A phase II study of guadecitabine combined with irinotecan vs regorafenib or TAS-102 in irinotecan-refractory metastatic colorectal cancer patients.

DNA methyltransferase inhibitors (DNMTi) have demonstrated benefit in reversing resistance to systemic therapies for several cancer types. In a phase II trial of guadecitabine and irinotecan compared to regorafenib or TAS-102 in pts with advanced mCRC refractory to irinotecan. Patients with mCRC refractory to irinotecan were randomized 2:1 to guadecitabine and irinotecan (Arm A) vs standard of care regorafenib or TAS-102 (Arm B) on a 28-day cycle.

Prognostic utility of self-reported sarcopenia (SARC-F) in the Multiethnic Cohort.

Background: Age-related loss in skeletal muscle mass, quality, and strength, known as sarcopenia, is a well-known phenomenon of aging and is determined clinically using methods such as dual-energy X-ray absorptiometry (DXA). However, these clinical methods to measure sarcopenia are not practical for population-based studies, and a five-question screening tool known as SARC-F has been validated to screen for sarcopenia.

Methods: We investigated the relationship between appendicular skeletal lean mass/height (ALM/HT ) (kg/m ) assessed by DXA and SARC-F in a subset of 1538 (778 men and 760 women) participants in the Multiethnic Cohort (MEC) Study after adjustment for race/ethnicity, age, and body mass index (BMI) at the time of DXA measurement.

A phase I study of intravenous fenretinide (4-HPR) for patients with malignant solid tumors.

Background: Fenretinide is a synthetic retinoid that can induce cytotoxicity by several mechanisms. Achieving effective systemic exposure with oral formulations has been challenging. An intravenous lipid emulsion fenretinide formulation was developed to overcome this barrier.

Phase I trial of belinostat in combination with 13-cis-retinoic acid in advanced solid tumor malignancies: a California Cancer Consortium NCI/CTEP sponsored trial.

Purpose: The reported maximum tolerated dose (MTD) of single-agent belinostat is 1000 mg/m given days 1-5, every 21 days. Pre-clinical evidence suggests histone deacetylase inhibitors enhance retinoic acid signaling in a variety of solid tumors. We conducted a phase I study of belinostat combined with 50-100 mg/m/day 13-cis-retinoic acid (13-cRA) in patients with advanced solid tumors.

A phase I, pharmacokinetic, and pharmacodynamic evaluation of the DNA methyltransferase inhibitor 5-fluoro-2'-deoxycytidine, administered with tetrahydrouridine.

Purpose: Inhibitors of DNA (cytosine-5)-methyltransferases (DNMT) are active antineoplastic agents. We conducted the first-in-human phase I trial of 5-fluoro-2'-deoxycytidine (FdCyd), a DNMT inhibitor stable in aqueous solution, in patients with advanced solid tumors. Objectives were to establish the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of FdCyd + tetrahydrouridine (THU).

Multi-drug inhibition of the HER pathway in metastatic colorectal cancer: results of a phase I study of pertuzumab plus cetuximab in cetuximab-refractory patients.

Purpose: Resistance to cetuximab, a monoclonal antibody against the epithelial growth factor receptor (EGFR), in colorectal cancer (CRC) may result from compensatory signaling through ErbB receptors, ErbB2/neu/HER2 (HER2) and ErbB3/HER3 (HER3). Pertuzumab is a monoclonal antibody that blocks HER2 hetero-dimerization; thus the combination of pertuzumab and cetuximab could possibly overcome cetuximab resistance.

Patients And Methods: This single-arm, open-label, multicenter phase I/II study was designed to assess the safety and efficacy of pertuzumab and cetuximab in patients with cetuximab-resistant KRAS wild type metastatic CRC.

Systemic cytotoxic and biological therapies of colorectal liver metastases: expert consensus statement.

Systemic therapy for colorectal cancer liver metastases (CRLM) has undergone significant development in the past 15 years. Therapy regimens consisting of combinations of cytotoxic chemotherapeutic agents have demonstrated greater efficacy and contributed to a significant survival improvement. As the majority of patients who undergo resection for liver-only CRLM are at risk of disease recurrence and cancer-related death, combining resection with systemic therapy appears sensible.

S0356: a phase II clinical and prospective molecular trial with oxaliplatin, fluorouracil, and external-beam radiation therapy before surgery for patients with esophageal adenocarcinoma.

Purpose: Pathologic complete response (pCR) after neoadjuvant therapy for locally advanced esophageal adenocarcinoma is associated with improved survival. The Southwest Oncology Group designed a trimodality, phase II, single-arm trial with objectives of achieving a pCR rate of 40% with prospective exploratory analyses of intratumoral molecular markers postulated to affect response and survival.

Patients And Methods: Patients with clinically staged II or III esophageal adenocarcinoma received oxaliplatin 85 mg/m(2) on days 1, 15, and 29; protracted-infusion fluorouracil (PI-FU) 180 mg/m(2)/d on days 8 through 43; and external-beam radiation therapy (EBRT) 5 days a week at 1.

Phase I clinical trial of pegylated liposomal Doxorubicin and docetaxel in patients with advanced solid tumors.

Objective: The primary objective of this study was to determine the maximum tolerated dose (MTD) of pegylated liposomal doxorubicin (PLD) and docetaxel (T) administered in 4 week cycles in patients with advanced solid tumors.

Patients And Methods: Patients were treated with intravenous PLD on day 1 and T on days 1, 8, and 15. Once the MTD was reached the schedule of PLD was changed to days 1 and 15 to explore an alternative and potentially more manageable dosing schedule.

Japanese-US common-arm analysis of paclitaxel plus carboplatin in advanced non-small-cell lung cancer: a model for assessing population-related pharmacogenomics.

PURPOSE To explore whether population-related pharmacogenomics contribute to differences in patient outcomes between clinical trials performed in Japan and the United States, given similar study designs, eligibility criteria, staging, and treatment regimens. METHODS We prospectively designed and conducted three phase III trials (Four-Arm Cooperative Study, LC00-03, and S0003) in advanced-stage, non-small-cell lung cancer, each with a common arm of paclitaxel plus carboplatin. Genomic DNA was collected from patients in LC00-03 and S0003 who received paclitaxel (225 mg/m(2)) and carboplatin (area under the concentration-time curve, 6).

Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: clinical and pharmacogenomic results from SWOG S0124.

Purpose: Irinotecan plus cisplatin (IP) improved survival over etoposide plus cisplatin (EP) in Japanese patients with extensive-stage small-cell lung cancer (E-SCLC). To confirm those results and discern the potential role of population-related pharmacogenomics (PG) in outcomes, we conducted a large randomized trial of identical design to the Japanese trial in North American patients with E-SCLC.

Patients And Methods: Patients were randomly assigned to IP (irinotecan 60 mg/m(2) on days 1, 8, and 15; cisplatin 60 mg/m(2) day 1, every 4 weeks) or EP (etoposide 100 mg/m(2) on days 1 through 3; cisplatin 80 mg/m(2) day 1, every 3 weeks).

Phase II trial of sunitinib in patients with metastatic colorectal cancer after failure of standard therapy.

Purpose: Sunitinib is an oral, multitargeted receptor tyrosine kinase inhibitor of the vascular endothelial growth factor receptor and multiple other growth factor receptors. We assessed the safety and efficacy of sunitinib in patients with metastatic colorectal cancer after failure of standard therapy.

Patients And Methods: Eighty-four patients were enrolled onto this two-stage phase II trial and were stratified by whether they had received prior bevacizumab (n = 43) or not (n = 41).

Dose-escalating and pharmacologic study of oxaliplatin in adult cancer patients with impaired hepatic function: a National Cancer Institute Organ Dysfunction Working Group study.

Purpose: To determine the toxicities, pharmacokinetics, and maximally tolerated doses of oxaliplatin in patients with hepatic impairment and to develop formal guidelines for oxaliplatin dosing in this patient population.

Experimental Design: Sixty adult cancer patients with variable hepatic function received i.v.

Bortezomib plus docetaxel in advanced non-small cell lung cancer and other solid tumors: a phase I California Cancer Consortium trial.

Background: This phase I study was performed to determine the dose-limiting toxicity and maximum tolerated dose (MTD) of docetaxel in combination with bortezomib in patients with advanced non-small cell lung cancer (NSCLC) or other solid tumors.

Methods: Patients were enrolled in cohorts of three over six dose levels. Each treatment cycle was 3 weeks long and consisted of one docetaxel infusion (day 1) and four bortezomib injections (days 1, 4, 8, and 11).

Phase II clinical trial of capecitabine in the treatment of advanced, persistent or recurrent squamous cell carcinoma of the cervix with translational research: a gynecologic oncology group study.

Purpose: To evaluate the anti-tumor activity and adverse events of capecitabine in advanced, persistent or recurrent squamous cell carcinoma of the cervix, and to explore biomarkers with the potential to predict capecitabine response and toxicity.

Experimental Design: Eligible, consenting patients were treated with a starting dose of 2500 mg/m(2)/day or 1800 mg/m(2)/day (divided into two doses given every 12 h) for 14 days of each 21-day cycle. Prior chemotherapy was allowed only in the context of radiation "sensitization".

A randomized phase II trial of the matrix metalloproteinase inhibitor BMS-275291 in hormone-refractory prostate cancer patients with bone metastases.

Background: BMS-275291 is a selective matrix metalloproteinase inhibitor (MMPI) that does not inhibit sheddases implicated in the dose-limiting arthritis of older MMPIs. We conducted a randomized phase II trial of two doses of BMS-275291 (1,200 versus 2,400 mg) in hormone-refractory prostate cancer (HRPC) patients with bone metastases to probe for a dose-response relationship and to assess differential toxicities. Serial serum and urine specimens were collected to assess for markers of bone metabolism.

Phase I clinical trial of weekly docetaxel and exisulind, a novel inducer of apoptosis.

Background: The objective of this phase I study was to determine the maximal tolerated dose (MTD) of the combination of weekly docetaxel and exisulind in patients with advanced solid tumors.

Patients And Methods: Patients with advanced or refractory solid tumors were treated with intravenous weekly docetaxel with daily oral exisulind. The following dose levels (docetaxel/exisulind) were explored: 30-mg/m2/200 mg po bid, 35/200, 35/250 and 40/250.

Intermittent dosing of the farnesyl transferase inhibitor tipifarnib (R115777) in advanced malignant solid tumors: a phase I California Cancer Consortium Trial.

Tipifarnib (R115777) inhibits farnesylation of key proteins that modulate signaling pathways implicated in cell growth and proliferation, including members of the Ras and Rho families. It has broad-spectrum antiproliferative activity in vitro and in vivo. Clinical trials employing a continuous administration schedule have demonstrated dose-limiting neurotoxicity and myelosuppression.

Pharmacogenetic aspects in treatment of colorectal cancer--an update.

Pharmacogenomic analyses will become crucial to predict patients' toxicity to treatment and will also help to predict the tumor response. Processes of drug metabolism, drug efflux, DNA-repair and characteristics of drug targets are critical checkpoints of drug efficacy. These crucial pathways for drug action have been part of pharmacogenomic studies evaluating the impact of genomic variants on transcription, translation, protein structure and substrate binding of the genes involved.

SU5416 plus interferon alpha in advanced renal cell carcinoma: a phase II California Cancer Consortium Study with biological and imaging correlates of angiogenesis inhibition.

Purpose: Vascular endothelial growth factor (VEGF) is expressed in up to 70% of renal cell carcinomas (RCCs) and is a rational therapeutic target. SU5416 is a small molecule inhibitor of VEGF-mediated signaling through Flk-1, a transmembrane tyrosine kinase. IFN-alpha also possesses dose- and schedule-dependent antiangiogenic effects at doses lower than those used for RCC therapy.

Irinotecan and paclitaxel in metastatic adenocarcinoma of the esophagus and gastric cardia.

Both irinotecan (CPT-11, Camptosar) and paclitaxel have been shown to have single-agent activity in adenocarcinomas of the esophagus and gastric cardia. A phase I trial of the combination at UCLA established the dose as irinotecan at 225 mg/m2 and paclitaxel at 100 mg/m2 every 3 weeks. Preliminary data from a phase II trial of this regimen in adenocarcinomas of the gastroesophageal junction show good tolerability and promising activity (response rate of 27%), even in previously treated patients.

Tirapazamine plus carboplatin and paclitaxel in advanced malignant solid tumors: a california cancer consortium phase I and molecular correlative study.

Purpose: Tumor hypoxia confers chemotherapy resistance. Tirapazamine is a cytotoxin that selectively targets hypoxic cells and has supra-additive toxicity with platinums and taxanes in preclinical studies. We conducted a Phase I study of tirapazamine, carboplatin, and paclitaxel and assessed potential plasma markers of hypoxia as surrogates for response.

Pharmacogenomics in colorectal cancer.

The goal in administering chemotherapeutics is to develop the ability to predict the outcome of therapy in terms of response and toxicity. Technology has been developed to allow tumor profiling with the measurement of protein expression and gene expression levels of markers and even genetic polymorphisms that may predict response to particular chemotherapeutics. The chemotherapeutics for which particular markers have been shown to predict outcome include the fluoropyrimidines and platinums.