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1.
Oncotarget ; 6(16): 14139-52, 2015 Jun 10.
Article in English | MEDLINE | ID: mdl-25944621

ABSTRACT

Non-small cell lung cancer (NSCLC) is a leading cause of death worldwide. Targeted monotherapies produce high regression rates, albeit for limited patient subgroups, who inevitably succumb. We present a novel strategy for identifying customized combinations of triplets of targeted agents, utilizing a simplified interventional mapping system (SIMS) that merges knowledge about existent drugs and their impact on the hallmarks of cancer. Based on interrogation of matched lung tumor and normal tissue using targeted genomic sequencing, copy number variation, transcriptomics, and miRNA expression, the activation status of 24 interventional nodes was elucidated. An algorithm was developed to create a scoring system that enables ranking of the activated interventional nodes for each patient. Based on the trends of co-activation at interventional points, combinations of drug triplets were defined in order to overcome resistance. This methodology will inform a prospective trial to be conducted by the WIN consortium, aiming to significantly impact survival in metastatic NSCLC and other malignancies.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Precision Medicine/methods , Adult , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Female , Humans , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Male , Middle Aged , Molecular Targeted Therapy/methods , Transcriptome
2.
Clin Cancer Res ; 21(19): 4286-93, 2015 Oct 01.
Article in English | MEDLINE | ID: mdl-25977344

ABSTRACT

PURPOSE: This phase I study evaluated the safety, maximum tolerated dose, antitumor activity, and pharmacokinetics and pharmacodynamics of pembrolizumab in patients with advanced solid tumors. EXPERIMENTAL DESIGN: In a 3 + 3 dose escalation study, 10 patients received pembrolizumab 1, 3, or 10 mg/kg intravenously every 2 weeks until progression or intolerable toxicity. Seven additional patients received 10 mg/kg every 2 weeks. Thirteen patients participated in a 3-week intrapatient dose escalation (dose range, 0.005-10 mg/kg) followed by 2 or 10 mg/kg every 3 weeks. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. RESULTS: No dose-limiting toxicities were observed. Maximum administered dose was 10 mg/kg every 2 weeks. One patient with melanoma and one with Merkel cell carcinoma experienced complete responses of 57 and 56+ weeks' duration, respectively. Three patients with melanoma experienced partial responses. Fifteen patients with various malignancies experienced stable disease. One patient died of cryptococcal infection 92 days after pembrolizumab discontinuation, following prolonged corticosteroid use for grade 2 gastritis considered drug related. Pembrolizumab exhibited pharmacokinetic characteristics typical of humanized monoclonal antibodies. Maximum serum target engagement was reached with trough levels of doses greater than or equal to 1 mg/kg every 3 weeks. Mechanism-based translational models with a focus on intratumor exposure prediction suggested robust clinical activity would be observed at doses ≥2 mg/kg every 3 weeks. CONCLUSIONS: Pembrolizumab was well tolerated and associated with durable antitumor activity in multiple solid tumors. The lowest dose with full potential for antitumor activity was 2 mg/kg every 3 weeks.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/therapeutic use , Molecular Targeted Therapy , Neoplasms/drug therapy , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/pharmacology , Antineoplastic Agents/pharmacology , Drug Monitoring , Female , Humans , Male , Middle Aged , Neoplasm Staging , Neoplasms/immunology , Neoplasms/metabolism , Neoplasms/pathology , Treatment Outcome
3.
Eur J Cancer ; 42(12): 1797-806, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16846734

ABSTRACT

PURPOSE: The purpose was to evaluate the activity and toxicity of split-dose paclitaxel or docetaxel in combination with gemcitabine in patients with metastatic breast cancer (MBC) who had previously received anthracyclines. PATIENTS AND METHODS: A total of 210 patients were randomly assigned to one of three treatment arms: gemcitabine 1,250 mg/m(2) Days 1 and 8 and paclitaxel 175 mg/m(2) as a 3-h infusion on Day 1 (GP1); gemcitabine 1,000 mg/m(2) Days 1 and 8 and paclitaxel 100 mg/m(2) as a 1-h infusion on Days 1 and 8 (GP2); gemcitabine 1,000 mg/m(2) Days 1 and 8 and docetaxel 40 mg/m(2) as a 1-h infusion on Days 1 and 8 (GD). Cycles were repeated every 3 weeks. RESULTS: For the 204 patients evaluable for response assessment, the response rates were 48.6% for GP1, 52.2% for GP2, and 52.3% for GD. Median response duration, time to treatment failure, and time to progression (TTP) were similar in each arm. Median TTP for GP1, GP2 and GD was 7.5, 7.0 and 7.4 months, respectively. For the 208 patients evaluable for safety, the most common grade 3/4 toxicity for each regimen was neutropaenia, with 64%, 57%, and 68% for GP1, GP2, and GD, respectively. Grade 4 neutropaenia, grade 3/4 anaemia, febrile neutropaenia, and diarrhoea were more common in the docetaxel arm, as was the use of intravenous antibiotics and blood transfusions. CONCLUSION: The study confirmed the high activity of gemcitabine-taxane combinations in MBC. Split-dose paclitaxel had similar activity and toxicity to the 3-weekly administration. The split-dose docetaxel regimen had similar activity to the paclitaxel combinations though associated with higher toxicity.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Adolescent , Adult , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/analogs & derivatives , Docetaxel , Female , Humans , Middle Aged , Neoplasm Metastasis , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Taxoids/administration & dosage , Taxoids/adverse effects , Treatment Failure , Gemcitabine
4.
J Thorac Oncol ; 1(2): 135-40, 2006 Feb.
Article in English | MEDLINE | ID: mdl-17409842

ABSTRACT

BACKGROUND: The aim of this single-arm phase II study was to evaluate the efficacy, feasibility, and safety of the gemcitabine-carboplatin-paclitaxel combination as neoadjuvant chemotherapy in patients with operable non-small cell lung cancer (NSCLC). METHODS: Patients with stage IB, II, or IIIA NSCLC were given three cycles of chemotherapy followed by tumor resection. Each 21-day cycle consisted of gemcitabine 1000 mg/m on days 1 and 8, carboplatin AUC 5 on day 1, and paclitaxel 175 mg/m on day 1. RESULTS: Forty-four patients were enrolled: 18.2% of patients had stage IB, 15.9% had stage II, and 65.9% had stage IIIA NSCLC. All patients received three cycles of treatment. The clinical tumor response rate was 76.2% (32 of 42 patients; 95% CI, 60.5-87.9%). Thirty-six patients had a complete tumor resection, five of whom had a complete pathological response with no viable tumor cells in the resected tumor on histological examination. Median time to progression was 13.6 months (95% CI, 8.9, >16 months), and 26 of 44 patients (59.1%) had progressed. The 1-year disease-free survival rate was 53.6% (95% CI, 38.7-68.5%), and the 1-year survival rate was 86.0% (95% CI, 75.7-96.4%). Grade 3 and 4 neutropenia each occurred in 38.6% of patients, and grade 3 infection occurred in 2.3% of patients; grade 3 and 4 thrombocytopenia occurred in 25.0% and 0% of patients, respectively. CONCLUSION: The gemcitabine-carboplatin-paclitaxel combination showed promising efficacy and seemed to be safe and feasible as neoadjuvant chemotherapy in patients with operable-stage NSCLC.


Subject(s)
Antineoplastic Agents/therapeutic use , Carboplatin/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Deoxycytidine/analogs & derivatives , Immunosuppressive Agents/therapeutic use , Lung Neoplasms/drug therapy , Paclitaxel/therapeutic use , Adult , Aged , Antineoplastic Agents/administration & dosage , Carboplatin/administration & dosage , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Deoxycytidine/administration & dosage , Deoxycytidine/therapeutic use , Drug Therapy, Combination , Female , Follow-Up Studies , Humans , Immunosuppressive Agents/administration & dosage , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Neoadjuvant Therapy/methods , Neoplasm Staging , Paclitaxel/administration & dosage , Ribonucleotide Reductases/antagonists & inhibitors , Severity of Illness Index , Survival Rate/trends , Gemcitabine
5.
Cancer Chemother Pharmacol ; 52(2): 153-8, 2003 Aug.
Article in English | MEDLINE | ID: mdl-12750842

ABSTRACT

PURPOSE: To determine the maximally tolerated dose (MTD) of gemcitabine administered at a fixed dose-rate of 10 mg/m(2) per min in combination with fixed dose carboplatin, to evaluate the toxicity of this regimen and to determine the pharmacokinetics of plasma gemcitabine. METHODS: Patients with advanced stage non-small-cell lung cancer (NSCLC) received carboplatin (AUC 5) on day 1 followed by gemcitabine at a fixed dose rate of 10 mg/m(2) per min in escalating durations of infusion on days 1 and 8 every 21 days. Pharmacokinetic sampling was obtained on day 1, cycle 1 of treatment. RESULTS: A total of 15 patients received carboplatin and gemcitabine in cohorts of three to six patients at three dose levels. The doses of gemcitabine studied were 600, 750, and 900 mg/m(2). The MTD was reached at 900 mg/m(2). Dose-limiting toxicities were thrombocytopenia and liver failure, and with repeated dosing neutropenia was commonly observed. The recommended phase II dose of gemcitabine was 750 mg/m(2). Partial responses were observed at 600 and 750 mg/m(2) of gemcitabine. Plasma gemcitabine did not reach steady state except in one patient with the durations of infusion studied. Plasma concentrations, however, were above 10 micro mol/l between 20 and 90 min in all patients. CONCLUSIONS: Gemcitabine administered as a 75-min infusion at a fixed dose rate of 10 mg/m(2)/min on days 1 and 8 in combination with carboplatin on day 1 every 21 days is tolerable and active in NSCLC. Pharmacokinetic studies demonstrated that the target plasma gemcitabine concentration above 10 micro mol/l was achieved. Further studies are warranted to compare this regimen against standard regimens of carboplatin and gemcitabine.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Deoxycytidine/analogs & derivatives , Lung Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/blood , Area Under Curve , Carboplatin/administration & dosage , Carcinoma, Non-Small-Cell Lung/pathology , Deoxycytidine/administration & dosage , Dose-Response Relationship, Drug , Female , Humans , Infusions, Intravenous , Lung Neoplasms/pathology , Male , Maximum Tolerated Dose , Middle Aged , Neoplasm Staging , Treatment Outcome , Gemcitabine
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