Circulating KRAS G12D but not G12V is associated with survival in metastatic pancreatic ductal adenocarcinoma.

While high circulating tumor DNA (ctDNA) levels are associated with poor survival for multiple cancers, variant-specific differences in the association of ctDNA levels and survival have not been examined. Here we investigate KRAS ctDNA (ctKRAS) variant-specific associations with overall and progression-free survival (OS/PFS) in first-line metastatic pancreatic ductal adenocarcinoma (mPDAC) for patients receiving chemoimmunotherapy ("PRINCE", NCT03214250), and an independent cohort receiving standard of care (SOC) chemotherapy. For PRINCE, higher baseline plasma levels are associated with worse OS for ctKRAS G12D (log-rank p = 0.

A plain language summary of the PHAROS study: the combination of encorafenib and binimetinib for people with BRAF V600E-mutant metastatic non-small-cell lung cancer.

What Is This Summary About?: This is a summary of the results of a study called PHAROS. This study looked at combination treatment with encorafenib (BRAFTOVI) and binimetinib (MEKTOVI). This combination of medicines was studied in people with metastatic non-small-cell lung cancer (NSCLC).

Encorafenib plus binimetinib in patients with -mutant non-small cell lung cancer: phase II PHAROS study design.

oncogenic driver mutations occur in 1-2% of non-small-cell lung cancers (NSCLCs) and have been shown to be a clinically relevant target. Preclinical/clinical evidence support the efficacy and safety of BRAF and MEK inhibitor combinations in patients with NSCLC with these mutations. We describe the design of PHAROS, an ongoing, open-label, single-arm, phase II trial evaluating the BRAF inhibitor encorafenib plus the MEK inhibitor binimetinib in patients with metastatic -mutant NSCLC, as first- or second-line treatment.

A phase I dose escalation trial of nab-paclitaxel and fixed dose radiation in patients with unresectable or borderline resectable pancreatic cancer.

Purpose: Patients with locally advanced pancreatic cancer typically have poor outcomes, with a median survival of approximately 16 months. Novel methods to improve outcomes are needed. Nab-paclitaxel (Abraxane) has shown efficacy in pancreatic cancer and is FDA-approved for metastatic disease in combination with gemcitabine.

Activity of the oral mitogen-activated protein kinase kinase inhibitor trametinib in RAS-mutant relapsed or refractory myeloid malignancies.

Background: RAS/RAF/mitogen-activated protein kinase activation is common in myeloid malignancies. Trametinib, a mitogen-activated protein kinase kinase 1 (MEK1)/MEK2 inhibitor with activity against multiple myeloid cell lines at low nanomolar concentrations, was evaluated for safety and clinical activity in patients with relapsed/refractory leukemias.

Methods: This phase 1/2 study accrued patients with any relapsed/refractory leukemia in phase 1.

A randomized, double-blind, placebo-controlled phase II study to assess the efficacy and safety of mapatumumab with sorafenib in patients with advanced hepatocellular carcinoma.

Background: This randomized, double-blind, placebo-controlled, phase II study evaluated the efficacy and safety of mapatumumab (a human agonistic monoclonal antibody against tumor necrosis factor-related apoptosis-inducing ligand receptor 1) in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC).

Patients And Methods: Patients with advanced HCC (stratified by Barcelona Clinic Liver Cancer stage and Eastern Cooperative Oncology Group performance status) were randomized 1:1 to receive sorafenib (400 mg, twice daily per 21-day cycle) and either placebo (placebo-sorafenib arm) or mapatumumab (30 mg/kg on day 1 per 21-day cycle; mapatumumab-sorafenib arm). The primary end point was time to (radiologic) progression (TTP), assessed by blinded independent central review.

Postoperative Adjuvant Lapatinib and Concurrent Chemoradiotherapy Followed by Maintenance Lapatinib Monotherapy in High-Risk Patients With Resected Squamous Cell Carcinoma of the Head and Neck: A Phase III, Randomized, Double-Blind, Placebo-Controlled Study.

Purpose: This multicenter phase III study evaluated the efficacy and safety of lapatinib, an epidermal growth factor receptor/ErbB2 inhibitor, administered concomitantly with chemoradiotherapy and as maintenance monotherapy in patients with high-risk surgically treated squamous cell carcinoma of the head and neck (SCCHN).

Patients And Methods: Patients with resected stage II to IVA SCCHN, with a surgical margin ≤ 5 mm and/or extracapsular extension, were randomly assigned to chemoradiotherapy (66 Gy total radiation dose and cisplatin 100 mg/m(2) per day administered on days 1, 22, and 43) plus placebo or lapatinib (1,500 mg per day) before and during chemoradiotherapy, followed by 12 months of maintenance monotherapy.

Results: Six hundred eighty-eight patients were enrolled (lapatinib, n = 346; placebo, n = 342).

Phase I and pharmacological study of pazopanib in combination with oral topotecan in patients with advanced solid tumours.

Background: This phase I study evaluated the safety, tolerability, maximum tolerated dose (MTD) and pharmacokinetics of two dosing schedules of oral topotecan in combination with pazopanib in patients with advanced solid tumours.

Methods: Stage I of this study was to determine whether there was an impact of pazopanib on topotecan exposure. In stage II, the MTD and safety profile of oral topotecan given weekly on days 1, 8 and 15 in a 28-day cycle; or daily-times-five on days 1-5 in a 21-day cycle, both in combination with daily pazopanib, were explored.

A phase II trial of gemcitabine, irinotecan and panitumumab in advanced cholangiocarcinoma.

Background: Current data suggest that chemotherapy combinations may be superior to single agents in biliary tract cancer. The epidermal growth factor receptor (EGFR) pathway appears to be associated with tumor stage, prognosis and response to therapy. This trial was designed to evaluate the tolerability and efficacy of the combination of panitumumab, a monoclonal anti-EGFR antibody, with gemcitabine and irinotecan.

Efficacy and safety of casopitant mesylate, a neurokinin 1 (NK1)-receptor antagonist, in prevention of chemotherapy-induced nausea and vomiting in patients receiving cisplatin-based highly emetogenic chemotherapy: a randomised, double-blind, placebo-controlled trial.

Background: Chemotherapy-induced nausea and vomiting (CINV) remains a clinical management problem after treatment with highly emetogenic chemotherapy (HEC). We therefore designed and carried out a multicentre, randomised, double-blind, placebo-controlled trial to assess whether a three-drug antiemetic regimen of ondansetron, dexamethasone, and the neurokinin-1-receptor antagonist casopitant mesylate was able to prevent acute and delayed CINV events in patients naive to chemotherapy with a malignant solid tumour who were scheduled to receive cisplatin-based HEC regimens.

Methods: The study was done between Nov 6, 2006, and Oct 9, 2007, in 77 participating centres in 22 countries.

Adjuvant therapy with the monoclonal antibody Edrecolomab plus fluorouracil-based therapy does not improve overall survival of patients with stage III colon cancer.

Purpose: Edrecolomab (ED) is a murine monoclonal antibody targeting the EpCam antigen. This phase III randomized multicenter trial investigated the benefit of adding ED to fluorouracil (FU) based therapy in patients with stage III colorectal cancer.

Patients And Methods: Patients with stage III colon cancer were randomly assigned to one of two treatments after curative surgery.

Topotecan therapy in patients with relapsed small-cell lung cancer and poor performance status.

Purpose: Topotecan is generally well tolerated and active in patients with relapsed small-cell lung cancer (SCLC) and poor performance status (PS). In this study, we investigated whether treatment with topotecan is associated with improvement in PS as measured by the rate of conversion from PS 2 to PS 0/1.

Patients And Methods: A retrospective analysis of data from 7 clinical trials (N = 795) investigating topotecan in patients with relapsed SCLC was performed.

Open-label, multicenter, randomized, phase III study comparing oral topotecan/cisplatin versus etoposide/cisplatin as treatment for chemotherapy-naive patients with extensive-disease small-cell lung cancer.

Purpose: This open-label, randomized, multicenter phase III study compared oral topotecan/intravenous cisplatin (TC) with intravenous (IV) etoposide/cisplatin (PE) in patients with untreated extensive-disease small-cell lung cancer (ED-SCLC).

Patients And Methods: A total of 784 patients were randomly assigned to either oral topotecan 1.7 mg/m2/d x 5 with IV cisplatin 60 mg/m2 on day 5 (n = 389) or IV etoposide 100 mg/m2/d x 3 with IV cisplatin 80 mg/m2 on day 1 (n = 395) every 21 days.

A phase I and pharmacologic study of the MDR converter GF120918 in combination with doxorubicin in patients with advanced solid tumors.

Background: Resistance to chemotherapy can partly be explained by the activity of membrane bound P-glycoprotein. Competitive inhibition of P-glycoprotein, by multidrug resistance (MDR) converters, may overcome this MDR. Previously studied MDR converters either have serious intrinsic side effects or considerably influence the pharmacokinetics of cytotoxic agents at concentrations theoretically required to convert MDR.

A pilot study of edrecolomab (Panorex, 17-1A antibody) and capecitabine in patients with advanced or metastatic adenocarcinoma.

Edrecolomab (Panorex) is a monoclonal antibody directed against the 17-1A antigen located on the cell surfaces of carcinomas. Clinical activity has been seen in colon and breast cancer. This trial investigated the feasibility of combining edrecolomab with the oral fluoropyrimidine capecitabine (Xeloda).

Population pharmacokinetic and dynamic analysis of the topoisomerase I inhibitor lurtotecan in phase II studies.

Population pharmacokinetic-dynamic analysis was prospectively integrated in a broad phase II program of lurtotecan (GI147211), a novel camptothecin derived topoisomerase I inhibitor, to determine the population pharmacokinetic profile in a larger population, to estimate individual pharmacokinetic parameters and to investigate relationships with clinical outcome. A sparse sampling method was applied during course one, which involved two sampling time-points. A Bayesian algorithm was used to estimate individual pharmacokinetic parameters, in particular total plasma clearance (CL) and volume of distribution.

Androgen antagonists: Potential role in prostate cancer prevention.

This article summarizes discussions of the importance of androgens and androgen antagonists in the genesis of prostate cancer. These discussions occurred at a recent symposium on prostate cancer chemoprevention sponsored by the National Cancer Institute. Considerable information exists indicating the importance of androgens in the development of prostate cancer.

Antiplatelet effects of MK-852, a platelet fibrinogen receptor antagonist, in healthy volunteers.

MK-852, a cyclic heptapeptide, is a potent platelet fibrinogen receptor antagonist. When administered to normal healthy male subjects by 1- and 4-hour constant rate intravenous infusions, it provides a generally well-tolerated and reversible means of inhibition of platelet function. At infusion rates of 1 microgram/kg/min for 1 hour and 0.

Second-line treatment of small-cell lung cancer with the camptothecin-derivative GI147211: a study of the EORTC Early Clinical Studies Group (ECSG).

Background: GI147211, a 10,11-ethylenedioxy substituted analogue of camptothecin (CPT), was brought into clinical development because of its higher water solubility and greater potency as compared to topotecan (TPT). The antitumor activity of GI147211 as second-line therapy in small-cell lung cancer (SCLC) was assessed after stratification of patients in refractory (no response to initial treatment or relapse within three months from last cycle) and chemosensitive (relapse more than three months from last cycle).

Patients And Methods: Sixty-seven patients were entered in the study and sixty-two were evaluable for response, twenty-eight in the refractory and thirty-four in the chemosensitive group.

Clinical pharmacokinetics of doxorubicin in combination with GF120918, a potent inhibitor of MDR1 P-glycoprotein.

Previous clinical investigations with doxorubicin indicated that modulators of P-glycoprotein dramatically decrease the systemic clearance of the drug, which complicates the interpretation of toxicity and response data. In the present study, we examined the pharmacokinetics of doxorubicin and GF120918, a novel potent P-glycoprotein inhibitor, in cancer patients in a search for more selective modulation of multidrug resistance (MDR). Seven cohorts (46 patients) received sequential treatments with doxorubicin alone by a 5 min i.

Phase I/pharmacokinetic study of the topoisomerase I inhibitor GG211 administered as a 21-day continuous infusion.

Background: Preclinical results support a prolonged schedule of administration for topoisomerase I inhibitors, and we have previously demonstrated the safety and activity of the novel water-soluble topoisomerase I inhibitor GG211 when given as a 72-hour continuous infusion to cancer patients.

Patients And Methods: In a three-center international phase I trial, 38 patients received GG211 doses from 0.3 to 0.

Evaluation of the feasibility and use of a prototype remote drug delivery capsule (RDDC) for non-invasive regional drug absorption studies in the GI tract of man and beagle dog.

Purpose: Evaluate a prototype Remote Drug Delivery Capsule (RDDC) for use in beagle dogs and human volunteers for non-invasive drug absorption studies in different regions of the gastrointestinal tract.

Methods: The device was dual radiolabeled and GI transit of the RDDC was monitored by gamma scintigraphy. Beagles were used initially to demonstrate the functional utility of the device where a solution of ranitidine hydrochloride (150 mg) was non-invasively delivered to the stomach, proximal small intestine and distal small intestine.

A phase I clinical and pharmacokinetic study of the new topoisomerase inhibitor GI147211 given as a 72-h continuous infusion.

GI147211 is a novel, totally synthetic camptothecin with promising preclinical and early clinical activity. This study was designed to determine the maximum tolerated dose of Gl147211 as a 72-h infusion and to describe its pharmacokinetics and pharmacodynamics on this schedule. In a single-arm, rising-dose study in patients with advanced cancer, eight cohorts of three or more patients received 72-h infusions of Gl147211 at doses ranging from 0.

Phase I and pharmacokinetic study of GI147211, a water-soluble camptothecin analogue, administered for five consecutive days every three weeks.

GI1147211 is a 7-substituted 10,11-ethylenedioxy-20(S)-camptothecin analogue that inhibits the nuclear enzyme topoisomerase I. In this Phase I and pharmacological study, 24 patients with advanced solid malignancies received a total of 72 courses of GI147211 as a 30-min infusion daily for 5 consecutive days, at doses ranging from 0.3 to 1.