Phase I clinical trial of lenalidomide in combination with temsirolimus in patients with advanced cancer.

Background: Lenalidomide, an immunomodulatory and anti-angiogenic drug, and temsirolimus, an mTOR inhibitor, have synergistic anti-cancer effects in preclinical models. We conducted a phase I study of the combination in patients with advanced cancers.

Patients And Methods: A "3 + 3" study design was used.

Combining erlotinib and cetuximab is associated with activity in patients with non-small cell lung cancer (including squamous cell carcinomas) and wild-type EGFR or resistant mutations.

Preclinical data suggest that combined EGF receptor (EGFR) targeting with an EGFR tyrosine kinase inhibitor and an anti-EGFR monoclonal antibody may be superior over single-agent targeting. Therefore, as part of a phase I study, we analyzed the outcome of 20 patients with non-small cell lung cancer treated with the combination of erlotinib and cetuximab. EGFR mutation status was ascertained in a Clinical Laboratory Improvement Amendment-approved laboratory.

Body composition and survival in the early clinical trials setting.

Purpose: Delineate the relationships between body composition parameters, 90-day mortality and overall survival, and correlate them with known prognostic factors in an early clinical trials clinic.

Patients And Methods: We studied 306 consecutive patients with various tumours; body composition was analysed by computerised tomography images. Survival was measured from the first clinic visit, at 90-day period and until death/last follow-up visit.

Revisiting clinical trials using EGFR inhibitor-based regimens in patients with advanced non-small cell lung cancer: a retrospective analysis of an MD Anderson Cancer Center phase I population.

Purpose: Single-agent EGFR inhibitor therapy is effective mainly in patients with lung cancer and EGFR mutations. Treating patients who develop resistance, or who are insensitive from the outset, often because of resistant mutations, other aberrations or the lack of an EGFR mutation, probably requires rational combinations. We therefore investigated the outcome of EGFR inhibitor-based combination regimens in patients with heavily-pretreated non-small cell lung cancer (NSCLC) referred to a Phase I Clinic.

Phase I clinical trial of lenalidomide in combination with sorafenib in patients with advanced cancer.

Background: Preclinical data have shown that lenalidomide and sorafenib target endothelial cells, inhibiting growth of ocular melanoma cells in a xenograft model. We conducted a Phase I study of lenalidomide and sorafenib in patients with advanced cancer.

Methods: During the escalation phase, lenalidomide (days 1-21) and sorafenib (days 1-28) were given orally once daily at the following respective doses: level 1 (10 mg, 200 mg); level 2 (10 mg, 400 mg); level 3 (20 mg, 400 mg); and level 4 (25 mg, 400 mg) (1 cycle = 28 days).

P53 mutations in advanced cancers: clinical characteristics, outcomes, and correlation between progression-free survival and bevacizumab-containing therapy.

Background: Mutations in the p53 gene are amongst the most frequent aberrations seen in human cancer. Our objective was to characterize the clinical characteristics associated with p53 mutation in patients with advanced cancer.

Methods: We retrospectively reviewed and analyzed the clinical features and response to standard systemic therapy of 145 patients with documented tumor p53 mutational status (mutant-type [mtp53] vs.

Melanoma patients in a phase I clinic: molecular aberrations, targeted therapy and outcomes.

Background: The purpose of the study was to assess the outcome of patients with advanced melanoma treated with matched molecularly targeted therapy.

Patients And Methods: We reviewed 160 consecutive patients with metastatic melanoma treated in the phase I program (N = 35 protocols). Treatment was considered to be 'matched' (N = 84) if at least one drug in the regimen was known to inhibit the functional activity of at least one of the patient's mutations.

Factors related to biopsy willingness in patients with advanced cancer in a phase 1 clinic for molecularly targeted therapy.

Purpose: Tumor biopsies are critical for delineating pharmacodynamic effects of drugs and for optimal patient selection during oncology clinical trials of molecular targeted therapies. The purpose of this study was to identify factors related to patients' willingness to provide study-related tumor biopsies in phase 1 clinical trials of molecularly targeted therapy.

Methods: An investigator-designed survey, that assessed biopsy willingness, demographic and clinical factors, was completed anonymously by patients with advanced cancer in a phase 1 clinic for targeted therapy.

Dual EGFR inhibition in combination with anti-VEGF treatment: a phase I clinical trial in non-small cell lung cancer.

Background: Preclinical data indicate EGFR signals through both kinase-dependent and independent pathways and that combining a small-molecule EGFR inhibitor, EGFR antibody, and/or anti-angiogenic agent is synergistic in animal models.

Methods: We conducted a dose-escalation, phase I study combining erlotinib, cetuximab, and bevacizumab. The subset of patients with non-small cell lung cancer (NSCLC) was analyzed for safety and response.

Targeted therapy of advanced gallbladder cancer and cholangiocarcinoma with aggressive biology: eliciting early response signals from phase 1 trials.

Purpose: Patients with advanced cholangiocarcinoma (CC) and gallbladder carcinoma (GC) have few therapeutic options for relapsed disease. methods: Given the overall poor prognosis in this population and the availability of novel targeted therapies, we systematically analyzed the characteristics and outcomes for GC and CC patients treated on phase I trials with an emphasis on targeted agents and locoregional therapies.

Results: Of 40 treated patients (GC=6; CC=34; median age, 60 years), 8 (20%) had stable disease (SD) > 6 months, 3 (8%) partial response (PR), on protocols with hepatic arterial drug infusion and anti-angiogenic, anti-HER-2/neu or novel MAPK/ERK kinase (MEK) inhibitors.

PIK3CA mutations in advanced cancers: characteristics and outcomes.

PIK3CA mutations are frequently diagnosed in diverse cancers and may predict response to PI3K/AKT/mTOR inhibitors. It remains unclear whether they are associated with other characteristics. We analyzed characteristics and outcome of 90 consecutive patients with diverse advanced tumors and PIK3CA mutations and 180 wild-type PIK3CA controls matched by tumor type, gender, and age referred to the Clinical Center for Targeted Therapy.

A phase 1 study of gemcitabine combined with dasatinib in patients with advanced solid tumors.

Purpose: Dasatinib has been shown preclinically to overcome resistance to gemcitabine. We evaluated the safety and biological activity of the combination of dasatinib and gemcitabine in patients with advanced solid tumors.

Experimental Design: In a phase 1 study (3 + 3 design), patients received daily dasatinib with weekly gemcitabine on days 1, 8 and 15 of a 28-day cycle (except cycle 1 which was 8 weeks).

Dose-finding study of hepatic arterial infusion of oxaliplatin-based treatment in patients with advanced solid tumors metastatic to the liver.

Background: Liver metastases in patients with cancer are associated with poor survival. We hypothesized that hepatic arterial infusion (HAI) of oxaliplatin combination therapy would have antitumor activity in these patients.

Patients And Methods: Patients with advanced cancer and predominant liver metastases were treated on a phase I study of HAI oxaliplatin in combination with systemic bevacizumab, with or without HAI or systemic fluorouracil and/or leucovorin and/or cetuximab.

Aberrations in the epidermal growth factor receptor gene in 958 patients with diverse advanced tumors: implications for therapy.

Background: Epidermal growth factor receptor (EGFR) mutations are associated with the response to EGFR inhibitors in patients with non-small-cell lung cancer (NSCLC). We sought to investigate EGFR aberrations in patients with diverse advanced cancers.

Patients And Methods: Patients referred to the phase I clinic were evaluated for the presence of EGFR mutations and response to therapy.

PIK3CA mutation H1047R is associated with response to PI3K/AKT/mTOR signaling pathway inhibitors in early-phase clinical trials.

PIK3CA mutations may predict response to PI3K/AKT/mTOR inhibitors in patients with advanced cancers, but the relevance of mutation subtype has not been investigated. Patients with diverse cancers referred to the Clinical Center for Targeted Therapy were analyzed for PIK3CA and, if possible, KRAS mutations. Patients with PIK3CA mutations were treated, whenever possible, with agents targeting the PI3K/AKT/mTOR pathway.

Co-administration of vismodegib with rosiglitazone or combined oral contraceptive in patients with locally advanced or metastatic solid tumors: a pharmacokinetic assessment of drug-drug interaction potential.

Purpose: Vismodegib, a first-in-class oral hedgehog pathway inhibitor, is an effective treatment for advanced basal cell carcinoma. Based on in vitro data, a clinical drug-drug interaction (DDI) assessment of cytochrome P450 (CYP) 2C8 was necessary; vismodegib's teratogenic potential warranted a DDI study with oral contraceptives (OCs).

Methods: This single-arm, open-label study included two cohorts of patients with locally advanced or metastatic solid malignancies [Cohort 1: rosiglitazone 4 mg (selective CYP2C8 probe); Cohort 2: OC (norethindrone 1 mg/ethinyl estradiol 35 μg; CYP3A4 substrate)].

The "shield sign" in two men with metastatic salivary duct carcinoma to the skin: cutaneous metastases presenting as carcinoma hemorrhagiectoides.

Background: Salivary duct carcinoma is an infrequent and highly aggressive cancer that rarely metastasizes to the skin. Inflammatory cutaneous metastatic carcinoma is characterized by tumor cells predominantly in dermal lymphatics (carcinoma erysipelatoides) or blood vessels (carcinoma telangiectoides).

Purpose: The authors present a distinctive cutaneous distribution of skin metastases from a visceral malignancy that resembles a medieval knight's shield and introduce a third pattern of inflammatory cutaneous metastatic carcinoma-carcinoma hemorrhagiectoides-which has a distinctive clinical presentation and pathological correlation.

Personalized medicine in a phase I clinical trials program: the MD Anderson Cancer Center initiative.

Purpose: We initiated a personalized medicine program in the context of early clinical trials, using targeted agents matched with tumor molecular aberrations. Herein, we report our observations.

Patient And Methods: Patients with advanced cancer were treated in the Clinical Center for Targeted Therapy.

Advance care planning in patients with cancer referred to a phase I clinical trials program: the MD Anderson Cancer Center experience.

Purpose: Patients with advanced malignancies referred for early clinical trials have a short life expectancy. We designed this survey to ascertain the status of advance care planning in this population.

Patients And Methods: Patients who were seen in a phase I clinic were asked to anonymously complete an investigator-designed survey.

Survival of 1,181 patients in a phase I clinic: the MD Anderson Clinical Center for targeted therapy experience.

Purpose: To determine whether the Royal Marsden Hospital (RMH; London, UK) prognostic score for phase I patients can be validated in a large group of individuals seen in a different center and whether other prognostic variables are also relevant, we present an analysis of 1,181 patients treated in the MD Anderson Cancer Center (MDACC; Houston, TX) phase I clinic.

Experimental Design: Medical records of 1,181 consecutive patients who were treated on at least one trial in the phase I clinic were reviewed.

Results: The median age was 58 years and 50% were women.

PIK3CA mutations in patients with advanced cancers treated with PI3K/AKT/mTOR axis inhibitors.

Preclinical data suggest that PIK3CA mutations predict response to PI3K/AKT/mTOR inhibitors. Concomitant KRAS or BRAF mutations may mediate resistance. Therefore, tumors from patients referred to the phase I program for targeted therapy starting in October 2008 were analyzed for PIK3CA mutations using PCR-based DNA sequencing of exons 9 and 20.