cancer patients for predisposing variants is traditionally based on age at onset, family history and type of cancer. Whereas the clinical guidelines have proven efficient in identifying families exhibiting classical attributes of hereditary cancer, the frequency of patients with alternative presentations is unclear. We identified and characterized germline variants in 636 patients with advanced solid cancer using whole exome sequencing. Pathogenic and likely pathogenic germline variants among 168 genes associated with hereditary cancer were considered. These variants were identified in 17.8% of the patients and within a wide range of cancer types. In particular, patients with mesothelioma, ovarian cancer, cervical cancer, urothelial cancer, and cancer of unknown primary origin displayed high frequencies of pathogenic variants. Variants were predominantly found in DNA-repair pathways and about half were within genes involved in homologous recombination repair. Twenty-two BRCA1 and BRCA2 germline variants were identified in 12 different cancer types, of which 10 (45%) were not previously identified in these patients based on the current clinical guidelines. Loss of heterozygosity and somatic second hits were identified in several of the affected genes, supporting possible causality for cancer development. A potential treatment target based on the pathogenic germline variant could be suggested in 25 patients (4%). The study demonstrates a high frequency of pathogenic germline variants in the homologous recombination pathway in patients with advanced solid cancers. We infer that genetic screening in this group of patients may reveal high-risk families and identify patients with potential PARP inhibitor sensitive tumors., Competing Interests: Competing interestsE.S-R. has received lecture honoraria from Roche, Pfizer, Novartis, and Boehringer Ingelheim. M.M-S. has received lecture honoraria and support to participate in scientific conference from Roche. All other authors declare no competing interests.

Purpose: Access to genomic tumor material is required to select patients for targeted therapies. However, tissue biopsies are not always feasible and therefore circulating cell-free DNA (cfDNA) has emerged as an alternative. Here we investigate the utility of cfDNA for genomic tumor profiling in the phase I setting., Study Design: Peripheral blood was collected from patients with advanced solid cancers eligible for phase I treatment. Patients failing the initial tissue biopsy due to inaccessible lesions or insufficient tumor cellularity (<10%) were included in the study. Genomic profiling of cfDNA including whole exome sequencing (WES) and somatic copy number alterations (SCNAs) analysis (OncoScan)., Results: Plasma cfDNA was pro- and retrospectively profiled from 24 and 20 patients, respectively. The median turnaround time was 29 days ( N = 24, range 13-87 days) compared to tissue re-analyses of median 60 days ( N = 6, range 29-98). Selected cancer-associated alterations (SCAAs) were identified in 70% (31/44) of patients, predominantly by WES due to the low sensitivity of OncoScan on cfDNA. Primarily, inaccessible cases of prostate and lung cancers could benefit from cfDNA profiling. In contrast, breast cancer patients showed a low level of tumor-specific cfDNA which might be due to cancer type and/or active treatment at the time of plasma collection., Conclusion: Plasma cfDNA profiling using WES is feasible within a clinically relevant timeframe and represents an alternative to invasive tissue biopsies to identify possible treatment targets. Especially, difficult-to-biopsy cancers can benefit from cfDNA profiling, but tumor tissue remains the gold standard for molecular analyses., Competing Interests: CONFLICTS OF INTEREST ES-R has received lecture honoraria from Pfizer, Novartis, Boehringer Ingelheim, and Takeda. MMS has received lecture honoraria and support to participate in scientific conference from Roche. KSR received support to participate in scientific conference from Roche and Sanofi. All remaining authors have declared no conflicts of interest.

Purpose: We evaluated longitudinal tracking of BRAF V600E in circulating cell-free DNA (cfDNA) as a marker of treatment response to BRAF inhibitor (BRAFi) combination therapies in non-melanoma solid tumors included in the Copenhagen Prospective Personalized Oncology (CoPPO) program., Experimental Design: Patients with BRAF V600E-mutated tumors were treated with combination therapies including BRAFi. Quantification of mutant cfDNA from plasma was determined and correlated to clinical outcomes. Exome sequencing was performed to identify possible resistance mutations., Results: Twenty-three patients had BRAF-mutated tumors out of 455 patients included in CoPPO and 17 started BRAFi combination (EGFRi/MEKi) therapy. Tumor responses were achieved in 8 out of 16 evaluable patients and the median overall- and progression-free survival (OS and PFS) was 15 and 4.8 months, respectively. Longitudinal measurements of BRAF V600E-mutant cfDNA indicated disease progression prior to radiological evaluation and a reduction in the mutant fraction of more than 50% after 4 and 12 weeks of therapy was associated with a significantly longer PFS (p=0.003 and p=0.029) and OS (p=0.029 and p=0.017). Furthermore, the baseline mutant fraction and total level of cfDNA positively correlated with tumor burden (p=0.026 and p=0.024). Finally, analysis of cfDNA at progression revealed novel mutations potentially affecting the MAPK pathway., Conclusion: BRAFi combination therapies showed a response rate of 50% in BRAF V600E-mutated non-melanoma tumors. The fraction of BRAF-mutant cfDNA represent a sensitive indicator for clinical outcomes with plasma collected at week 4 and 12 as crucial time points for monitoring response and disease progression., Competing Interests: CONFLICTS OF INTEREST Eric Santoni-Rugiu has received lecture honoraria from Roche, Pfizer, Novartis, and Boehringer Ingelheim. Morten Mau-Sørensen has received lecture honoraria and support to participate in scientific conference from Roche. All other authors declare no potential conflicts of interest.

Objectives: The primary objective of this feasibility study was to identify quality of life (QoL) scores and symptom scales as tools for measuring patient-reported outcomes (PRO) associated with haemoglobin level in chemotherapy-treated cancer patients. Secondary objectives included comparing QoL and symptoms between randomisation arms., Background: Anaemia in cancer patients undergoing chemotherapy is associated with decreased QoL. One treatment option is red blood cell transfusion (RBCT). However, the optimal haemoglobin trigger for transfusion is unknown., Methods: Patients were randomised to a haemoglobin trigger for RBCT of either < 9·7 g dL -1 (arm A) or < lower normal level, female: 11·5 g dL -1 , male: 13·1 g dL -1 (arm B). Four PROs were used: Functional Assessment of Cancer Therapy-General (FACT-G) and the FACT-Anaemia (FACT-An), a Numeric Rating Scale on symptoms of anaemia and self-reported Performance Status (PS). The association between haemoglobin and PRO variables was assessed using a linear mixed model with random effects., Results: A total of 133 patients were enrolled, of which 86 patients received RBCT (28 in arm A, 58 in arm B). Baseline questionnaires were filled out in 79·7% of cases. Haemoglobin levels were significantly correlated with FACT-An, FACT-An Total Outcome Index (TOI), Functional Well-Being, fatigue and PS. Improvement on several PRO variables was observed in both arms after RBCT, with clinically minimal important differences observed in FACT-G, Physical Well-Being, FACT-An, FACT-An TOI, fatigue and dyspnoea., Conclusions: QoL scores of physical and functional domains as well as self-reported anaemia-related symptoms correlated well with haemoglobin level in chemotherapy-treated cancer patients., (© 2017 British Blood Transfusion Society.)

Novel therapies are needed for patients with relapsed or refractory multiple myeloma (MM). We conducted a multicenter, phase 1 study in advanced hematological malignancies to assess the safety, efficacy, and recommended phase 2 dose (RP2D) of oral selinexor, a selective inhibitor of the nuclear export protein XPO1. In the dose-escalation phase, 25 patients with heavily pretreated MM (22) or Waldenstrom macroglobulinemia (3) were administered selinexor (3-60 mg/m 2 ) in 8 or 10 doses per 28-day cycle. In the dose-expansion phase, 59 patients with MM received selinexor at 45 or 60 mg/m 2 with 20 mg dexamethasone, twice weekly in 28-day cycles, or selinexor (40 or 60 mg flat dose) without corticosteroids in 21-day cycles. The most common nonhematologic adverse events (AEs) were nausea (75%), fatigue (70%), anorexia (64%), vomiting (43%), weight loss (32%), and diarrhea (32%), which were primarily grade 1 or 2. The most common grade 3 or 4 AEs were hematologic, particularly thrombocytopenia (45%). Single-agent selinexor showed modest efficacy with an objective response rate (ORR) of 4% and clinical benefit rate of 21%. In contrast, the addition of dexamethasone increased the ORR with all responses of ≥partial response occurring in the 45 mg/m 2 selinexor plus 20 mg dexamethasone twice weekly cohort (ORR = 50%). Furthermore, 46% of all patients showed a reduction in MM markers from baseline. Based on these findings, we conclude that selinexor in combination with dexamethasone is active in heavily pretreated MM and propose a RP2D of 45 mg/m 2 (80 mg) plus 20 mg dexamethasone given twice weekly. This trial was registered at clinicaltrials.gov as #NCT01607892., (© 2018 by The American Society of Hematology.)

Background: Small fragments of tumor DNA can be found in the circulation of cancer patients, providing a noninvasive access to tumor material (liquid biopsy). Analysis of circulating tumor DNA (ctDNA) has been used for diagnosis, treatment decisions, and detection of therapy resistance, including in patients with tumors inaccessible for biopsy, making ctDNA an important alternative source of tumor material. Immediate separation of plasma is widely used in standard isolation of cell-free DNA to ensure high quality plasma DNA. However, these procedures are labor intensive and logistically challenging in a clinical setting. Here we investigate the concordance between standard blood collection for molecular analysis using immediate separation of plasma, compared to the use of collection tubes allowing for delayed processing., Methods: In this study, we measured the fractional abundance of tumor specific mutations (BRAF p.V600E and PIK3CA p.H1047R) in ctDNA isolated from blood samples collected in either cell-stabilizing Cell-Free DNA BCT tubes (delayed processing within 72 hours) or standard K3EDTA tubes (immediate processing within 15 minutes). Twenty-five blood sample pairs (EDTA/BCT) were collected from patients with advanced solid cancers enrolled in early clinical trials., Results: Concordance in the fractional abundance of mutations in ctDNA isolated from blood collected in either K3EDTA or BCT tubes from patients with different solid cancers was observed., Conclusions: This study indicates that BCT tubes are preferable for collection of circulating DNA in a clinical setting due to the favorable storage and shipping conditions.

Purpose: This study investigated the safety, clinical activity, and target-associated biomarkers of lumretuzumab, a humanized, glycoengineered, anti-HER3 monoclonal antibody (mAb), in combination with the EGFR-blocking agents erlotinib or cetuximab in patients with advanced HER3-positive carcinomas. Experimental Design: The study included two parts: dose escalation and dose extension phases with lumretuzumab in combination with either cetuximab or erlotinib, respectively. In both parts, patients received lumretuzumab doses from 400 to 2,000 mg plus cetuximab or erlotinib according to standard posology, respectively. The effect of HRG mRNA and HER3 mRNA and protein expression were investigated in a dedicated extension cohort of squamous non-small cell lung cancer (sqNSCLC) patients treated with lumretuzumab and erlotinib. Results: Altogether, 120 patients were treated. One dose-limiting toxicity (DLT) in the cetuximab part and two DLTs in the erlotinib part were reported. The most frequent adverse events were gastrointestinal and skin toxicities, which were manageable. The objective response rate (ORR) was 6.1% in the cetuximab part and 4.2% in the erlotinib part. In the sqNSCLC extension cohort of the erlotinib part, higher tumor HRG and HER3 mRNA levels were associated with a numerically higher disease control rate but not ORR. Conclusions: The toxicity profile of lumretuzumab in combination with cetuximab and erlotinib was manageable, but only modest clinical activity was observed across tumor types. In the sqNSCLC cohort, there was no evidence of meaningful clinical benefit despite enriching for tumors with higher HRG mRNA expression levels. Clin Cancer Res; 23(18); 5406-15. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Purpose: The hallmark of neurofibromatosis type 2 (NF2) is bilateral vestibular schwannomas (VS). Approximately 80% of NF2 patients also have intracranial meningiomas. Vascular endothelial growth factor (VEGF) is expressed in both NF2-related and sporadic occurring meningiomas and anti-VEGF therapy (bevacizumab) may, therefore, be beneficial in NF2-related meningiomas. The purpose of the study was to report the effect of bevacizumab on meningiomas in NF2 patients., Materials and Methods: We retrospectively reviewed the effect of bevacizumab on the cross-sectional area (CSA) of 14 intracranial meningiomas in 7 NF2 patients. Bevacizumab 10 mg/kg was administered intravenously every two weeks for six months and 15 mg/kg every three weeks thereafter. Patients were evaluated according to the modified Macdonald criteria with repeated magnetic resonance (MR) scans., Results: The median duration of therapy was 27 months (range 16-34) and 42 MR scans (median 8, range 4-11) were reviewed. The median annual change in meningioma CSA prior to bevacizumab was 2% (range -4%-+76%). During treatment, a decrease in meningioma CSA was observed in 5 of 14 meningiomas (36%) in 5 of 7 patients (71%). The median decrease in CSA was -10% (range -3%--25%). One meningioma (7%) progressed and the remaining (93%) had stable disease., Conclusions: Bevacizumab may slow or reverse the growth of some NF-related meningiomas. However, we have previously reported a fatal case of intracerebral hemorrhage following bevacizumab in NF2 patients, wherefore, this effect needs to be balanced carefully against the risk of side effects.

Purpose: The TWEAK-Fn14 pathway represents a novel anticancer target that is being actively investigated. Understanding the relationship between pharmacokinetics of anti-TWEAK therapeutics and tumor pharmacodynamics is critical. We investigated exposure-response relationships of RG7212, an anti-TWEAK mAb, in patients with Fn14-expressing tumors., Experimental Design: Patients with Fn14-positive tumors (IHC ≥ 1+) treated in a phase I first-in-human study with ascending doses of RG7212 were the basis for this analysis. Pharmacokinetics of RG7212 and dynamics of TWEAK were determined, as were changes in tumor TWEAK-Fn14 signaling in paired pre- and posttreatment tumor biopsies. The objectives of the analysis were to define exposure-response relationships and the relationship between pretreatment tumor Fn14 expression and pharmacodynamic effect. Associations between changes in TWEAK-Fn14 signaling and clinical outcome were explored., Results: Thirty-six patients were included in the analysis. RG7212 reduced plasma TWEAK to undetectable levels at all observed RG7212 exposures. In contrast, reductions in tumor Fn14 and TRAF1 protein expression were observed only at higher exposure (≥ 300 mg*h/mL). Significant reductions in tumor Ki-67 expression and early changes in serum concentrations of CCL-2 and MMP-9 were observed exclusively in patients with higher drug exposure who had high pretreatment tumor Fn14 expression. Pretreatment tumor Fn14 expression was not associated with outcome, but a trend toward longer time on study was observed with high versus low RG7212 exposure., Conclusions: RG7212 reduced tumor TWEAK-Fn14 signaling in a systemic exposure-dependent manner. In addition to higher exposure, relatively high Fn14 expression might be required for pharmacodynamic effect of anti-TWEAK monoclonal antibodies., (©2015 American Association for Cancer Research.)

The hallmark of neurofibromatosis type 2 (NF2) is bilateral vestibular schwannomas (VS) and severe hearing loss is common in NF2 patients. Vascular endothelial growth factor (VEGF) expression level in NF2 correlates with tumour growth rate and bevacizumab, a VEGF-binding antibody, has previously been shown to induce tumour shrinkage and improve hearing. We retrospectively reviewed the effect of bevacizumab on hearing and VS tumour size in 12 consecutive NF2 patients. Bevacizumab 10 mg/kg was administered intravenously every second week for 6 months; hereafter, bevacizumab 15 mg/kg was administered every third week. Patients were evaluated with repeated audiometries, MR scans and clinical evaluations. Radiological response was defined as a 20 % or greater reduction in VS volume. A total of 398 treatments (median 36) were administered and the median duration on therapy was 22 months (range 7-34). We observed a radiological response (≥20 % tumour shrinkage) in seven out of 18 tumours (39 %) in six out of 12 patients (50 %). Sustained radiological responses were maintained in six tumours (33 %) for more than 2 months. Three patients had objectively improved hearing and five patients reported subjective benefit in neurological symptoms, including improved hearing. Toxicity was in general manageable; however, one patient died from cerebral haemorrhage which was possibly related to therapy. In conclusion, bevacizumab improved hearing and reduced the size of VS in some patients with progressive NF2 which corroborates previous findings; however, the risk of severe side effects should be carefully considered and discussed with the patients prior to treatment.

Background: Carbohydrate associated antigen (CA19-9) has been approved by the FDA as a biomarker for monitoring treatment effect in pancreatic cancer. However, the value of serum CA19-9 as a biomarker of response to chemotherapy in bile duct cancer is unclear. The aim of this study was to determine if a decline in CA19-9 (CA19-9 response) during chemotherapy is predictive of survival in patients with inoperable bile duct cancer., Methods: Consecutive patients with inoperable bile duct cancer treated at a University Hospital were retrospectively included in an investigational cohort (n = 212). Three validation cohorts were established including patients 1) participating in phase I/II trials at a Danish Hospital (n = 71), 2) identified retrospectively in a Canadian cohort (n = 196) and 3) randomized in the ABC-02 trial (n = 410). Patients with a baseline CA19-9 and at least one CA19-9 value measured 10-12 weeks after the start of chemotherapy were included. Multivariate Cox regression analyses were performed., Results: Patients meeting the criteria to be included were 54 in the investigational cohort and 34, 68 and 148 in the three validation sets, respectively. Multivariate analysis included radiological response, performance status, bilirubin, gender, site of cancer, extend of disease, CA19-9 at baseline and age. A hazard ratio (HR) of 0.60 (95%CI: 0.44-0.80, p = 0.0005) for death in CA19-9 responders was reached in the investigational cohort. The predictive value of CA 19-9 response was confirmed in all three validation cohorts., Conclusions: CA19-9 response is a robust predictor of survival in patients with inoperable bile duct cancer in four independent data sets., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Purpose: This multicenter, first-in-human study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of BI-505, a human anti-ICAM-1 monoclonal antibody, in advanced relapsed/refractory multiple myeloma patients., Experimental Design: BI-505 was given intravenously, every 2 weeks, at escalating doses from 0.0004 to 20 mg/kg, with extension of therapy until disease progression for responding or stable patients receiving 0.09 mg/kg or higher doses., Results: A total of 35 patients were enrolled. The most common adverse events were fatigue, pyrexia, headache, and nausea. Adverse events were generally mild to moderate, and those attributed to study medication were mostly limited to the first dose and manageable with premedication and slower infusion. No maximum tolerated dose was identified. BI-505's half-life increased with dose while clearance decreased, suggesting target-mediated clearance. The ICAM-1 epitopes on patient bone marrow myeloma were completely saturated at 10 mg/kg doses. Using the International Myeloma Working Group criteria, 7 patients on extended therapy had stable disease for more than 2 months., Conclusions: BI-505 can be safely administered at doses that saturate myeloma cell ICAM-1 receptors in patients. This study was registered at www.clinicaltrials.gov (NCT01025206)., (©2015 American Association for Cancer Research.)

Purpose: Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible molecule 14 (Fn14) are a ligand-receptor pair frequently overexpressed in solid tumors., Tweak: Fn14 signaling regulates multiple oncogenic processes through MAPK, AKT, and NFκB pathway activation. A phase I study of RG7212, a humanized anti-TWEAK IgG1κ monoclonal antibody, was conducted in patients with advanced solid tumors expressing Fn14., Experimental Design: Dose escalations, over a 200- to 7,200-mg range, were performed with patients enrolled in weekly (QW), bi-weekly (Q2W), or every-three-week (Q3W) schedules. Primary objectives included determination of dose and safety profile. Secondary endpoints included assessments related to inhibition of, Tweak: Fn14 signaling, tumor proliferation, tumor immune cell infiltration, and pharmacokinetics., Results: In 192 treatment cycles administered to 54 patients, RG7212 was well-tolerated with no dose-limiting toxicities observed. More than 95% of related adverse events were limited to grade 1/2. Pharmacokinetics were dose proportional for all cohorts, with a t1/2 of 11 to 12 days. Pharmacodynamic changes included clearance of free and total TWEAK ligand and reductions in tumor Ki-67 and TRAF1. A patient with BRAF wild-type melanoma who received 36 weeks of RG7212 therapy had tumor regression and pharmacodynamic changes consistent with antitumor effects. Fifteen patients (28%) received 16 or more weeks of RG7212 treatment., Conclusion: RG7212 demonstrated excellent tolerability and favorable pharmacokinetics. Pharmacodynamic endpoints were consistent with reduced, Tweak: Fn14 signaling. Tumor regression was observed and prolonged stable disease was demonstrated in multiple heavily pretreated patients with solid tumors. These encouraging results support further study of RG7212. Clin Cancer Res; 21(2); 258-66. ©2014 AACR., (©2014 American Association for Cancer Research.)