Dual CTLA-4 and PD-1 checkpoint blockade using CS1002 and CS1003 (nofazinlimab) in patients with advanced solid tumors: A first-in-human, dose-escalation, and dose-expansion study.

BACKGROUND: This study investigated the safety and efficacy of an anti-CTLA-4 monoclonal antibody (CS1002) as monotherapy and in combination with an anti-PD-1 monoclonal antibody (CS1003) in patients with advanced/metastatic solid tumors. METHODS: The phase 1 study involved phase 1a monotherapy dose-escalation (part 1) and phase 1b combination therapy dose escalation (part 2) and expansion (part 3). Various dosing schedules of CS1002 (0.3, 1, or 3 mg/kg every 3 weeks, or 3 mg/kg every 9 weeks) were evaluated with 200 mg CS1003 every 3 weeks in part 3. RESULTS: Parts 1, 2, and 3 included a total of 13, 18, and 61 patients, respectively. No dose-limiting toxicities or maximum tolerated doses were observed. Treatment-related adverse events (TRAEs) were reported in 30.8%, 83.3%, and 75.0% of patients in parts 1, 2, and 3, respectively. Grade ≥3 TRAEs were experienced by 15.4%, 50.0%, and 18.3% of patients in each part. Of 61 patients evaluable for efficacy, 23 (37.7%) achieved objective responses in multiple tumor types. Higher objective response rates were observed with conventional and high-dose CS1002 regimens (1 mg/kg every 3 weeks or 3 mg/kg every 9 weeks) compared to low-dose CS1002 (0.3 mg/kg every 3 weeks) in microsatellite instability-high/mismatch repair-deficient tumors, melanoma, and hepatocellular carcinoma (50.0% vs. 58.8%, 14.3% vs. 42.9%, and 0% vs. 16.7%). CONCLUSION: CS1002, as monotherapy, and in combination with CS1003, had a manageable safety profile across a broad dosing range. Promising antitumor activities were observed in patients with immune oncology (IO)-naive and IO-refractory tumors across CS1002 dose levels when combined with CS1003, supporting further evaluation of this treatment combination for solid tumors. PLAIN LANGUAGE SUMMARY: CS1002 is a human immunoglobulin (Ig) G1 monoclonal antibody that blocks the interaction of CTLA-4 with its ligands and increases T-cell activation/proliferation. CS1003, now named nofazinlimab, is a humanized, recombinant IgG4 monoclonal antibody that blocks the interaction between human PD-1 and its ligands. In this original article, we determined the safety profile of CS1002 as monotherapy and in combination with CS1003. Furthermore, we explored the antitumor activity of the combination in anti-programmed cell death protein (ligand)-1 (PD-[L]1)-naive microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) pan tumors, and anti-PD-(L)1-refractory melanoma and hepatocellular carcinoma (HCC). CS1002 in combination with CS1003 had manageable safety profile across a broad dosing range and showed promising antitumor activities across CS1002 dose levels when combined with CS1003. This supports further assessment of CS1002 in combination with CS1003 for the treatment of solid tumors.

Sex as a Predictor of Response to Immunotherapy in Advanced Cutaneous Squamous Cell Carcinoma.

Approximately 3-5% of patients with cutaneous squamous cell carcinoma (CSCC) develop advanced disease, accounting for roughly 1% of all cancer deaths in Australia. Immunotherapy has demonstrated significant clinical benefit in advanced CSCC in several key phase II studies; however, there are limited data for patients treated outside of clinical trials. This is particularly relevant in advanced CSCC, which is most often seen in elderly patients with significant comorbidities. Thus, we aim to describe our experience with immunotherapy in a cohort of patients with advanced CSCC in Australia. We retrospectively reviewed all advanced CSCC patients treated with immunotherapy within the Illawarra and Shoalhaven Local Health District. Among the 51 patients treated with immunotherapy, there was an objective response rate (ORR) of 53% and disease control rate (DCR) of 67%. Our most significant predictor of response was sex, with male patients more likely to have better responses compared to female patients (DCR 85% vs. 41%, p < 0.0001), as well as improved progression-free survival (HR 4.6, 95%CI 1.9-10.8, p = 0.0007) and overall survival (HR 3.0, 95%CI 1.3-7.1, p = 0.006). Differential expression analysis of 770 immune-related genes demonstrated an impaired CD8 T-cell response in female patients. Our observed ORR of 53% is similar to that described in current literature with durable responses seen in the majority of patients.

Low Pretreatment CD4+:CD8+ T Cell Ratios and CD39+CD73+CD19+ B Cell Proportions Are Associated with Improved Relapse-Free Survival in Head and Neck Squamous Cell Carcinoma.

The ectonucleotidases CD39 and CD73 are present on immune cells and play important roles in cancer progression by suppressing antitumour immunity. As such, CD39 and CD73 on peripheral blood mononuclear cells (PBMCs) are emerging as potential biomarkers to predict disease outcomes and treatment responses in cancer patients. This study aimed to examine T and B cells, including CD39 and CD73 expressing subsets, by flow cytometry in PBMCs from 28 patients with head and neck squamous cell carcinoma (HNSCC) and to assess the correlation with the treatment modality, human papillomavirus (HPV) status, and relapse-free survival (RFS). The PBMCs were examined pre-, mid-, and post-radiotherapy with concurrent cisplatin chemotherapy or anti-epidermal growth factor receptor antibody (cetuximab) therapy. Combination radiotherapy caused changes to T and B cell populations, including CD39 and CD73 expressing subsets, but no such differences were observed between concurrent chemotherapy and cetuximab. Pretreatment PBMCs from HPV+ patients contained increased proportions of CD39-CD73-CD4+ T cells and reduced proportions of CD39-/+CD73+CD4+ T cells compared to the equivalent cells from HPV- patients. Notably, the pretreatment CD4+:CD8+ T cell ratios and CD39+CD73+CD19+ B cell proportions below the respective cohort medians corresponded with an improved RFS. Collectively, this study supports the notion that CD39 and CD73 may contribute to disease outcomes in HNSCC patients and may assist as biomarkers, either alone or as part of immune signatures, in HNSCC. Further studies of CD39 and CD73 on PBMCs from larger cohorts of HNSCC patients are warranted.

Progress in the Treatment of Small Intestine Cancer.

OPINION STATEMENT: Small intestine cancer is rare, accounting for approximately 3% of all gastrointestinal malignancies. The most common histological subtypes include adenocarcinoma, neuroendocrine tumours (NETs) and gastrointestinal stromal tumours (GISTs). In localised disease, surgery remains the mainstay of treatment and the best approach to improve survival. Current treatment for small intestine adenocarcinoma (SIA) is extrapolated from small studies and data from colorectal cancer (CRC). There is limited evidence to guide therapy in the adjuvant setting. However, there are small phase II studies in the advanced setting providing evidence for the role of chemotherapy and immunotherapy. There is also limited evidence assessing the efficacy of targeted therapies. Small intestine NETs are rare, with evidence for somatostatin analogue therapy, particularly in the low to intermediate-grade well-differentiated tumours. Poorly differentiated NETs are generally managed with chemotherapy but have worse outcomes compared with well-differentiated NETs. The management of small intestine GISTs is largely targeting KIT mutations with imatinib. Recent trials have provided evidence for effective therapies in imatinib-resistant tumours and the potential role of immunotherapy. The aim of this article was to review the evidence for the current management and recent advances in the management of small intestine adenocarcinoma, NETs and GISTs.

HER2-Positive Gastroesophageal Cancers Are Associated with a Higher Risk of Brain Metastasis.

Brain metastasis from gastroesophageal adenocarcinomas (GOCs) is a rare but a devastating diagnosis. Human epidermal growth factor receptor 2 (HER2) is a prognostic and predictive biomarker in GOCs. The association of HER2 with GOC brain metastasis is not known. We performed a retrospective analysis of patients with GOCs with known HER2 status between January 2015 and November 2021. HER2 was assessed on either the primary tumour or metastasis by immunohistochemistry or in situ hybridization. The diagnosis of brain metastasis was made on standard imaging techniques in patients with symptoms or signs. HER2 results were available for 201 patients, with 34 patients (16.9%) HER2 positive. A total of 12 patients developed symptomatic brain metastasis from GOCs, of which 7 (58.3%) were HER2 positive. The development of symptomatic brain metastasis was significantly higher in the HER2-positive GOCs (OR8.26, 95%CI 2.09-35.60; p = 0.0009). There was no significant association of HER2 status and overall survival in patients with brain metastasis. Although the rate of brain metastasis remains low in GOCs, the incidence of symptomatic brain metastasis was significantly higher in patients with HER2-positive tumours.

Immune checkpoint inhibitor-induced myocarditis, myositis, myasthenia gravis and transaminitis: a case series and review.

Immune checkpoint inhibitors have been incorporated into the treatment of various malignancies. An increasing body of literature is reporting rare but potentially fatal adverse events associated with these agents. In this case series, the authors report the clinical features and outcomes of seven patients who received immune checkpoint inhibitors for different solid organ malignancies and developed a tetrad of immune-related myocarditis, myositis, myasthenia gravis and transaminitis. Herein the authors review the literature and describe the current diagnostic and management approach for this overlapping syndrome. The authors' series highlights the importance of a high index of clinical suspicion, prompt comprehensive investigations, early multidisciplinary team involvement and initiation of immunosuppressive therapy when immune-related adverse events are suspected.

Cancer immunotherapy is used in the treatment of different cancer types. Immunotherapy activates the immune system to detect and attack cancer cells, but side effects may arise from the immune system inadvertently attacking normal tissues and organs. The increased use of immunotherapy has led to an increase in the reporting of rare but potentially life-threatening treatment-related side effects. In this case series, the authors report the clinical features and outcomes of seven patients who developed inflammation of the heart, muscles, nerve and muscle junctions and liver following treatment with immunotherapy. The authors review the scientific literature and discuss the current understanding of and management approach to this rare syndrome. The authors' report highlights the importance of a high degree of clinical suspicion, prompt comprehensive testing to confirm diagnosis, early involvement of experts from different specialties and early initiation of treatment in the management of this unique syndrome.

Clinical and molecular profile of young adults with early-onset colorectal cancer: Experience from four Australian tertiary centers.

BACKGROUND: Patients with early-onset colorectal cancer (EO-CRC) have unique characteristics. Contemporary data on the pathological and molecular features, and survival of EO-CRC are limited in the Australian context. AIM: To determine the demographic, histopathological and molecular characteristics of adults with EO-CRC, and their survival. METHODS: We conducted a retrospective study of adults aged 18-49 years with EO-CRC who were referred to the Illawarra Shoalhaven Local Health District, South Eastern Sydney Local Health District and Royal North Shore Hospital in New South Wales, Australia, between 2014 and 2018. RESULTS: Of 257 patients included, 94 (37%) patients presented with de novo metastatic CRC, 80% patients had near-average risk family history and 89% had a symptomatic presentation. In 159 patients with nonmetastatic disease at diagnosis, stage III disease (OR 3.88 [95% CI: 1.13-13.3]; p = .03) and the presence of perineural invasion (PNI) (OR 6.63 [95% CI: 2.21-19.84]; p = .001) were risk factors associated with the development of metastatic disease. Among 94 patients with de novo metastatic disease, 43 (43%) and 12 (14%) patients harbored a KRAS or BRAF V600E mutation, respectively. The median overall survival was 29.6 months (95% CI: 20.4-38.7). BRAF mutation was associated with inferior survival (HR 3.00 [95% CI: 1.30-6.94]; p = .01). CONCLUSION: The prevalence of KRAS and BRAF mutations in our cohort is similar to the overseas experience. Stage III disease at diagnosis, presence of PNI and BRAF mutation are adverse prognostic indicators. A better understanding of the molecular landscape is needed for this patient cohort, so as to better tailor prevention strategies, screening and treatment pathways.

Localized delivery of immunotherapy via implantable scaffolds for breast cancer treatment.

Breast cancer remains a leading global cause of morbidity and mortality. While the field of immunotherapy is a promising avenue of investigation and has revolutionized the standard of care for melanoma and lung cancer, modest response rates and a high incidence of immune-related adverse events often necessitate the administration of a sub-therapeutic dose or treatment cessation. Injectable and implantable drug delivery devices present a novel strategy to achieve sustained delivery of potent concentrations of drug directly to the tumor site and minimize systemic toxicity. This review will address the current limitations with conventional immunotherapy for breast cancer treatment, and the recent developments and future prospects in localized delivery strategies. We describe implantable scaffolds and injectable biomaterials for the localized delivery of immunotherapy, which can improve the safety and efficacy of immunotherapies. We discuss the limitations of these delivery systems, such as the influence of shape and material type on drug release and tumor uptake. The challenges of clinical translation, such as the availability of appropriate preclinical animal models and accurate reporting are also discussed. Considerations of these issues will pave the way for effective new therapies that will improve treatment response, patient survival and quality of life for breast cancer patients.

Combination chemotherapy with NAB® -paclitaxel and capecitabine for patients with advanced biliary tract cancer (NAP-CAPABIL Pilot Study).

BACKGROUND:  Advanced biliary tract cancer (ABTC) is a highly aggressive malignancy, with a 5-year overall survival of < 10%. Although preliminary evidence suggests a role of targeted treatments or immunotherapy in a subset of patients, chemotherapy remains the standard second-line treatment in the majority. We conducted a pilot study of second-line chemotherapy with capecitabine and nab-paclitaxel after failure of gemcitabine and platinum. METHODS: Eligible patients had histologically proven, unresectable biliary tract cancer, which had progressed on a gemcitabine/platinum doublet. In this single-arm, multicenter trial, all patients received capecitabine (825 mg/m2 bd PO D1-14 q21d) and nab-paclitaxel (125 mg/m2 IV D1,8 q21d) until progression or unacceptable toxicity. The primary objective was feasibility of delivering the proposed regimen, with secondary objectives of disease control measures and QOL outcomes. RESULTS: Ten patients were enrolled between 2015 and 2016 from four cancer centers in NSW. Treatment was generally well tolerated with grade III toxicities in five patients (including infection, cholangitis, obstruction, and intestinal perforation) and no grade IV toxicity. Median treatment duration was 4.3 months, with a disease control rate of 80% (8/10), and median progression-free and overall survival of 5.7 and 12.1 months, respectively. Quality of life data and specimens for translational research have been collected. CONCLUSIONS: Our pilot study demonstrates that combination of capecitabine and nab-paclitaxel is feasible as a second-line treatment in ABTC. Adequate safety and promising early efficacy signals make further assessment of the combination in a formal phase II or III trial reasonable. CLINICAL TRIAL INFORMATION: ACTRN12615000504516.

Experimental and Clinical Evidence Supports the Use of Urokinase Plasminogen Activation System Components as Clinically Relevant Biomarkers in Gastroesophageal Adenocarcinoma.

Gastric and oesophageal cancers (GOCs) are lethal cancers which metastasise early and recur frequently, even after definitive surgery. The urokinase plasminogen activator system (uPAS) is strongly implicated in the invasion and metastasis of many aggressive tumours including GOCs. Urokinase plasminogen activator (uPA) interaction with its receptor, urokinase plasminogen activator receptor (uPAR), leads to proteolytic activation of plasminogen to plasmin, a broad-spectrum protease which enables tumour cell invasion and dissemination to distant sites. uPA, uPAR and the plasminogen activator inhibitor type 1 (PAI-1) are overexpressed in some GOCs. Accumulating evidence points to a causal role of activated receptor tyrosine kinase pathways enhancing uPAS expression in GOCs. Expression of these components are associated with poorer clinicopathological features and patient survival. Stromal cells, including tumour-associated macrophages and myofibroblasts, also express the key uPAS proteins, supporting the argument of stromal involvement in GOC progression and adverse effect on patient survival. uPAS proteins can be detected on circulating leucocytes, circulating tumour cells and within the serum; all have the potential to be developed into circulating biomarkers of GOC. Herein, we review the experimental and clinical evidence supporting uPAS expression as clinical biomarker in GOC, with the goal of developing targeted therapeutics against the uPAS.

Dual Delivery of Gemcitabine and Paclitaxel by Wet-Spun Coaxial Fibers Induces Pancreatic Ductal Adenocarcinoma Cell Death, Reduces Tumor Volume, and Sensitizes Cells to Radiation.

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, with surgical resection of the tumor in conjunction with systemic chemotherapy the only potential curative therapy. Up to 80% of diagnosed cases are deemed unresectable, prompting the need for alternative treatment approaches. Herein, coaxial polymeric fibers loaded with two chemotherapeutic agents, gemcitabine (Gem) and paclitaxel (Ptx), are fabricated to investigate the effect of local drug delivery on PDAC cell growth in vitro and in vivo. A wet-spinning fabrication method to form a coaxial fiber with a polycaprolactone shell and alginate core loaded with Ptx and Gem, respectively, is used. In vitro, Gem+Ptx fibers display significant cytotoxicity as well as radiosensitizing properties toward PDAC cell lines greater than the equivalent free drugs, which may be attributed to a radiosensitizing effect of the polymers. In vivo studies assessing Gem+Ptx fiber efficacy found that Gem+Ptx fibers reduce tumor volume in a xenograft mouse model of PDAC. Importantly, no difference in mouse weight, circulating cytokines, or liver function is observed in mice treated with Gem+Ptx fibers compared to the empty fiber controls confirming the safety of the implant approach. With further development, Gem+Ptx fibers can improve the treatment of unresectable PDAC in the future.

High body mass index is associated with an increased overall survival in rectal cancer.

BACKGROUND: The impact of increased body mass index (BMI) on clinical outcomes in locoregional rectal cancer is unknown. METHODS: This is a retrospective cohort study which included 453 consecutive rectal cancer patients undergoing definitive treatment, with confirmed stage I, II or III rectal adenocarcinoma. The association of BMI at diagnosis with overall survival (OS), cancer specific survival (CSS) and disease-free survival (DFS) was explored, controlling for key covariates using multivariable analyses. BMI as defined by the World Health Organization (WHO) is as follows: BMI <18.5-underweight; 18.5-24.9-normal; 25.0-29.9-pre-obesity; >30-obese. RESULTS: Overweight and obese patients had significantly better OS than underweight/normal weight patients (5-year OS 80% for overweight, 77% for obese, and 65% for underweight/normal weight patients, P=0.02). High BMI (>25) was significantly associated with improved OS in univariate [0.62 (0.4-0.8) P=0.007] and multivariable [0.65 (0.4-0.9) P=0.023] analyses. When stratified by stage, high BMI was associated with improved OS in stage III patients (P=0.0009), but not stage II (P=0.21) or stage I (0.54). High BMI was also significantly associated with improved CSS in univariate (HR 0.62, P=0.048) and multivariable analyses (HR 0.58, P=0.03). CONCLUSIONS: In our study a BMI greater than 25 is significantly associated with a longer OS and CSS in patients with locoregional rectal cancer. These findings may be due to the reduced metabolic capacity for non-obese patients to deal with rectal cancer treatment as well as the burden of disease, however further research is needed to evaluate this.

Factors influencing recurrence of stage I-III rectal cancer in regional Australia.

BACKGROUND: As treatments for rectal cancer improve with developments in surgical techniques, radiotherapy and chemotherapy, the nature of recurrences are evolving. We used a comprehensive database of a large Australian population with stage I-III rectal adenocarcinoma to identify timing and prognostic significance of recurrences, and factors associated with risk of developing recurrent disease. METHODS: All patients with locoregional rectal cancer treated with curative intent in our health district from 2006 to 2017 were included. Multivariate analysis using Cox regression models were used to identify factors associated with recurrence. RESULTS: A total of 483 patients were included. Recurrence occurred in 117 (24.2%) of 483 patients, being locoregional in 15 (3.1%) patients, distant in 85 patients (17.6%) and both locoregional and distant in 17 (3.5%) patients. Compared to those with locoregional recurrence, those with both locoregional and distant recurrence had worse cancer-specific survival. On univariate analysis, factors associated with recurrence included stage, grade, radiotherapy, chemotherapy, surgery type and distal tumour location. Factors which remained significant on multivariate analysis included higher grade and stage. CONCLUSION: In the era of multimodality therapy for rectal cancer, recurrences are predominantly distant. Traditional predictors including higher stage, grade and distal tumour location remain independently associated with recurrence, despite current treatment paradigms.

Establishment of novel long-term cultures from EpCAM positive and negative circulating tumour cells from patients with metastatic gastroesophageal cancer.

Circulating tumour cell (CTC) enumeration and profiling has been established as a valuable clinical tool in many solid malignancies. A key challenge in CTC research is the limited number of cells available for study. Ex vivo CTC culture permits expansion of these rare cell populations for detailed characterisation, functional assays including drug sensitivity testing, and investigation of the pathobiology of metastases. We report for the first time the establishment and characterisation of two continuous CTC lines from patients with gastroesophageal cancer. The two cell lines (designated UWG01CTC and UWG02CTC) demonstrated rapid tumorigenic growth in immunodeficient mice and exhibit distinct genotypic and phenotypic profiles which are consistent with the tumours of origin. UWG02CTC exhibits an EpCAM+, cytokeratin+, CD44+ phenotype, while UWG01CTC, which was derived from a patient with metastatic neuroendocrine cancer, displays an EpCAM-, weak cytokeratin phenotype, with strong expression of neuroendocrine markers. Further, the two cell lines show distinct differences in drug and radiation sensitivity which match differential cancer-associated gene expression pathways. This is strong evidence implicating EpCAM negative CTCs in metastasis. These novel, well characterised, long-term CTC cell lines from gastroesophageal cancer will facilitate ongoing research into metastasis and the discovery of therapeutic targets.

Expression of cancer stem cell markers is prognostic in metastatic gastroesophageal adenocarcinoma.

Gastroesophageal adenocarcinoma is a common and highly lethal malignancy. Cancer stem cells (CSCs) have a key role in the development and progression of metastatic disease. While expression of CSC markers CD44, CD133 and aldehyde dehydrogenase 1 (ALDH1) in locoregional gastroesophageal cancer is known to be associated with poorer clinical outcomes, the significance of CSC marker expression in distal metastatic disease is unknown. We investigated the clinicopathological and prognostic associations of the CSC markers, CD44, CD133, and ALDH1, on metastatic deposits from gastroesophageal adenocarcinomas, and evaluated the association of CSC expression with urokinase-type plasminogen activator receptor (uPAR) expression. Of the 36 patients included in the study, 16 (44%) were positive for CD44, 13 (36%) were positive for CD133, and 26 (72%) were positive for ALDH1. CD44 expression was significantly associated with poorer overall survival (OS) in univariate [hazard ratio (HR) 2.9, 95% confidence interval (CI) 1.3-6.9, p=0.008] and multivariate analyses (HR 2.5, 95%CI 1.1-6.2, p=0.04). ALDH1 expression was significantly associated with poorer OS in univariate (HR 2.4, 95% CI 1.01-5.7, p=0.04) analysis but was not significant in multivariate analysis. Both CD44 and ALDH1 expression were significantly associated with uPAR expression. We found no association between CD133 expression and OS. CD44 expression on metastatic disease from gastroesophageal adenocarcinomas is an independent prognostic marker associated with poorer OS. These results expand current evidence to support the role of CSCs as biomarkers in metastatic gastroesophageal cancer.

Disseminated intravascular coagulation and melanoma: a novel case occurring in metastatic melanoma with BRAF and NRAS mutations and systematic review.

Disseminated intravascular coagulation is a complex and potentially lethal complication of malignancy, in which the fundamental abnormality is excessive activation of the coagulation system. It is a rare complication of melanoma which can be difficult to diagnose in some circumstances, leading to delay in treatment. Herein, we describe the first case of disseminated intravascular coagulation occurring in BRAF and NRAS-mutant metastatic melanoma, and systematically review the literature regarding disseminated intravascular coagulation in melanoma. This review summarizes the reported cases of disseminated intravascular coagulation in melanoma and those secondary to the novel treatment of melanoma, and explores the pathophysiology of disseminated intravascular coagulation in melanoma, highlighting the key role of expression of markers of coagulation and fibrinolysis in disseminated intravascular coagulation, as well as more widely in melanoma. Current limitations in the literature are also identified and discussed, particularly with respect to improving the management of this lethal complication. Disseminated intravascular coagulation is a rare complication of melanoma that typically portends poor prognosis.

First-in-human phase I study of infusional and bolus schedules of Deflexifol, a novel 5-fluorouracil and leucovorin formulation, after failure of standard treatment.

BACKGROUND: 5-Fluorouracil (5-FU) is administered with leucovorin (LV) to enhance clinical activity. However, simultaneous administration is not feasible due to their chemical incompatibility, so conditions for the maximum possible beneficial interaction cannot be met. To overcome this, we developed a novel all-in-one, pH neutral stable solution of 5-FU plus LV with ß-cyclodextrin (termed Deflexifol) and assessed its safety and tolerability in a first-in-human phase I trial. METHODS: Patients with advanced solid malignancy received Deflexifol as weekly bolus (375-575 mg/m²) or two-weekly 46 h infusion (1200-3600 mg/m²) for six cycles in a 3+3 dose escalation design. Adverse events, pharmacokinetics and tumor response rates were assessed by standard methods. RESULTS: Forty patients were treated (19 bolus, 21 infusional, median age 67) with no grade 4 adverse events reported. Dose-limiting toxicities of grade 3 diarrhea and myelosuppression were reported for the bolus schedule at 575 mg/m2 (maximum tolerated dose 525 mg/m²), whereas none were reported for the infusional schedule. The recommended phase II infusional dose was declared as 3,000 mg/m², >25% that of 5-FU used in standard-of-care regimens. Pharmacokinetic analyses showed evidence of inter-patient variability, with no evidence of saturation in clearance, and a trend to linear increase in AUC with dose. Disease control rate was 64% despite most patients having failed previous 5-FU regimens. CONCLUSION: Deflexifol is safer and effective in bolus and infusion schedules at higher doses than that permitted by separate infusion of 5-FU and LV. A phase II study evaluating Deflexifol is planned.

Oral cannabinoid-rich THC/CBD cannabis extract for secondary prevention of chemotherapy-induced nausea and vomiting: a study protocol for a pilot and definitive randomised double-blind placebo-controlled trial (CannabisCINV).

INTRODUCTION: Chemotherapy-induced nausea and vomiting (CINV) remains an important issue for patients receiving chemotherapy despite guideline-consistent antiemetic therapy. Trials using delta-9-tetrahydrocannabinol-rich (THC) products demonstrate limited antiemetic effect, significant adverse events and flawed study design. Trials using cannabidiol-rich (CBD) products demonstrate improved efficacy and psychological adverse event profile. No definitive trials have been conducted to support the use of cannabinoids for this indication, nor has the potential economic impact of incorporating such regimens into the Australian healthcare system been established. CannabisCINV aims to assess the efficacy, safety and cost-effectiveness of adding TN-TC11M, an oral THC/CBD extract to guideline-consistent antiemetics in the secondary prevention of CINV. METHODS AND ANALYSIS: The current multicentre, 1:1 randomised cross-over, placebo-controlled pilot study will recruit 80 adult patients with any malignancy, experiencing CINV during moderate to highly emetogenic chemotherapy despite guideline-consistent antiemetics. Patients receive oral TN-TC11M (THC 2.5mg/CBD 2.5 mg) capsules or placebo capsules three times a day on day -1 to day 5 of cycle A of chemotherapy, followed by the alternative drug regimen during cycle B of chemotherapy and the preferred drug regimen during cycle C. The primary endpoint is the proportion of subjects attaining a complete response to CINV. Secondary and tertiary endpoints include regimen tolerability, impact on quality of life and health system resource use. The primary assessment tool is patient diaries, which are filled from day -1 to day 5. A subsequent randomised placebo-controlled parallel phase III trial will recruit a further 250 patients. ETHICS AND DISSEMINATION: The protocol was approved by ethics review committees for all participating sites. Results will be disseminated in peer-reviewed journals and at scientific conferences. DRUG SUPPLY: Tilray. PROTOCOL VERSION: 2.0, 9 June 2017. TRIAL REGISTRATION NUMBER: ANZCTR12616001036404; Pre-results.

Safety and Efficacy of Oxaliplatin Doublet Adjuvant Chemotherapy in Elderly Patients With Stage III Colon Cancer.

BACKGROUND: Colon cancer is common in the elderly, but owing to under representation in clinical trials, the benefit of standard therapies is uncertain in this age group. We aimed to clarify the efficacy and complications of adjuvant oxaliplatin and fluoropyrimidine chemotherapy for patients 70 years and older with stage III colon cancer. PATIENTS AND METHODS: All patients with stage III colon adenocarcinoma were identified from an Australian cancer registry (2006-2013). Multivariable Cox hazard regression was used to determine prognostic factors for all-cause mortality. Chemotherapy complications were quantified using discontinuation rates, hospital admissions, and mortality for 12 months after starting chemotherapy. RESULTS: A total of 2164 patients fulfilled our inclusion criteria, including 1080 (49.9%) patients ≥ 70 years. Patients ≥ 70 years were less likely to receive adjuvant chemotherapy (60.7% vs. 89.6%) or oxaliplatin doublet chemotherapy (18.8% vs. 71.2%). Older patients receiving oxaliplatin were more likely to cease treatment early (18.7% vs. 7.6%) and require hospital admission (67.0% vs. 53.5%). The addition of oxaliplatin provided an overall survival benefit for patients < 70 years (hazard ratio, 0.44; 95% confidence interval, 0.3-0.6; P < .0001) and for patients ≥ 70 years (hazard ratio, 0.64; 95% confidence interval, 0.5-0.9; P = .005). CONCLUSIONS: Despite a modestly increased rate of hospital admission and early chemotherapy cessation, we demonstrate a persistent survival benefit for the addition of oxaliplatin to a fluoropyrimidine as adjuvant treatment for stage III colon cancer in elderly patients.