Paclitaxel With or Without Cixutumumab as Second-Line Treatment of Metastatic Esophageal or Gastroesophageal Junction Cancer: A Randomized Phase II ECOG-ACRIN Trial

BACKGROUND: Patients with advanced esophageal cancer carry poor prognoses; limited data exist to guide second-line therapy in the metastatic setting. Paclitaxel has been used yet is associated with limited efficacy. There is preclinical evidence of synergy between paclitaxel and cixutumumab, a monoclonal antibody targeting insulin-like growth factor-1 receptor. We conducted a randomized phase II trial of paclitaxel (arm A) versus paclitaxel plus cixutumumab (arm B) in the second-line for patients with metastatic esophageal or gastroesophageal junction (GEJ) cancers. METHODS: The primary endpoint was progression-free survival (PFS); 87 patients (43 in arm A, 44 in arm B) were treated. RESULTS: Median PFS was 2.6 months in arm A [90% CL 1.8-3.5] and 2.3 months in arm B [90% 2.0-3.5], P = .86. Stable disease was observed in 29 (33%) patients. Objective response rates for Arms A and B were 12% [90% CI, 5-23%] and 14% [90% CI, 6-25%]. Median overall survival was 6.7 months [90% CL 4.9-9.5] in arm A and 7.2 months [90% CL 4.9-8.1] in arm B, P = 56. CONCLUSION: The addition of cixutumumab to paclitaxel in second-line therapy of metastatic esophageal/GEJ cancer was well tolerated but did not improve clinical outcomes relative to standard of care (ClinicalTrials.gov Identifier: NCT01142388)

Precision medicine in colorectal cancer: the molecular profile alters treatment strategies

When considering treatment options for patients with metastatic colorectal cancer (mCRC), molecular profiling has become a pivotal component in guiding clinical decisions. FOLFOX and FOLFIRI (fluorouracuil, leucovorin plus oxaliplatin or ininotecan, respectively) are the standard base regimens used for the treatment of mCRC. Biologic agents, such as the epidermal growth factor receptor (EGFR) targeted therapies, cetuximab and panitumumab and the vascular endothelial growth factor monoclonal antibody, bevacizumab, are safe and effective in the first-line setting. The most efficacious use of these agents in terms of timing and selection of the right patient population continues to be debated. Here we review multiple investigations into the effectiveness of treatment options as a function of the mutations present in colon cancers. Early studies have reported that KRAS mutations at exon 2 predict resistance to EGFR targeted therapies. More recently the data have expanded to include KRAS mutations at exons 3 and 4 and NRAS mutations at exons 2, 3 and 4 as well as other biomarkers including BRAF and PIK3CA , leading to the evolution of the treatment of mCRC to a more precision-based approach. As our understanding of relevant biomarkers increases, and data from both molecular profiling and treatment response become more readily available, treatment options will become more precise and their outcomes more effective

A Preclinical and Clinical Study of Lithium in Low-Grade Neuroendocrine Tumors

The efficacy of lithium chloride in patients with low-grade neuroendocrine tumors was evaluated and it was found to be ineffective in obtaining radiographic responses

Phospholipid ether analogs for the detection of colorectal tumors.

The treatment of localized colorectal cancer (CRC) depends on resection of the primary tumor with adequate margins and sufficient lymph node sampling. A novel imaging agent that accumulates in CRCs and the associated lymph nodes is needed. Cellectar Biosciences has developed a phospholipid ether analog platform that is both diagnostic and therapeutic. CLR1502 is a near-infrared fluorescent molecule, whereas 124/131I-CLR1404 is under clinical investigation as a PET tracer/therapeutic agent imaged by SPECT. We investigated the use of CLR1502 for the detection of intestinal cancers in a murine model and 131I-CLR1404 in a patient with metastatic CRC. Mice that develop multiple intestinal tumors ranging from adenomas to locally advanced adenocarcinomas were utilized. After 96 hours post CLR1502 injection, the intestinal tumors were analyzed using a Spectrum IVIS (Perkin Elmer) and a Fluobeam (Fluoptics). The intensity of the fluorescent signal was correlated with the histological characteristics for each tumor. Colon adenocarcinomas demonstrated increased accumulation of CLR1502 compared to non-invasive lesions (total radiant efficiency: 1.76×10(10) vs 3.27×10(9) respectively, p = 0.006). Metastatic mesenteric tumors and uninvolved lymph nodes were detected with CLR1502. In addition, SPECT imaging with 131I-CLR1404 was performed as part of a clinical trial in patients with advanced solid tumors. 131I-CLR1404 was shown to accumulate in metastatic tumors in a patient with colorectal adenocarcinoma. Together, these compounds might enhance our ability to properly resect CRCs through better localization of the primary tumor and improved lymph node identification as well as detect distant disease

A Pilot Phase II Study of Valproic Acid for Treatment of Low-Grade Neuroendocrine Carcinoma

Notch1 has been shown to be a tumor suppressor in neuroendocrine tumors. Previous in vitro studies in neuroendocrine tumor cell lines have also suggested that valproic acid, a histone deacetylase inhibitor, can induce Notch1 and that Notch1 activation correlates with a decrease in tumor markers for neuroendocrine tumors. This study showed that valproic acid activates Notch1 signaling in vivo and may have a role in treating low-grade neuroendocrine tumors

¹³¹I-CLR1404 accumulates in a patient with metastatic colon cancer.

<p>As part of a phase I clinical trial, SPECT images were acquired between 6 and 21 days after administration of ¹³¹I-CLR1404. Areas of increased signal intensity corresponded to known areas of metastatic colon cancer in both lungs. Prolonged retention of this agent within these lesions was also demonstrated. T, tumor; H. heart.</p

Intestinal tumors demonstrate accumulation of CLR1502.

<p>The entire colon (A) and the distal segment of the small intestine (B) were removed at necropsy 96 hours after administration of 50 µg of CLR1502 per mouse. Areas of increased signal intensity were observed using the IVIS Spectrum (excitation 745 nm and emission 800 nm). These areas were found to be non-invasive (colon C and G; distal small intestine F and J) and invasive (colon D and H; distal small intestine E and I) tumors. C, D, E and F are magnified×in G,H, I and J, respectively. Arrows point to malignant glands within the musculature of the intestine. Scale bars C, D, E and F = 1 mm.</p