Phase Ib study of talimogene laherparepvec in combination with atezolizumab in patients with triple negative breast cancer and colorectal cancer with liver metastases.

BACKGROUND: Talimogene laherparepvec (T-VEC), a first-in-class oncolytic viral immunotherapy, enhances tumor-specific immune activation. T-VEC combined with atezolizumab, which blocks inhibitor T-cell checkpoints, could provide greater benefit than either agent alone. Safety/efficacy of the combination was explored in patients with triple negative breast cancer (TNBC) or colorectal cancer (CRC) with liver metastases. METHODS: In this phase Ib, multicenter, open-label, parallel cohort study of adults with TNBC or CRC with liver metastases, T-VEC (106 then 108 PFU/ml; ≤4 ml) was administered into hepatic lesions via image-guided injection every 21 (±3) days. Atezolizumab 1200 mg was given on day 1 and every 21 (±3) days thereafter. Treatment continued until patients experienced dose-limiting toxicity (DLT), had complete response, progressive disease, needed alternative anticancer treatment, or withdrew due to an adverse event (AE). The primary endpoint was DLT incidence, and secondary endpoints included efficacy and AEs. RESULTS: Between 19 March 2018 and 6 November 2020, 11 patients with TNBC were enrolled (safety analysis set: n = 10); between 19 March 2018 and 16 October 2019, 25 patients with CRC were enrolled (safety analysis set: n = 24). For the 5 patients in the TNBC DLT analysis set, no patient had DLT; for the 18 patients in the CRC DLT analysis set, 3 (17%) had DLT, all serious AEs. AEs were reported by 9 (90%) TNBC and 23 (96%) CRC patients, the majority with grade ≥3 [TNBC, 7 (70%); CRC, 13 (54%)], and 1 was fatal [CRC, 1 (4%)]. Evidence of efficacy was limited. Overall response rate was 10% (95% confidence interval 0.3-44.5) for TNBC; one (10%) patient had a partial response. For CRC, no patients had a response; 14 (58%) were unassessable. CONCLUSIONS: The safety profile reflected known risks with T-VEC including risks of intrahepatic injection; no unexpected safety findings from addition of atezolizumab to T-VEC were observed. Limited evidence of antitumor activity was observed.

A Randomized, Double-Blind, Placebo-Controlled Phase II Study of the Efficacy and Safety of Monotherapy Ontuxizumab (MORAb-004) Plus Best Supportive Care in Patients with Chemorefractory Metastatic Colorectal Cancer.

Purpose: The purpose of this study was to evaluate the safety and efficacy of ontuxizumab (MORAb-004), a monoclonal antibody that interferes with endosialin (tumor endothelial marker-1) function, in patients with chemorefractory metastatic colorectal cancer and to identify a responsive patient population based on biomarkers.Experimental Design: This was a randomized, double-blind, placebo-controlled, phase II study. Patients were randomly assigned in a 2:1 ratio to receive weekly intravenous ontuxizumab (8 mg/kg) or placebo plus best supportive care until progression or unacceptable toxicity. Tissue and blood biomarkers were evaluated for their ability to identify a patient population that was responsive to ontuxizumab.Results: A total of 126 patients were enrolled. No significant difference between the ontuxizumab and placebo groups was evident for the primary endpoint of progression-free survival (PFS), with a median PFS of 8.1 weeks in each group (HR, 1.13; 95% confidence interval, 0.76-1.67; P = 0.53). There were no significant differences between groups for overall survival (OS) or overall response rate (ORR). The most common treatment-emergent adverse events (TEAEs) in the ontuxizumab group (vs. the placebo group, respectively) were fatigue (53.7% vs. 47.5%), nausea (39.0% vs. 35.0%), decreased appetite (34.1% vs. 27.5%), and constipation (28.0% vs. 32.5%). The most common grade 3/4 TEAE in the ontuxizumab group versus placebo was back pain (11.0% vs. 0%). No single biomarker clearly identified patients responsive to ontuxizumab.Conclusions: No benefit with ontuxizumab monotherapy compared with placebo for clinical response parameters of PFS, OS, or ORR was demonstrated. Ontuxizumab was well tolerated. Clin Cancer Res; 24(2); 316-25. ©2017 AACR.

Phase II trial of modified FOLFOX6 and erlotinib in patients with metastatic or advanced adenocarcinoma of the oesophagus and gastro-oesophageal junction.

BACKGROUND: There is increased recognition that cancers of the upper GI tract comprise distinct epidemiological and molecular entities. Erlotinib has shown activity in patients with adenocarcinoma of the oesophagus/gastro-oesophageal junction (GEJ), but not in distal gastric cancer. mFOLFOX6 is one of several active regimens used to treat adenocarcinoma of the Eso/GEJ. This study evaluates the efficacy and safety of mFOLFOX6 and erlotinib in patients with metastatic or advanced Eso/GEJ cancers. METHODS: Patients with previously untreated advanced or metastatic Eso/GEJ adenocarcinoma are treated with oxaliplatin 85 mg m(-2), 5-FU 400 mg m(-2), LV 400 mg m(-2) on day 1, 5-FU 2400 mg m(-2) over 48 h and erlotinib 150 mg PO daily. Treatment was repeated every 14 days. The primary objective was response rate (RR), secondary objectives include toxicity, progression-free survival (PFS), overall survival (OS) and to correlate clinical outcome with expression patterns and molecular alterations in the epidermal growth factor receptor-dependent pathways. RESULTS: A total of 33 patients were treated and evaluable: there were two complete responses, 15 partial responses for an objective RR of 51.5% (95% CI, 34.5-68.6%). Median PFS was 5.5 months (95% CI, 3.1-7.5 months) and median OS was 11.0 months (95% CI, 8.0-17.4 months). The most common grade 3-4 toxicities were: diarrhoea (24%), nausea/vomiting (11%), skin rash (8%) and peripheral neuropathy (8%). The frequency of alterations was KRAS mutations (8%), EGFR mutations (0%) and HER2 amplification (19%). CONCLUSION: In patients with Eso/GEJ adenocarcinoma, mFOLFOX6 and erlotinib is active, has an acceptable toxicity profile and FOLFOX ± erlotinib could be considered for further development.

Low-dose trimetrexate glucuronate and protracted 5-fluorouracil infusion in previously untreated patients with advanced pancreatic cancer.

BACKGROUND: 5-Fluorouracil (5-FU)-based regimens have not been shown to prolong survival or provide clinical benefit in patients with advanced pancreatic cancer. The purpose of this study was to determine the tolerability of protracted venous infusion (PVI) of 5-FU, modulated by a low dose of the synthetic antifolate trimetrexate, in patients with advanced pancreatic cancer. PATIENTS AND METHODS: Twenty-three chemotherapy-naïve patients were evaluated. Patients were enrolled in four consecutive cohorts in which the weekly dose of trimetrexate was escalated in 10 mg/m2 increments, from 20 to 50 mg/m2. PVI 5-FU was administered at a fixed dose of 225 mg/m2/day. Treatment was administered for 6 successive weeks, every 8 weeks. RESULTS: Twenty-two patients were assessable. The maximum tolerated dose of trimetrexate was 40 mg/m2. The most common grade 3 and 4 toxicity was diarrhea. There were no treatment-related deaths. Preliminary analysis of activity revealed a response rate of 9%, with 41% of the patients having stable disease for a median duration of 3.8 months. The median survival for the entire group was 6.9 months (range 1-29 months). A clinical benefit response was experienced by 27.2% of patients. CONCLUSIONS: Low-dose trimetrexate can be safely administered in combination with PVI 5-FU. This treatment is well tolerated and is associated with palliative activity in advanced pancreatic cancer.

Adjuvant therapy for gastric cancer: a reality at last.

Gastric cancer remains a significant healthcare problem throughout the world and is usually diagnosed at a fairly advanced stage in the West. Despite complete resection of the primary tumor, most patients eventually experience a relapse and die of recurrent disease. Extended surgery has not been shown to improve survival in Western studies. There have been a large number of adjuvant chemotherapy trials over the past several decades, most with negative results. More recently, there is hope for improving these dismal results with a meta-analysis showing a benefit for adjuvant chemotherapy and a large randomized trial, INT-0116, which has just reported a significant survival advantage with combined chemoradiation. These results make adjuvant therapy for completely resected gastric carcinoma the new standard of care, except in the uncommon setting of early intramucosal cancers.

CT colonography: value of scanning in both the supine and prone positions.

OBJECTIVE: The purpose of this study was to evaluate the effectiveness of CT colonography when patients were imaged in both the supine and prone positions. We evaluated whether imaging in two positions decreased the number of collapsed colonic segments and increased sensitivity for polyp detection. MATERIALS AND METHODS: Twenty-three patients underwent CT colonography in both the supine and prone positions. Colonic distention for each of the 46 scans was graded. Adequacy of distention for either position alone was compared with that of the combination of the two positions. Polyp data revealed by colonoscopy were reviewed, and the CT data were then retrospectively reviewed for polyp detection. RESULTS: When each scan was considered alone without benefit of the scan obtained in the opposite position, 27 (58.7%) of 46 scans showed inadequate distention. When scans obtained in both positions were considered together, 20 (87.0%) of 23 patients had adequate distention with the grading system used. However, this value increased to 23 (100%) of 23 patients when the reasons for inadequate distention in the three patients were considered. Of the 27 polyps detected with colonoscopy, 21 (77.8%) were also detected retrospectively with CT colonography. Colonoscopy showed 20 polyps that were 5 mm or larger; nineteen (95.0%) of these 20 polyps were also detected retrospectively with CT colonography, nine (47.4%) of which were seen in only one position. CONCLUSION: Use of both the supine and prone positions for patients undergoing CT colonography improves evaluation of the colon and increases sensitivity for polyp detection.

Immunohistochemical evaluation of K-ras, p53, and HER-2/neu expression in hyperplastic, dysplastic, and carcinomatous lesions of the pancreas: evidence for multistep carcinogenesis.

The pathobiology of precursor lesions leading to invasive pancreatic adenocarcinoma remains a controversial area, but knowledge of the mechanisms of tumorigenesis may lead to possibly earlier detection, prevention, and treatment in the future. We hypothesize that ductal hyperplasia and dysplasia of the pancreas represent precursor lesions and are part of a continuous developmental spectrum evolving into ductal adenocarcinoma of the pancreas. To further define this sequence, we studied the immunohistochemical markers HER-2/neu, K-ras, and p53 in 15 adenocarcinomas and 15 nonmalignant specimens of the pancreas. The 15 nonmalignant specimens of the pancreas included both normal pancreas and chronic pancreatitis. Overall, HER-2/neu was positive in normal ducts, ductal hyperplasia, dysplasia, and carcinoma cells in 0 of 30, 11 of 20 (55%), 10 of 15 (67%), and 12 of 15 (80%), respectively, with progressive increase in the intensity of staining; p53 was positive in 1 of 30 (3%), 0 of 20, 3 of 15 (20%), and 13 of 15 (80%), respectively, and K-ras was positive in 1 of 30 (3%), 6 of 20 (30%), 11 of 15 (73%), and 8 of 15% (53%), respectively. These data support the hypothesis that ductal hyperplasia and dysplasia of the pancreas represent precursor lesions, and, in a fashion similar to that in colorectal tumorigenesis, pancreatic cancer seems to accumulate progressive genetic alterations.

Gastrointestinal toxicity or irinotecan.

Irinotecan (CPT-11 [Camptosar]) is an important new chemotherapeutic drug that demonstrates activity against a broad spectrum of malignancies, including carcinomas of the colon, stomach, and lung. Unfortunately, frequent and often severe gastrointestinal toxicities, particularly diarrhea, have limited its more widespread use. A cholinergic syndrome resulting from the inhibition of acetylcholinesterase activity by irinotecan is frequently seen within the first 24 hours after irinotecan administration but is easily controlled with atropine. Late diarrhea occurs in the majority of patients, however, and is National Cancer Institute (NCI) grade 3 or 4 in up to 40%. The late syndrome appears to be related to the effects on the bowel of SN-38, the active metabolite of irinotecan, which undergoes biliary excretion and inactivation. Early recognition and treatment of late diarrhea with high-dose loperamide have reduced, although not entirely eliminated, patient morbidity. Further study is needed to identify the mechanism of irinotecan-induced late diarrhea and to evaluate potential new therapies.

Metastasis in colorectal cancer: what makes the tumor aggressive?

While local control of colorectal cancer can usually be obtained, distant spread is frequent and nearly always results in incurable disease and death. Therefore, the critical determinant of aggressiveness of colorectal cancers is the ability to disseminate widely. While the molecular biology of colorectal carcinogenesis is comparatively well understood, the mechanisms important in metastasis remain relatively cryptic. Conceptually, metastasis is a multistep process with a number of potential therapeutic targets. Critical steps include angiogenesis, local invasion, embolization to distant sites, and extravasation. Identification of high risk tumors may allow more judicious use of effective, but nonselective, cytotoxic adjuvant therapy. Specific inhibitors of particular steps of metastasis are already in various stages of testing.

Prolonged nausea and vomiting after high dose chemotherapy and autologous peripheral stem cell transplantation in the treatment of high risk breast carcinoma.

BACKGROUND: Nausea and vomiting immediately after chemotherapy is a well recognized complication of cancer drug treatment; it is usually short-lived and controllable by modem antiemetics. The authors report a high incidence of prolonged nausea and vomiting after high dose chemotherapy with autologous peripheral stem cell transplantation (PSCT) in the treatment of high risk breast carcinoma patients. METHODS: Patients with high risk breast carcinoma were conditioned with high dose carmustine, cisplatin, and cyclophosphamide followed by autologous PSCT. In Part I of the study, patients who received PSCT at UCLA Medical Center were identified if they were either readmitted with dehydration secondary to nausea and vomiting or referred to a gastroenterology specialist for the treatment of intractable nausea and vomiting. In Part II of the study, the authors examined a series of 38 women treated at UCLA Medical Center in 1993 for high risk breast carcinoma to determine the incidence of prolonged postchemotherapy nausea and vomiting (PPNV) after PSCT. These women were followed at 2-week intervals with a quality of life evaluation that included questions about nausea and vomiting. RESULTS: In Part I of the study, the authors identified 9 women with more than 1 month of significant nausea and vomiting after PSCT without evidence of obstruction or mucositis. Hospitalization was frequently required for hydration. Gastroparesis was found in all four patients who underwent gastric emptying studies. The nausea and vomiting responded to the promotility drug cisapride and high dose corticosteroids. In Part II of the study, the authors found that PPNV was frequent; 24% of patients had significant nausea and 18% had significant vomiting 6 weeks after PSCT, despite treatment with standard antiemetics. CONCLUSIONS: PPNV is a frequent complication of high dose chemotherapy with the aforementioned regimen. It may be due to gastroparesis and represents a form of gastrointestinal toxicity to chemotherapy not previously reported.

Gastrin-releasing peptide-induced expression of prostaglandin synthase-2 in Swiss 3T3 cells.

Prostaglandins, produced in response to mitogens and cytokines, are potent modulators of gastrointestinal physiology and pathophysiology. We investigated modulation of Prostaglandin synthase 2 (PGS-2) expression by the gastrin-releasing peptide (GRP) receptor in Swiss 3T3 cells. PGS-2 mRNA expression in Swiss 3T3 cells was determined by Northern blot analysis. PGS-2 protein expression in Swiss 3T3 cells was measured by Western blot analysis. GRP caused a transient induction of PGS-2 mRNA in Swiss 3T3 cells that resulted in GRP-dependent expression of PGS-2 protein. Transcriptional activation of PGS-2 by GRP was independent of de novo protein synthesis and was not affected by pertussis toxin. Comparison of signaling pathways used by PMA or EGF to those used by GRP showed that PGS-2 induction by GRP increased under conditions that inhibit PKC activity. Dexamethasone, which blocks PMA and EGF induction of PGS-2, also inhibited GRP-induced accumulation of PGS-2 mRNA. These results show that PGS-2 expression in Swiss 3T3 cells is not only controlled by PKC and receptor tyrosine kinase pathways but also by G-protein coupled receptor signaling pathways.

Polymerase chain reaction-based K-ras mutation detection of pancreatic adenocarcinoma in routine cytology smears.

The cytologic diagnosis of pancreatic carcinoma is notoriously difficult, particularly in distinguishing benign atypia from well-differentiated adenocarcinoma. Mutation of codon 12 in the K-ras oncogene is frequently found with pancreatic cancers. Detection by polymerase chain reaction (PCR) followed by restriction endonuclease digestion can provide a powerful tool to improve and confirm diagnosis. The authors examined the utility of PCR-based detection in the diagnosis of pancreatic carcinoma using routinely obtained cytology smears that could be collected at most hospitals. Pancreatic cytology smears were collected retrospectively from 60 patients. DNA was extracted from the slides and amplified by PCR using mismatched primers that generated a Bst-N1 recognition site with the wild type codon 12 but not with the mutant allele. Results were compared with clinical follow-up. K-ras codon 12 mutations were observed in 44 of 46 (95.7%) cases of pancreatic cancer, but not in 12 benign cases nor in 2 cases of islet cell tumor. The amplification and digestion steps proved robust and sensitive, capable of detecting mutant K-ras alleles from cytology smears that contained only small foci of suspicious cells. Our results indicate that K-ras mutation analysis can be done reliably within 1 to 2 days from routine cytology slides without special handling, increasing the sensitivity of diagnosis in ambiguous cases while maintaining cost-effective and relatively noninvasive sampling strategy.

Dietary fat and colon cancer.

Dietary fat in general, and perhaps animal and polyunsaturated fats in particular, appear to increase colon carcinogenesis in animal models and epidemiologic studies. This observation holds the potential to shed light on the underlying mechanisms of colorectal carcinogenesis and reduce morbidity and mortality from the disease by dietary and chemoprevention. While research continues into the relationship between prostglandins and other putative mediators of the effects of fats on the colon, we can suggest that a diet which protects against colorectal cancer would be low in fat with most of that fat coming from vegetable sources. Prospective dietary trials are ongoing which may strengthen or modify these preliminary recommendations.

Male breast cancer.

Breast cancer in men is a rare condition affecting only 1,000 men each year in the United States. Hormonal, genetic, and perhaps environmental factors appear to be important in development of the disease. Clinically, breast cancer in men resembles that seen in woman. Histologically the diseases are indistinguishable, although lobular cancer is rare in men. Tumors from men are more likely to be estrogen-receptor positive. Treatment strategies draw from experience in women and usually begin with surgical removal of the tumor. Additional modalities often include hormonal, radiation, and cytotoxic therapies. The prognosis corrected for age and stage is similar to that of women. The study of breast cancer in men may provide new insights into epidemiologic and pathogenic factors that affect both sexes.

Clostridium difficile colitis secondary to intravenous vancomycin.

Nearly every known antibiotic has been implicated as a cause of Clostridium difficile colitis. We report the first case resulting from monotherapy with intravenous vancomycin. The patient was on chronic hemodialysis and was treated with intravenous vancomycin for presumed cervical osteomyelitis. After 29 days of therapy he developed abdominal pain and diarrhea and his stool was found to contain both C. difficile and cytotoxin. The patient responded with symptomatic and microbiological recovery to withdrawal of the drug and treatment with oral metronidazole. The prolonged elevation of serum vancomycin levels in patients with renal failure may predispose them to the development of C. difficile colitis.