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Background This was a phase I/IIa study to investigate the tolerability, efficacy and pharmacokinetics (PK)/ pharmacodynamics (PD) of CRLX301, CDP-based nanoparticle formulation of docetaxel. Methods The study was conducted in two parts. In part 1, dose-escalation using a standard 3 + 3 design was performed in two dosing schedules (every week (QW) and every 3 weeks (Q3W)). Part 2 was comprised of a dose expansion at 75 mg/m2 Q3W. PK studies were performed on both dosing schedules. Results Forty-two patients were recruited onto the study with a median age of 64(range 38-76); median number of prior systemic therapies was 5(range 0-10). Grade 3/4 treatment-related toxicities included: neutropenia (21.4 %), infusion related reaction (11.9 %), anemia (7.1 %), fatigue (4.8 %), diarrhea (4.8 %), and peripheral neuropathy (4.8 %). The maximum tolerated dose was 75 mg/m2 given on the Q3W schedule and was not determined on the QW schedule. In this heavily pre-treated population, four patients (12.9 %) achieved stable disease (SD) ≥ 4 months and 2 patients (6.5 %) achieved partial response (PR) for a clinical benefit rate (CBR) of 19.4 % (6/31 patients). The PRs were seen in prostate and breast adenocarcinoma (one each). CRLX301 exhibited some PK advantages over docetaxel including higher retention of drug in plasma, slower clearance and controlled slow release of docetaxel from the carrier. Conclusions In this heavily pretreated patient population, the safety profile was acceptable for CRLX301 therapy. There was some evidence of preliminary tumor efficacy, but further work is necessary to find the optimal dose and schedule of this formulation.Clinicaltrials.gov trial registration number: NCT02380677 (Date of registration: March 2, 2015).

Summary Background Systemic adjuvant treatment might mitigate the high risk of disease recurrence in patients with resected stage IIC–III melanoma. The BRIM8 study evaluated adjuvant vemurafenib monotherapy in patients with resected, BRAF V600 mutation-positive melanoma. Methods BRIM8 was a phase 3, international, double-blind, randomised, placebo-controlled study that enrolled 498 adults (aged ≥18 years) with histologically confirmed stage IIC–IIIA–IIIB (cohort 1) or stage IIIC (cohort 2) BRAF V600 mutation-positive melanoma that was fully resected. Patients were randomly assigned (1:1) by an interactive voice or web response system to receive twice-daily adjuvant oral vemurafenib 960 mg tablets or matching placebo for 52 weeks (13 × 28-day cycles). Randomisation was done by permuted blocks (block size 6) and was stratified by pathological stage and region in cohort 1 and by region in cohort 2. The investigators, patients, and sponsor were masked to treatment assignment. The primary endpoint was disease-free survival in the intention-to-treat population, evaluated separately in each cohort. Hierarchical analysis of cohort 2 before cohort 1 was prespecified. This trial is registered with ClinicalTrials.gov, number NCT01667419. Findings The study enrolled 184 patients in cohort 2 (93 were assigned to vemurafenib and 91 to placebo) and 314 patients in cohort 1 (157 were assigned to vemurafenib and 157 to placebo). At the time of data cutoff (April 17, 2017), median study follow-up was 33·5 months (IQR 25·9–41·6) in cohort 2 and 30·8 months (25·5–40·7) in cohort 1. In cohort 2 (patients with stage IIIC disease), median disease-free survival was 23·1 months (95% CI 18·6–26·5) in the vemurafenib group versus 15·4 months (11·1–35·9) in the placebo group (hazard ratio [HR] 0·80, 95% CI 0·54–1·18; log-rank p=0·026). In cohort 1 (patients with stage IIC–IIIA–IIIB disease) median disease-free survival was not reached (95% CI not estimable) in the vemurafenib group versus 36·9 months (21·4–not estimable) in the placebo group (HR 0·54 [95% CI 0·37–0·78]; log-rank p=0·0010); however, the result was not significant because of the prespecified hierarchical prerequisite for the primary disease-free survival analysis of cohort 2 to show a significant disease-free survival benefit. Grade 3–4 adverse events occurred in 141 (57%) of 247 patients in the vemurafenib group and 37 (15%) of 247 patients in the placebo group. The most common grade 3–4 adverse events in the vemurafenib group were keratoacanthoma (24 [10%] of 247 patients), arthralgia (17 [7%]), squamous cell carcinoma (17 [7%]), rash (14 [6%]), and elevated alanine aminotransferase (14 [6%]), although all keratoacanthoma events and most squamous cell carcinoma events were by default graded as grade 3. In the placebo group, grade 3–4 adverse events did not exceed 2% for any of the reported terms. Serious adverse events were reported in 40 (16%) of 247 patients in the vemurafenib group and 25 (10%) of 247 patients in the placebo group. The most common serious adverse event was basal cell carcinoma, which was reported in eight (3%) patients in each group. One patient in the vemurafenib group of cohort 2 died 2 months after admission to hospital for grade 3 hypertension; however, this death was not considered to be related to the study drug. Interpretation The primary endpoint of disease-free survival was not met in cohort 2, and therefore the analysis of cohort 1 showing a numerical benefit in disease-free survival with vemurafenib versus placebo in patients with resected stage IIC–IIIA–IIIB BRAF V600 mutation-positive melanoma must be considered exploratory only. 1 year of adjuvant vemurafenib was well tolerated, but might not be an optimal treatment regimen in this patient population. Funding F Hoffman–La Roche Ltd.

While many patients with early-stage colon cancer are cured with surgery alone, the standard of care remains a uniform approach to adjuvant chemotherapy based primarily on tumor stage. Recently, increasing awareness of the need for more individualized decision-making in cancer care has led to the development of several potential prognostic and predictive markers in colon cancer. While adjuvant chemotherapy with 5-fluorouracil, leucovorin and oxaliplatin is clearly beneficial to patients with stage III disease, well-validated molecular markers might help define which patients with stage II disease are likely to benefit from adjuvant therapy as well. Here, we review the data on the clinical development of molecular markers to individualize adjuvant therapy in colon cancer.

Lung cancer is the leading cause of cancer deaths worldwide. Small cell lung cancer (SCLC), which comprises 15% of all lung cancers, is almost exclusively due to smoking and is highly aggressive due to early widespread metastasis. While combination chemotherapy has lead to modest improvements in outcome, the five-year overall survival for SCLC remains at 5%. Identifying distinct biochemical pathways of metastasis and chemotherapy resistance in SCLC may lead to novel therapeutic approaches and improve survival in SCLC patients. The chemokine receptor CXCR4 is emerging as an important target in cancer growth, metastasis, relapse and resistance to therapy. In this article, we review the structure and function of CXCR4 and its ligand, CXCL12, as well as mechanisms of CXCR4/CXCL12 signal transduction in lung cancer. We review the current preclinical and translational research involving this pathway in lung cancer and the clinical development of several novel agents targeting the CXCR4/CXCL12 pathway. Further understanding of the CXCR4/CXCL12 pathway in SCLC and NSCLC may provide a rationale for innovative research on the CXCR4 receptor as a potential novel therapeutic target in lung cancer.

Purpose: Sirolimus is the prototypical mTOR inhibitor. Sorafenib and sunitinib are small molecule inhibitors of multiple kinases including VEGF receptor (VEGFR) kinases. These agents have different mechanisms of action, providing a strong rationale for combination. Experimental Design: Patients with advanced cancer were assigned to receive either sirolimus or the VEGFR inhibitor alone for a 2-week lead-in period, followed by combination therapy. The primary end point of each trial was to determine whether a drug interaction exists between sirolimus and either sorafenib or sunitinib, as defined by a difference in Cmax for each drug alone compared with its Cmax during combination therapy. Results: The sorafenib and sunitinib trials enrolled 34 and 23 patients, respectively. There were no clinically significant differences in Cmax for any of the drugs alone compared with the Cmax during combination therapy. Toxicity profiles were similar to those expected for each drug alone. One patient with adrenal cortical cancer had a partial response to sirolimus and sunitnib. Conclusions: Sirolimus can be safely combined with sorafenib or sunitinib. Our trial design is feasible and informative in screening for potential drug–drug interactions, using a relatively small number of patients and limited pharmacokinetic sampling. Clin Cancer Res; 17(7); 1956–63. ©2011 AACR.

The Thoracic Oncology Program Database Project was created to serve as a comprehensive, verified, and accessible repository for well-annotated cancer specimens and clinical data to be available to researchers within the Thoracic Oncology Research Program. This database also captures a large volume of genomic and proteomic data obtained from various tumor tissue studies. A team of clinical and basic science researchers, a biostatistician, and a bioinformatics expert was convened to design the database. Variables of interest were clearly defined and their descriptions were written within a standard operating manual to ensure consistency of data annotation. Using a protocol for prospective tissue banking and another protocol for retrospective banking, tumor and normal tissue samples from patients consented to these protocols were collected. Clinical information such as demographics, cancer characterization, and treatment plans for these patients were abstracted and entered into an Access database. Proteomic and genomic data have been included in the database and have been linked to clinical information for patients described within the database. The data from each table were linked using the relationships function in Microsoft Access to allow the database manager to connect clinical and laboratory information during a query. The queried data can then be exported for statistical analysis and hypothesis generation.

4502 Background: Targeting several critical pathways may be more effective than single pathway blockade in a resistant cancer like PC. In preclinical PC models, combining EGFR + VEGF targeted agents is synergistic. Methods: We conducted a multicenter, randomized phase II trial of dual targeted therapy, GBC or GBE, in advanced PC pts who had: no prior therapy for metastatic disease, PS 0–2, measurable disease, no bleeding risk or duodenal invasion. Primary endpoint: response; 2 parallel, Simon 2-stage designs. Baseline correlatives: plasma VEGF, serum VEGFR2. All pts received G 1000 mg/m2 over 30’ days (D) 1, 8, 15 Q28D; B 10 mg/kg D 1, 15 Q28D. Pts, stratified by PS and site, were randomized to C 400 mg/m2 D1 then 250 mg/m2 Q7D, or E 150 mg D1–5, 8- 12, 15–26 Q28D. Results: 139 evaluable pts (GBC/GBE 68/71) enrolled at 16 sites 9/04–2/07. Pt characteristics: median age 63/63 (range 36–83/39–86); male 49%/70%; PS 0 35%/48%, 1 59%/46%, 2 6%/6%. Cycles: 343/373 (median 4/4; range 1–18/1–18). Grade 3/4 toxici...

2545 Background: R inhibits the mammalian target of rapamycin (mTOR) and is active in preclinical tumor models. S inhibits multiple kinases. S and mTOR inhibitors have activity in similar tumor typ...