ABSTRACT
Samuraciclib is a selective oral CDK7-inhibitor. A multi-modular, open-label Phase I study to evaluate safety and tolerability of samuraciclib in patients with advanced malignancies was designed (ClinicalTrials.gov: NCT03363893). Here we report results from dose escalation and 2 expansion cohorts: Module 1A dose escalation with paired biopsy cohort in advanced solid tumor patients, Module 1B-1 triple negative breast cancer (TNBC) monotherapy expansion, and Module 2A fulvestrant combination in HR+/HER2- breast cancer patients post-CDK4/6-inhibitor. Core study primary endpoints are safety and tolerability, and secondary endpoints are pharmacokinetics (PK), pharmacodynamic (PD) activity, and anti-tumor activity. Common adverse events are low grade nausea, vomiting, and diarrhea. Maximum tolerated dose is 360 mg once daily. PK demonstrates dose proportionality (120 mg-480 mg), a half-life of approximately 75 hours, and no fulvestrant interaction. In dose escalation, one partial response (PR) is identified with disease control rate of 53% (19/36) and reduction of phosphorylated RNA polymerase II, a substrate of CDK7, in circulating lymphocytes and tumor tissue. In TNBC expansion, one PR (duration 337 days) and clinical benefit rate at 24 weeks (CBR) of 20.0% (4/20) is achieved. In combination with fulvestrant, 3 patients achieve PR with CBR 36.0% (9/25); in patients without detectable TP53-mutation CBR is 47.4% (9/19). In this study, samuraciclib exhibits tolerable safety and PK is supportive of once-daily oral administration. Clinical activity in TNBC and HR+/HER2-breast cancer post-CDK4/6-inhibitor settings warrants further evaluation.
Subject(s)
Triple Negative Breast Neoplasms , Humans , Fulvestrant , Administration, Oral , Biopsy , Cyclin-Dependent Kinase Inhibitor Proteins , Cyclin-Dependent Kinases , Enzyme InhibitorsABSTRACT
INTRODUCTION: Targeted therapy in non-small cell lung cancer (NSCLC) patients with mesenchymal epithelial transition (MET) exon 14 skipping mutations (METex14) and MET amplifications has improved patients' outcomes. The development of more potent MET kinase inhibitors could further benefit these patients. The aim of this trial is to determine the safety and recommended phase 2 dose (RP2D) of OMO-1 (an oral dual MET kinase/OCT-2 inhibitor) and to assess preliminary clinical efficacy in METex14-positive NSCLC and other MET-positive solid tumors. MATERIALS AND METHODS: This was a first-in-patient, open-label, multicenter study of OMO-1 in patients with locally advanced or metastatic solid malignancies. A standard 3 + 3 dose escalation design was utilized starting at a dose level of 100 mg BID continuously. Preliminary efficacy was investigated in patients with METex14-positive NSCLC, and MET amplified NSCLC and other solid tumors (MET basket). RESULTS: In the dose-escalation part, 24 patients were included in 5 dose levels ranging from 100 mg twice daily (BID) to 400 mg BID. Most common adverse events (≥ 20%) were nausea, fatigue, vomiting, increased blood creatinine, and headache. The RP2D was determined at 250 mg BID. In the expansion cohorts, 15 patients were included (10 in METex14-positive NSCLC cohort and 5 in MET basket cohort) and received either 200 or 250 mg BID. Eight out of the 10 patients with METex14 positive NSCLC had stable disease as the best response. CONCLUSION: OMO-1 was tolerated at the dose of 250 mg BID and shows initial signs of MET inhibition and anti-tumor activity in METex14 mutated NSCLC patients.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Neoplasms, Second Primary , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Proto-Oncogene Proteins c-met/genetics , Protein Kinase Inhibitors/adverse effects , Neoplasms, Second Primary/genetics , Exons , MutationABSTRACT
PURPOSE: This study reports the safety, tolerability, MTD, recommended phase II dose (RP2D), pharmacokinetic/pharmacodynamic profile, and preliminary antitumor activity of ceralasertib combined with carboplatin in patients with advanced solid tumors. It also examined exploratory predictive and pharmacodynamic biomarkers. PATIENTS AND METHODS: Eligible patients (n = 36) received a fixed dose of carboplatin (AUC5) with escalating doses of ceralasertib (20 mg twice daily to 60 mg once daily) in 21-day cycles. Sequential and concurrent combination dosing schedules were assessed. RESULTS: Two ceralasertib MTD dose schedules, 20 mg twice daily on days 4-13 and 40 mg once daily on days 1-2, were tolerated with carboplatin AUC5; the latter was declared the RP2D. The most common treatment-emergent adverse events (Common Terminology Criteria for Adverse Events grade ≥3) were anemia (39%), thrombocytopenia (36%), and neutropenia (25%). Dose-limiting toxicities of grade 4 thrombocytopenia (n = 2; including one grade 4 platelet count decreased) and a combination of grade 4 thrombocytopenia and grade 3 neutropenia occurred in 3 patients. Ceralasertib was quickly absorbed (tmax â¼1 hour), with a terminal plasma half-life of 8-11 hours. Upregulation of pRAD50, indicative of ataxia telangiectasia mutated (ATM) activation, was observed in tumor biopsies during ceralasertib treatment. Two patients with absent or low ATM or SLFN11 protein expression achieved confirmed RECIST v1.1 partial responses. Eighteen of 34 (53%) response-evaluable patients had RECIST v1.1 stable disease. CONCLUSIONS: The RP2D for ceralasertib plus carboplatin was established as ceralasertib 40 mg once daily on days 1-2 administered with carboplatin AUC5 every 3 weeks, with pharmacokinetic and pharmacodynamic studies confirming pharmacodynamic modulation and preliminary evidence of antitumor activity observed.
Subject(s)
Neoplasms , Neutropenia , Thrombocytopenia , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Ataxia Telangiectasia Mutated Proteins/genetics , Carboplatin , Humans , Indoles , Maximum Tolerated Dose , Morpholines , Neoplasms/etiology , Neutropenia/chemically induced , Nuclear Proteins , Protein Kinase Inhibitors/adverse effects , Pyrimidines , Sulfonamides , Sulfoxides , Thrombocytopenia/chemically inducedABSTRACT
BACKGROUND: The continual reassessment method (CRM) requires an underlying model of the dose-toxicity relationship ("prior skeleton") and there is limited guidance of what this should be when little is known about this association. In this manuscript the impact of applying the CRM with different prior skeleton approaches and the 3 + 3 method are compared in terms of ability to determine the true maximum tolerated dose (MTD) and number of patients allocated to sub-optimal and toxic doses. METHODS: Post-hoc dose-escalation analyses on real-life clinical trial data on an early oncology compound (AZD3514), using the 3 + 3 method and CRM using six different prior skeleton approaches. RESULTS: All methods correctly identified the true MTD. The 3 + 3 method allocated six patients to both sub-optimal and toxic doses. All CRM approaches allocated four patients to sub-optimal doses. No patients were allocated to toxic doses from sigmoidal, two from conservative and five from other approaches. CONCLUSIONS: Prior skeletons for the CRM for phase 1 clinical trials are proposed in this manuscript and applied to a real clinical trial dataset. Highly accurate initial skeleton estimates may not be essential to determine the true MTD, and, as expected, all CRM methods out-performed the 3 + 3 method. There were differences in performance between skeletons. The choice of skeleton should depend on whether minimizing the number of patients allocated to suboptimal or toxic doses is more important. TRIAL REGISTRATION: NCT01162395 , Trial date of first registration: July 13, 2010.
Subject(s)
Antineoplastic Agents/administration & dosage , Bayes Theorem , Clinical Trials, Phase I as Topic , Dose-Response Relationship, Drug , Maximum Tolerated Dose , Algorithms , Androgen Antagonists/administration & dosage , Computer Simulation , Humans , Male , Models, Theoretical , Prostatic Neoplasms, Castration-Resistant/drug therapy , Pyridazines/administration & dosageABSTRACT
In countries with the best cancer outcomes, approximately 60% of patients receive radiotherapy as part of their treatment, which is one of the most cost-effective cancer treatments. Notably, around 40% of cancer cures include the use of radiotherapy, either as a single modality or combined with other treatments. Radiotherapy can provide enormous benefit to patients with cancer. In the past decade, significant technical advances, such as image-guided radiotherapy, intensity-modulated radiotherapy, stereotactic radiotherapy, and proton therapy enable higher doses of radiotherapy to be delivered to the tumour with significantly lower doses to normal surrounding tissues. However, apart from the combination of traditional cytotoxic chemotherapy with radiotherapy, little progress has been made in identifying and defining optimal targeted therapy and radiotherapy combinations to improve the efficacy of cancer treatment. The National Cancer Research Institute Clinical and Translational Radiotherapy Research Working Group (CTRad) formed a Joint Working Group with representatives from academia, industry, patient groups and regulatory bodies to address this lack of progress and to publish recommendations for future clinical research. Herein, we highlight the Working Group's consensus recommendations to increase the number of novel drugs being successfully registered in combination with radiotherapy to improve clinical outcomes for patients with cancer.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasms/radiotherapy , Cell Hypoxia/radiation effects , Clinical Trials as Topic/methods , Combined Modality Therapy , Drug Approval , Humans , Neoplasms/drug therapy , Patient Education as Topic , Patient Participation , Quality Assurance, Health Care , Quality of Health Care , Radiation Dosage , Radiation Tolerance/radiation effects , Treatment OutcomeABSTRACT
Nausea and vomiting are components of a complex mechanism that signals food avoidance and protection of the body against the absorption of ingested toxins. This response can also be triggered by pharmaceuticals. Predicting clinical nausea and vomiting liability for pharmaceutical agents based on pre-clinical data can be problematic as no single animal model is a universal predictor. Moreover, efforts to improve models are hampered by the lack of translational animal and human data in the public domain. AZD3514 is a novel, orally-administered compound that inhibits androgen receptor signaling and down-regulates androgen receptor expression. Here we have explored the utility of integrating data from several pre-clinical models to predict nausea and vomiting in the clinic. Single and repeat doses of AZD3514 resulted in emesis, salivation and gastrointestinal disturbances in the dog, and inhibited gastric emptying in rats after a single dose. AZD3514, at clinically relevant exposures, induced dose-responsive "pica" behaviour in rats after single and multiple daily doses, and induced retching and vomiting behaviour in ferrets after a single dose. We compare these data with the clinical manifestation of nausea and vomiting encountered in patients with castration-resistant prostate cancer receiving AZD3514. Our data reveal a striking relationship between the pre-clinical observations described and the experience of nausea and vomiting in the clinic. In conclusion, the emetic nature of AZD3514 was predicted across a range of pre-clinical models, and the approach presented provides a valuable framework for predicition of clinical nausea and vomiting.
Subject(s)
Models, Animal , Nausea/chemically induced , Pyridazines/adverse effects , Receptors, Androgen/physiology , Vomiting/chemically induced , Animals , Dogs , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Female , Ferrets , Humans , Male , Nausea/blood , Nausea/diagnosis , Predictive Value of Tests , Rats , Rats, Wistar , Vomiting/blood , Vomiting/diagnosisABSTRACT
BRAF mutation testing from circulating free DNA (cfDNA) using the amplification refractory mutation testing system (ARMS) holds potential as a surrogate for tumor mutation testing. Robust assay validation is needed to establish the optimal clinical matrix for measurement and cfDNA-specific mutation calling criteria. Plasma- and serum-derived cfDNA samples from 221 advanced melanoma patients were analyzed for BRAF c.1799T>A (p.V600E) mutation using ARMS in two stages in a blinded fashion. cfDNA-specific mutation calling criteria were defined in stage 1 and validated in stage 2. cfDNA concentrations in serum and plasma, and the sensitivities and specificities of BRAF mutation detection in these two clinical matrices were compared. Sensitivity of BRAF c.1799T>A (p.V600E) mutation detection in cfDNA was increased by using mutation calling criteria optimized for cfDNA (these criteria were adjusted from those used for archival tumor biopsies) without compromising specificity. Sensitivity of BRAF mutation detection in serum was 44% (95% CI, 35% to 53%) and in plasma 52% (95% CI, 43% to 61%). Specificity was 96% (95% CI, 90% to 99%) in both matrices. Serum contains significantly higher total cfDNA than plasma, whereas the proportion of tumor-derived mutant DNA was significantly higher in plasma. Using mutation calling criteria optimized for cfDNA improves sensitivity of BRAF c.1799T>A (p.V600E) mutation detection. The proportion of tumor-derived cfDNA in plasma was significantly higher than in serum.
Subject(s)
DNA Mutational Analysis/methods , DNA/genetics , Melanoma/genetics , Proto-Oncogene Proteins B-raf/genetics , DNA/blood , DNA, Neoplasm/genetics , Humans , Melanoma/blood , Melanoma/pathology , Point Mutation , Polymerase Chain Reaction/methods , Sensitivity and SpecificityABSTRACT
We previously demonstrated that circulating tumour cells (CTCs) are detectable by the MelCAM and high molecular weight melanoma-associated antigen (HMW-MAA)-dependent CellSearch platform. However, CTCs which do not express these capture and detection markers are not detectable by CellSearch. Consequently, we explored the use of isolation by size of epithelial tumour cells (ISET), a marker independent, filtration-based device to determine the prevalence and heterogeneity of CTCs in metastatic cutaneous melanoma patients. Ninety patients were prospectively recruited and blood samples taken before treatment. Patients' blood was filtered using the ISET platform. CTCs were enumerated using dual immunohistochemistry with positive selection by S100 expression and exclusion of leucocytes and endothelial cells expressing CD45 or CD144, respectively. A panel of markers (Melan-A, MITF, MelCAM, high molecular melanoma-associated antigen, CD271 and MAGEC) was also examined. Fifty-one patients (57%) had CTCs (range 1-44 CTCs/4 ml blood) and 12 patients also had circulating tumour microemboli. Seven patients had S100- CTCs, 11 patients' CTCs were S100+ and 33 patients had S100+ and S100- CTCs. Substantial intrapatient and interpatient heterogeneity was observed for all other melanoma-associated markers. CTCs in metastatic cutaneous melanoma are detectable using the flexible marker-independent ISET platform. CTCs display significant marker expression heterogeneity implying that marker-dependent platforms would not detect all CTCs and multimarker assays are now required to reveal the biological significance of this CTC heterogeneity.
Subject(s)
Biomarkers, Tumor/blood , Melanoma/pathology , Neoplastic Cells, Circulating/pathology , Skin Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Female , Genetic Heterogeneity , Humans , Immunophenotyping , Male , Melanoma/blood , Melanoma/genetics , Middle Aged , Prevalence , Skin Neoplasms/blood , Skin Neoplasms/genetics , Melanoma, Cutaneous MalignantABSTRACT
The incidence of melanoma is increasing worldwide. Advances in targeted agents and immunotherapy have improved outcomes in metastatic disease, but biomarkers are required to optimize treatment. We determined the prevalence of circulating tumor cells (CTCs) and explored their utility as prognostic and pharmacodynamic biomarkers. A total of 101 patients with metastatic cutaneous melanoma were recruited prospectively. CTC number was determined using the CellSearch platform and melanoma kits in samples taken at baseline and serially during treatment. CTC numbers ranged between 0 and 36 per 7.5 ml blood; 26% of patients had ≥ 2 CTCs. Baseline CTC number was prognostic for median overall survival (OS) in univariate analysis (2.6 vs. 7.2 months (P<0.011) for patients with ≥ 2 CTCs vs. <2 CTCs, respectively). In multivariate analysis, CTC number was an independent prognostic biomarker of OS (hazard ratio (HR) 2.403, 95% confidence interval (CI) 1.303-4.430, P=0.005). Patients receiving treatment in whom CTC number remained ≥ 2 CTCs during treatment had shorter median OS than those who maintained <2 CTCs (7 vs. 10 months, HR 0.34, 95% CI 0.14-0.81, log-rank test P=0.015). In conclusion, CTC number in metastatic cutaneous melanoma patients is prognostic for OS with a cutoff of 2 CTCs per 7.5 ml blood. CTC number measured before and throughout treatment provided additional prognostic information. Larger studies are warranted to confirm CTC biomarker utility in melanoma patients.
Subject(s)
Biomarkers, Tumor/metabolism , Melanoma/epidemiology , Melanoma/secondary , Neoplastic Cells, Circulating/pathology , Skin Neoplasms/epidemiology , Skin Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Drug Monitoring/methods , Female , Humans , Incidence , Male , Melanoma/metabolism , Middle Aged , Multivariate Analysis , Neoplastic Cells, Circulating/metabolism , Predictive Value of Tests , Prevalence , Prognosis , Proportional Hazards Models , Reagent Kits, Diagnostic , Skin Neoplasms/metabolismABSTRACT
Lipid profiles in women with early breast cancer receiving anastrozole with or without risedronate were examined within an international Phase III/IV study to assess for possible treatment related changes. Postmenopausal women with hormone receptor-positive breast cancer were assigned to 1 of 3 strata by risk of fragility fracture. Patients with the highest risk for fracture received anastrozole plus risedronate (A + R). Moderate-risk patients were randomized in a double-blind manner to A + R or anastrozole and placebo (A + P). Lower-risk patients received anastrozole (A) alone. Serial fasting blood samples were assessed for changes in lipid parameters relative to baseline after 12 months of treatment with anastrozole with or without risedronate. Samples were centrally analyzed for low-density lipoprotein cholesterol (LDL-cholesterol), high-density lipoprotein (HDL) cholesterol, total cholesterol (TC) and triglycerides (TG). Analysis was performed as primary analysis population for lipids (A plus A + P), lipid intention to treat population and secondary population (A + R). Of the 119 patients treated with A plus A + P, there were 66 patients eligible for inclusion in the primary analysis population. Of the 115 patients treated with secondary population (A + R) there were 65 patients eligible for lipid profiling. For LDL-cholesterol, HDL-cholesterol, TC and TG there were no significant changes between the baseline and 12 months assessments to suggest that any of these therapies have a negative impact on the lipid profile. In this study of postmenopausal women with early breast cancer receiving adjuvant anastrozole with or without risedronate, there was no adverse effect on LDL-cholesterol, HDL-cholesterol, TC or TG values over the 12 months monitoring period.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Lipids/blood , Adult , Aged , Anastrozole , Antineoplastic Agents, Hormonal/administration & dosage , Bone Density Conservation Agents/administration & dosage , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Etidronic Acid/administration & dosage , Etidronic Acid/analogs & derivatives , Female , Humans , Middle Aged , Nitriles/administration & dosage , Risedronic Acid , Treatment Outcome , Triazoles/administration & dosage , Triglycerides/bloodABSTRACT
Saracatinib (AZD0530) is an orally active once-daily Src kinase inhibitor which modulates key signaling pathways in cancer cells. In a Phase I study in patients with advanced solid malignancies resistant to standard treatment we assessed the effect of saracatinib on bone turnover. Fifty-one patients were randomized into three parallel groups to receive saracatinib 50, 125 or 175 mg/day. After a single dose followed by a 7-day washout, patients received once-daily doses for 21 days. Bone turnover markers were measured in serum and urine samples collected before dosing on days 1, 2, 3, 17 and 28. Samples were available at baseline and more than one other time point for 44 patients. Bone resorption markers were significantly decreased by saracatinib. Serum cross-linked C-terminal telopeptide of type I collagen (sCTX) changed in the 50, 125 and 175 mg/day groups by -36% (95% CI -58, -4), -64% (95% CI -75, -48) and -75% (95% CI -83, -61), respectively, at day 28. Urinary cross-linked N-terminal telopeptide of type I collagen/creatinine ratio (uNTX/Cr) changed in the 50, 125 and 175 mg/day groups by; -13% (95% CI -33, 13), -48% (95% CI -59, -34) and -50% (95% CI -62, -35), respectively, at day 28. The significant decreases in bone resorption markers indicate that suppression of Src kinase inhibits osteoclast activity in patients with advanced cancer. This result suggests that saracatinib may have therapeutic benefit in metastatic bone disease.
Subject(s)
Benzodioxoles/pharmacology , Benzodioxoles/therapeutic use , Bone Remodeling/drug effects , Neoplasms/drug therapy , Neoplasms/physiopathology , Protein Kinase Inhibitors/therapeutic use , Quinazolines/pharmacology , Quinazolines/therapeutic use , src-Family Kinases/antagonists & inhibitors , Adult , Aged , Benzodioxoles/adverse effects , Biomarkers, Tumor/metabolism , Dose-Response Relationship, Drug , Female , Humans , Male , Middle Aged , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacology , Quinazolines/adverse effects , Young Adult , src-Family Kinases/metabolismABSTRACT
INTRODUCTION: Epithelial circulating tumor cells (CTCs) are detectable in patients with non-small cell lung cancer (NSCLC). However, epithelial to mesenchymal transition, a widely reported prerequisite for metastasis, may lead to an underestimation of CTC number. We compared directly an epithelial marker-dependent (CellSearch) and a marker-independent (isolation by size of epithelial tumor cells [ISET]) technology platform for the ability to identify CTCs. Molecular characteristics of CTCs were also explored. METHODS: Paired peripheral blood samples were collected from 40 chemonäive, stages IIIA to IV NSCLC patients. CTCs were enumerated by Epithelial Cell Adhesion Molecule-based immunomagnetic capture (CellSearch, Veridex) and by filtration (ISET, RareCell Diagnostics). CTCs isolated by filtration were assessed by immunohistochemistry for epithelial marker expression (cytokeratins, Epithelial Cell Adhesion Molecule, epidermal growth factor receptor) and for proliferation status (Ki67). RESULTS: CTCs were detected using ISET in 32 of 40 (80%) patients compared with 9 of 40 (23%) patients using CellSearch. A subpopulation of CTCs isolated by ISET did not express epithelial markers. Circulating tumor microemboli (CTM, clusters of ≥ 3 CTCs) were observed in 43% patients using ISET but were undetectable by CellSearch. Up to 62% of single CTCs were positive for the proliferation marker Ki67, whereas cells within CTM were nonproliferative. CONCLUSIONS: Both technology platforms detected NSCLC CTCs. ISET detected higher numbers of CTCs including epithelial marker negative tumor cells. ISET also isolated CTM and permitted molecular characterization. Combined with our previous CellSearch data confirming CTC number as an independent prognostic biomarker for NSCLC, we propose that this complementary dual technology approach to CTC analysis allows more complete exploration of CTCs in patients with NSCLC.
Subject(s)
Adenocarcinoma, Bronchiolo-Alveolar/pathology , Adenocarcinoma/pathology , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Squamous Cell/pathology , Epithelial Cells/pathology , Lung Neoplasms/pathology , Neoplastic Cells, Circulating/pathology , Adenocarcinoma/metabolism , Adenocarcinoma, Bronchiolo-Alveolar/metabolism , Aged , Biomarkers, Tumor/metabolism , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Squamous Cell/metabolism , Cell Proliferation , Cell Separation , Epithelial Cells/metabolism , Female , Humans , Lung Neoplasms/metabolism , Male , Middle Aged , Neoplastic Cells, Circulating/metabolism , Prognosis , Prospective StudiesABSTRACT
Circulating tumor cell (CTC) number in metastatic cancer patients yields prognostic information consistent with enhanced cell migration and invasion via loss of adhesion, a feature of epithelial-to-mesenchymal transition (EMT). Tumor cells also invade via collective migration with maintained cell-cell contacts and consistent with this is the circulating tumor microemboli (CTM; contiguous groups of tumor cells) that are observed in metastatic cancer patients. Using a blood filtration approach, we examined markers of EMT (cytokeratins, E-cadherin, vimentin, neural cadherin) and prevalence of apoptosis in CTCs and CTM to explore likely mechanism(s) of invasion in lung cancer patients and address the hypothesis that cells within CTM have a survival advantage. Intra-patient and inter-patient heterogeneity was observed for EMT markers in CTCs and CTM. Vimentin was only expressed in some CTCs, but in the majority of cells within CTM; E-cadherin expression was lost, cytoplasmic or nuclear, and rarely expressed at the surface of the cells within CTM. A subpopulation of CTCs was apoptotic, but apoptosis was absent within CTM. This pilot study suggests that EMT is not prosecuted homogeneously in tumor cells within the circulation of lung cancer patients and that collective migration and enhanced survival of cells within CTM might contribute to lung cancer metastasis. Multiplex analysis and further detailed exploration of metastatic potential and EMT in CTCs/CTM is now warranted in a larger patient cohort.
Subject(s)
Lung Neoplasms/pathology , Neoplastic Cells, Circulating/pathology , Aged , Biomarkers, Tumor/metabolism , Cell Survival , Epithelial Cells/metabolism , Epithelial Cells/pathology , Female , Humans , Lung Neoplasms/metabolism , Male , Mesoderm/metabolism , Mesoderm/pathology , Middle Aged , Neoplasm Metastasis , Neoplastic Cells, Circulating/metabolismABSTRACT
PURPOSE: Lung cancer is the leading cause of cancer-related death worldwide. Non-small-cell lung cancer (NSCLC) lacks validated biomarkers to predict treatment response. This study investigated whether circulating tumor cells (CTCs) are detectable in patients with NSCLC and what their ability might be to provide prognostic information and/or early indication of patient response to conventional therapy. PATIENTS AND METHODS: In this single-center prospective study, blood samples for CTC analysis were obtained from 101 patients with previously untreated, stage III or IV NSCLC both before and after administration of one cycle of standard chemotherapy. CTCs were measured using a semiautomated, epithelial cell adhesion molecule-based immunomagnetic technique. RESULTS: The number of CTCs in 7.5 mL of blood was higher in patients with stage IV NSCLC (n = 60; range, 0 to 146) compared with patients with stage IIIB (n = 27; range, 0 to 3) or IIIA disease (n = 14; no CTCs detected). In univariate analysis, progression-free survival was 6.8 v 2.4 months with P < .001, and overall survival (OS) was 8.1 v 4.3 months with P < .001 for patients with fewer than five CTCs compared with five or more CTCs before chemotherapy, respectively. In multivariate analysis, CTC number was the strongest predictor of OS (hazard ratio [HR], 7.92; 95% CI, 2.85 to 22.01; P < .001), and the point estimate of the HR was increased with incorporation of a second CTC sample that was taken after one cycle of chemotherapy (HR, 15.65; 95% CI, 3.63 to 67.53; P < .001). CONCLUSION: CTCs are detectable in patients with stage IV NSCLC and are a novel prognostic factor for this disease. Further validation is warranted before routine clinical application.
Subject(s)
Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/pathology , Neoplastic Cells, Circulating/pathology , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/analysis , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/immunology , Cell Adhesion Molecules/analysis , Disease-Free Survival , England , Female , Humans , Immunomagnetic Separation , Kaplan-Meier Estimate , Lung Neoplasms/drug therapy , Lung Neoplasms/immunology , Male , Middle Aged , Neoplasm Staging , Neoplastic Cells, Circulating/drug effects , Neoplastic Cells, Circulating/immunology , Predictive Value of Tests , Proportional Hazards Models , Prospective Studies , Risk Assessment , Risk Factors , Time Factors , Treatment OutcomeABSTRACT
PURPOSE To investigate the management of bone health in women with early breast cancer (EBC) who were scheduled to receive anastrozole. PATIENTS AND METHODS Postmenopausal women with hormone receptor-positive EBC were assigned to one of three strata by risk of fragility fracture. Patients with the highest risk (H) received anastrozole 1 mg/d plus risedronate 35 mg/wk orally. Patients with moderate-risk (M) were randomly assigned in a double-blind manner to anastrozole and risedronate (A + R) or to anastrozole and placebo (A + P). Patients with lower-risk (L) received anastrozole (A) alone. Calcium and vitamin D were recommended for all patients. Lumbar spine and total hip bone mineral density (BMD) were assessed at baseline, 12 months, and 24 months. Results At 24 months, in the M group, treatment with A + R resulted in a significant increase in lumbar spine and total hip BMD compared with A + P treatment (2.2% v -1.8%; treatment ratio, 1.04; P < .0001; and 1.8% v -1.1%; treatment ratio, 1.03; P < .0001, respectively). In the H stratum, lumbar spine and total hip BMD increased significantly (3.0%; P = .0006; and 2.0%; P = .0104, respectively). Patients in the L stratum showed a significant decrease in lumbar spine BMD (-2.1%; P = .0109) and a numerical decrease in total hip BMD (-0.4%; P = .5988). Safety profiles for anastrozole and risedronate were similar to those already established. CONCLUSION In postmenopausal women at risk of fragility fracture who were receiving adjuvant anastrozole for EBC, the addition of risedronate at doses established for preventing and treating osteoporosis resulted in favorable effects in BMD during 24 months.
Subject(s)
Aromatase Inhibitors/adverse effects , Bone Density Conservation Agents/therapeutic use , Breast Neoplasms/drug therapy , Etidronic Acid/analogs & derivatives , Fractures, Bone/prevention & control , Nitriles/adverse effects , Osteoporosis, Postmenopausal/prevention & control , Triazoles/adverse effects , Aged , Anastrozole , Bone Density/drug effects , Breast Neoplasms/pathology , Double-Blind Method , Etidronic Acid/therapeutic use , Female , Fractures, Bone/chemically induced , Hormone Replacement Therapy , Humans , Middle Aged , Neoplasm Staging , Osteoporosis, Postmenopausal/chemically induced , Postmenopause , Prognosis , Risedronic Acid , Survival Rate , Treatment OutcomeABSTRACT
Src is a nonreceptor tyrosine kinase thought to be essential for osteoclast function and bone resorption. We investigated the effect of the orally available Src inhibitor saracatinib (AZD0530) on bone turnover in healthy men. The study was part of a randomized, double-blind, placebo-controlled multiple-ascending-dose phase I trial of saracatinib. Fifty-nine healthy men (mean age 34.6 years) were divided into five cohorts; four with 12 subjects and one with 11 subjects, and randomized within each cohort in the ratio 3:1 to receive a single dose of saracatinib or placebo, respectively, followed 7 to 10 days later with daily doses for a further 10 to 14 days. Dosing levels of saracatinib ascended by cohort (60 to 250 mg). Markers of bone turnover were measured predose and 24 and 48 hours after the initial single dose and immediately before and 24 and 48 hours and 10 to 14 days after the final dose. Data from 44 subjects were included in the analysis. There was a dose-dependent decrease in bone resorption markers [serum cross-linked C-telopeptide of type I collagen (sCTX) and urinary cross-linked N-telopeptide of type I collagen normalized to creatinine (uNTX/Cr)]. At a dose of 250 mg (maximum tolerated dose), sCTX decreased by 88% [95% confidence interval (CI) 84-91%] and uNTX/Cr decreased by 67% (95% CI 53-77%) from baseline 24 hours after the final dose. There was no significant effect on bone formation markers. There were no significant adverse events. We conclude that inhibition of Src reduces osteoclastic bone resorption in humans. Saracatinib is a potentially useful treatment for diseases characterized by increased bone resorption, such as metastatic bone disease and osteoporosis.
Subject(s)
Benzodioxoles/pharmacology , Bone Remodeling/drug effects , Quinazolines/pharmacology , Adult , Benzodioxoles/administration & dosage , Biomarkers/blood , Double-Blind Method , Drug Administration Schedule , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacology , Humans , Male , Men's Health , Quinazolines/administration & dosageABSTRACT
Biomarker measurements have become an essential component of oncology drug development, particularly so in this era of targeted therapies. Such measurements ensure that clinical studies are testing our biological hypotheses and can help make the difficult decisions required to choose which drugs to stop developing or de-prioritise. For those drugs taken forward, biomarker measurements may also help choose the appropriate dose, schedule and patient population. In this review we discuss the intrinsic properties of biological sample based efficacy measurements and how these relate to their implementation in oncology drug development by way of points to consider and examples.
Subject(s)
Biomarkers , Drug Design , Animals , Chemistry, Pharmaceutical/methods , Drug Industry/methods , HumansABSTRACT
PURPOSE: The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial (median follow-up, 68 months) has shown that adjuvant anastrozole has superior efficacy and better tolerability than tamoxifen. However, anastrozole reduces circulating estrogen, and low estradiol levels are associated with decreased bone mineral density (BMD) and increased fracture risk. It is therefore important to understand the effects of long-term aromatase inhibitor therapy on BMD. PATIENTS AND METHODS: This prospective substudy of the ATAC trial assessed BMD changes in postmenopausal women with invasive primary breast cancer receiving anastrozole (1 mg/d) or tamoxifen (20 mg/d) as adjuvant therapy for 5 years. Lumbar spine and total hip BMD were assessed at baseline and after 1, 2, and 5 years. RESULTS: One hundred ninety-seven women from the monotherapy arms of the ATAC trial were recruited onto the bone substudy, and 108 were included in the primary analysis. Among anastrozole-treated patients, there was a decrease in median BMD from baseline to 5 years in lumbar spine (-6.08%) and total hip (-7.24%) compared with the tamoxifen group (lumbar spine, +2.77%; total hip, +0.74%). No patients with normal BMD at baseline became osteoporotic at 5 years. CONCLUSION: Anastrozole is associated with accelerated bone loss over the 5-year treatment period. However, although patients with pre-existing osteopenia are likely to require monitoring and bone-protection strategies, patients with normal BMD would not appear to require monitoring beyond the recommendation for healthy postmenopausal women. The effect of anastrozole on bone should be weighed against its superior efficacy and better tolerability profile versus tamoxifen in the main ATAC trial.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Density/drug effects , Breast Neoplasms/drug therapy , Anastrozole , Case-Control Studies , Chemotherapy, Adjuvant , Female , Humans , Neoplasm Invasiveness , Nitriles/administration & dosage , Postmenopause , Prospective Studies , Tamoxifen/administration & dosage , Treatment Outcome , Triazoles/administration & dosageABSTRACT
Demonstration of pharmacodynamic activity of new, targeted cancer drugs in tumour tissue is potentially important in guiding early drug development. However, delays between tumour sampling and sample fixation may result in variability of pharmacodynamic biomarkers. The aim of this study, was to assess the impact of delays in fixation on biomarkers of Src kinase activity. A total of 20 patients with locally advanced breast cancer and 5 with early bladder cancer had multiple tissue samples taken which were fixed at documented time points up to 60 min after biopsy. These were examined to determine if the amount of Paxillin, phospho-Paxillin, phospho-focal adhesion kinase (FAK) and total phospho-Tyrosine changed over time, using a quantitative lysate immunoassay. In breast cancer, there was an increase in the amount of phospho-Paxillin (60% per h; P = 0.019) up to 60 min after biopsy. The amount of total Paxillin decreased (28% per h; P = 0.034) over the same time course. In early bladder cancer, no changes were noted in any endpoints up to 45 min. Standardisation of the time taken between biopsy and fixation may be critical, particularly in studies using phosphorylated protein biomarkers.