Fluoropyrimidines are used widely to treat cancer but their cardiotoxicity, which remains incompletely understood, has serious consequences for some patients. The fluoropyrimidine S-1 (Teysuno®) has recently been approved for the management of colorectal cancer in patients who develop cardiovascular toxicity with other fluoropyrimidines. This was a single-centre phase II prospective randomised open-label blinded endpoint trial that investigated the cardiotoxicity of capecitabine and S-1 in patients treated between May 2014 and March 2020. Patients were randomized 1:1 to receive oral capecitabine or S-1, alone or with oxaliplatin, for days 1-14 of a 21-day cycle. Baseline computed tomography coronary angiogram (CTCA) was performed. Myocardial ischaemia was quantified by ST-segment analysis of continuous 12-lead electrocardiography before and during days 3-5 of oral chemotherapy, by a blinded analyst. Alpha-fluoro-beta-alanine (FBAL) was measured using a validated liquid chromatography tandem mass spectrometry method. Fifty-nine patients (29 capecitabine; 30 S-1; mean age 64 years (range 40-83)) were enrolled, 56 started treatment and 72% (capecitabine) and 70% (S-1) received oxaliplatin. CTCA was performed in 53 patients, coronary artery disease (CAD) was seen in 30 (capecitabine, n=14/26; S-1, n=16/27). Duration of ST change was not significantly different between groups (p = 0.2198) but change in mean daily ischaemic burden (p=0.0442) was significantly higher for capecitabine compared to S-1. Ischaemic burden was unrelated to the presence of underlying CAD. FBAL (precursor to cardiotoxic fluoroacetate) was significantly increased with capecitabine compared to S-1 during treatment (Table). Table: 2157PMean FBAL (ng/mL) during fluoropyrimidine treatmentWeekCapecitabine (n=23)S-1 (n=23)P value1250795<0.000122632103<0.000131230.0083 Open table in a new tab In this prospective randomised trial, capecitabine was associated with significantly higher ischaemic burden and higher levels of FBAL than S-1 and this was unrelated to presence of CAD.

Predictive biomarkers for immune checkpoint blockade (ICB) are desperately needed. Retrospective studies demonstrate that tsMHC-II positivity is a strong predictive biomarker for anti-PD-1 activity in melanoma, Hodgkins disease and breast cancer. Deficient mismatch repair (dMMR) CRC responds readily to anti-PD-1 and has significantly higher tsMHC-II expression than pMMR CRC but some pMMR patients have strong primary tsMHC-II positivity and it is prognostic. We report here a prospective trial of nivolumab in locally advanced and metastatic tsMHC-II positive pMMR CRC (NCT03981146). pMMR CRC patients who had progressed on all standard of care therapies and whose tumors exhibited >1% tsMHC-II were prospectively treated with 480mg nivolumab every 4 weeks. Primary outcome measure was durable clinical benefit (DCB – no progression at 27 weeks), key secondary outcomes were objective response (OR), progression-free survival time (PFS) and overall survival (OS). Of 455 patients screened, 12.8% were tsMHC-II positive (8.6% ≥5% and 0.7% >50% staining). Of 35 patients treated, 65.7% has tsMHC-II ≥5%, 2.9% >50%. Liver metastases were present in 62.9%. At a median follow-up time of 57 weeks, only 1 patient was still on treatment. 3/35 (8.6%) had DCB, none of whom had liver metastases; of 9 patients remaining on therapy >18 weeks, 7 had no liver metastases. The OR was 0%. Currently mPFS is 9.1 weeks (95% Confidence Interval (CI): 9.0, 9.8) and mOS 29.6 weeks (95% CI: 17.3, 42.1). The one patient with tsMHC-II expression >50% remained on treatment for one cycle. Staining of matched primaries and secondaries showed discordance is common with <40% tsMHC-II positive primaries giving rise to positive secondaries. There were no new safety signals. In this first prospective trial of tsMHC-II as a predictive biomarker for anti-PD-1 we show that tsMHC-II expression is not a useful stratifier in advanced pMMR CRC. We discuss likely reasons for this which include the liver predominance of metastatic CRC, the discordance of tsMHC-II status by site and the nature of the IFNg producing T cells in those with tsMHC-II positive pMMR primaries that subsequently relapse.

Background: Survival prediction in patients presenting with malignancy of undefined primary origin (MUO) is challenging, with a lack of validated prognostic tools. Biomarkers of the systemic inflammatory response independently predict survival in other cancer types, but their role in MUO is unclear. The aim of this study was to assess biomarkers of the systemic inflammatory response in patients presenting with MUO. Patients and methods: A biobank of 1049 patients presenting with MUO referred to a regional oncology service in Scotland was analysed. Key inflammatory biomarkers (white cell count, neutrophil count and C-reactive protein combined with albumin [to give the modified Glasgow Prognostic Score {mGPS}]) were examined. The relationship between these and survival was examined using Kaplan-Meier and Cox regression methods. Results: Data were available for 1049 patients. Median survival was 4.3 months (interquartile range: 1.7-16.0 months). On multivariate analysis mGPS was independently associated with survival and stratified survival from 13.6 months (mGPS: 0) to 2.3 months (mGPS: 2) (p < 0.001). The mGPS was predictive of survival on multivariate analysis in patients found to have a non-cancer diagnosis (p = 0.034), an identified primary cancer (0.002), cancer of unknown primary (CUP) ( p = 0.011), those for whom biopsy was not done (MUO) (p = 0.036), those found to have an identified primary cancer (0.002) and even those found to have a non-cancer diagnosis (p = 0.034) after further detailed investigations. In patients with CUP mGPS predicted survival regardless of the recognised clinicopathological prognostic subgroup (p < 0.001). Conclusions: The results of the present study demonstrate that biomarkers of the systemic inflammatory response are reliable prognostic factors in patients presenting with MUO. These simple, objective, routine clinical tests may inform clinical management. (C) 2020 Elsevier Ltd. All rights reserved.

PM00104 (Zalypsis®) is a synthetic tetrahydroisoquinoline alkaloid with potent antiproliferative activity against tumor cell lines. This phase I study evaluated the safety, dose-limiting toxicities (DLTs), recommended dose for phase II trials (RD), pharmacokinetics (PK) and preliminary antitumor activity of PM00104 as a 24-h intravenous (i.v.) infusion every 3 weeks (q3wk).

Estimation of renal function is crucial to guidance of systemic chemotherapy. With stable creatinine levels, the glomerular filtration rate (GFR) is often estimated from a single measurement of serum creatinine. We compared accuracy of the Cockroft and Gault (C&G), modifying diet in renal diseases (MDRD) and Wright estimates in Oncology patients with renal impairment. Analysis was carried out on the basis of monodentate platinum treatment as the nephrotoxic mechanism of these drugs may affect accuracy of these estimates. Sixty-two consecutive patients with stable creatinine levels who had isotopic GFR measurement of ≤ 60 ml min−1 at a regional cancer center were reviewed. Twenty-nine were on monodentate platinum treatment. Isotopic GFR was compared with estimated GFR by the three equations. We defined three categories of estimate based on the fractional difference from isotopic GFR: ‘perfect’ (< 10%), ‘reasonable’ (≥ 10% but < 30%) and ‘poor’ (≥ 30%). There was a trend toward provision of more perfect estimates by the MDRD equation particularly in patients on monodentate platinum treatment. Similar numbers had poor estimates from either of these equations, particularly at extremes of body weight. The MDRD formula may be the most accurate of these equations in Oncology patients with renal impairment, particularly with monodentate platinum treatment.

BACKGROUND:There is speculation that peripheral neuropathy (PN) with capecitabine and oxaliplatin (CapOx; 130 mg/m(2), day 1, every 21 days) may be more common than with FOLFOX4 (5-fluorouracil and oxaliplatin 85 mg/m(2), day 1, every 14 days). We aimed to determine PN incidence and associations during CapOx, and 6 and 12 months after CapOx.PATIENTS AND METHODS:Retrospective audit of 188 oxaliplatin-naive colorectal cancer patients (87 adjuvant, 101 palliative) who received at least one cycle of CapOx. Neurosensory Common Toxicity Criteria Adverse Events version 3 were applied.RESULTS:Overall, 94% experienced acute PN. Worst severities for adjuvant and palliative patients, respectively, were grade 1, 44% and 54%; grade 2, 35% and 32%; grade 3, 16% and 3%; grade 4, 0% and 1% and grade unclear 1% and 1%. Two patients developed PN after CapOx completion despite no symptoms during treatment. Chronic PN at 6 months affected 57% and 18% of adjuvant and palliative patients, respectively. At 12 months, 35% and 16% were affected. Chronic PN at 12 months was associated with cumulative oxaliplatin dose but not age, gender, acute myotonia, pseudolaryngospasm or grade 2 or more PN during treatment.CONCLUSION:Incidence of acute PN during CapOx appears similar to FOLFOX4 but chronic PN in adjuvant patients may be more common with CapOx.

Background: Capecitabine is known to rarely cause raised serum triglycerides (TG). In our centre, several patients receiving capecitabine developed raised TG levels corresponding to the ‘very high risk’ category for potentially serious acute pancreatitis. Methods: A fasting blood lipid screening protocol was introduced into clinical practice for patients receiving capecitabine. Patients with TGs >5 mmol l −1 were treated and followed up. An 18-month prospective audit was performed to establish the incidence and severity of capecitabine-induced hypertriglyceridaemia (CIHT). Results: A total of 304 patients received capecitabine for colorectal cancer between January 2008 and June 2009. Of these, 212 patients (70%) were screened and 8 (3.7%) developed clinically significant hypertriglyceridaemia requiring lipid-lowering therapy. Two of the eight patients had diabetes and one had pre-existing dyslipidaemia. One suffered cerebral infarction during chemotherapy. There were no cases of acute pancreatitis. Follow-up showed that serum TGs safely and rapidly returned to normal with appropriate treatment without discontinuation of capecitabine. Conclusions: This is the first prospective study evaluating CIHT. These results suggest that it should be classed as a ‘common’ undesired effect of capecitabine. Despite this, the incidence does not justify routine screening in all patients. Targeted screening in those with diabetes or pre-existing hyperlipidaemia is recommended, together with adoption of a clear management policy.

2579 Background: We have designed DNA fusion vaccines encoding a tumor-derived peptide, linked to a tolerance-breaking domain sequence (DOM) from tetanus toxin. One peptide sequence from prostate cancer is in clinical trial with CD8+ T-cell responses detected in 60% of patients. For patients with CEA expressing cancers, the target peptide is an HLA-A2-binding sequence, CAP-1 (CEA605–613). Methods: We undertook a single dose level, two-arm phase I/II study to examine the safety and immunogenicity of the DNA fusion vaccine (p.DOM-CAP-1) in patients with CEA-expressing cancers (bowel, lung, and breast cancer). 1mg/dose of DNA was given at weeks 0, 1, 2, 4, 8 and 12. 15 patients with measurable disease were recruited to arm I, 12 patients without radiological evidence of disease to arm II of the study. Results: Interim immunological results reveal humoral and cellular responses to the DOM vaccine component in both arms, confirming successful delivery of the vaccine. CAP1–specific CD8+ T-cells were detected using ex vivo and cultured IFNγ ELISPOT, demonstrating CAP-1 antigenicity. To date immune assessment is mainly in patients with advanced disease (15/15 arm I, 5/12 arm II). In these 20 patients 50% have developed a FrC cellular responses, 35% a CAP-1 cellular response. Follow-up is almost complete with 1 timepoint each in two patients outstanding. We observed an unexpected, high incidence of gastrointestinal adverse events (GI AE) notably diarrhoea (12/27) in vaccinated patients, not observed in the trial of prostate cancer patients. This occurred early after vaccination in patients both with and without measurable disease. In arm 1 these adverse events appear to be coincident with an increased time to clinical and radiological disease progression, longer on-study follow up, decreases in, or stable CEA levels, and longer duration of positive anti-DOM cellular responses (mean 35±14 weeks compared to 7.5± 5 weeks [p<0.006] for those without diarrhea). Conclusions: The early clinical and immunological data indicate that the vaccine is immunogenic. Immune responses correlate with GI-associated effects and an increased time to disease progression. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genvax Genvax Genvax

2568 Background: PM00104 is a novel synthetic alkaloid related to the marine compounds jorumycin and renieramycins. Preliminary preclinical studies suggest changes in cell cycle and DNA binding properties and transcriptional inhibition as main mechanisms of action. PM00104 has shown broad in vitro and in vivo anti-tumor activity (IC50 ≤ 10-8 M) with an acceptable toxicology profile. Methods: The aim of this phase I study was to assess the safety profile, dose-limiting toxicities (DLT), maximum tolerated dose (MTD), recommended dose (RD), pharmacokinetics (PK), relationship between PK and pharmacodynamics (PD) and anti-tumor activity of PM00104 administered as a 24-hour i.v. infusion q3w. Sequential cohorts of 3–6 pts were treated at 133, 266, 400, 800, 900, 1600, 3200, 4000 and 5000 μg/m2. Results: Twenty nine pts have been treated (18 male, 11 female; median age: 59, range: 44–78; ECOG PS ≤2). Five pts developed DLTs: 2 pts at 5000 μg/m2 (grade 4 thrombocytopenia/neutropenia and grade 3 nausea/vomiting in 1 pt; and grade 3 nausea in 1 pt); 1 at 4000 μg/m2 (grade 4 neutropenia/thrombocytopenia and grade 3 asthenia); 1 at 3200 μg/m2 (grade 3 tumor pain) and 1 at 266 μg/m2 (grade 3 transaminase increase). The MTD was reached at 5000 μg/m2 and the RD at 4000 μg/m2. At the RD 6 more pts have been included in order to further evaluate the safety profile and anti-tumor activity. Other adverse events included nausea and vomiting (more frequent at doses ≥800 μg/m2), fatigue, anorexia and diarrhea; most of them being of ≤grade 2 severity. No objective responses were seen but 3 pts with pancreatic adenocarcinoma, hepatocarcinoma and lower esophagus adenocarcinoma presented stable disease lasting >3 months. PM00104 shows a dose-proportional PK profile, the half-life being 20–30 hours and the volume of distribution around 1000 L. Conclusions: PM00104 has shown an acceptable safety profile with signs of anti-tumor activity in pts with advanced malignancies when administered as a 24-hour i.v. infusion q3w. PM00104 is also being evaluated with other administration schedules as monotherapy and in combination with other anti-tumor agents. [Table: see text]

2549 Background: Panobinostat (PAN), a hydroxamic acid derivative, is a potent pan-deacetylase inhibitor, demonstrating anti-tumor activities in a wide variety of preclinical models and showing promising clinical activity. This study elucidates the metabolic and elimination pathways of PAN using [14C]-PAN. METHODS Four patients with advanced cancer received a single oral 20 mg dose of [14C]-PAN (50 μCi). Whole blood, plasma, urine, and feces were collected over 7 days. Total radioactivity was measured in blood, plasma, and excreta by liquid scintillation counting. PAN and its metabolite concentrations in plasma and excreta were measured by LC-MS/MS and HPLC with radiometric detection. Patients were monitored for safety. RESULTS The single PAN dose was well tolerated with no clinically significant laboratory or ECG abnormalities observed. PAN had a rapid oral absorption [median Tmax 0.8 h (range, 0.5-1 h)] and moderate elimination (median t1/2 31 h). The median t1/2 for blood and plasma radioactivity was 54 and 75 hours, respectively. Mass balance was achieved with ≥87% of the administered radioactivity being recovered in the excreta of all patients after 7 days. 44-77% and 29-51% of the dose was recovered in the feces and urine, respectively. Unchanged PAN accounted for ≤3% of the administered dose in the feces, suggesting good oral absorption. The most prominent metabolic pathways involved modifications of the hydroxamic acid (HA) side chain, to form an amide via reduction, carboxylic acid via either hydrolysis or one- and two-carbon (M1) shortening of the HA side chain. Oxygenation and glucuronidation were also observed. PAN accounted for ≤9% of the total radioactivity AUC. The most abundant circulating metabolites in plasma were the glucuronide of M1 (19%) and carbamoyl glucuronide of PAN (13%). At least 40 metabolites, many at trace levels, were observed circulating in plasma. CONCLUSIONS PAN and its metabolites are equally excreted in the urine and feces. Elimination of PAN is primarily by metabolism via reduction, hydrolysis, oxidation and glucuronidation. The balanced elimination and absence of a single major route of PAN metabolism suggest that clinical drug-drug interactions are unlikely with PAN. [Table: see text].

2549 Background: Panobinostat (PAN), a hydroxamic acid derivative, is a potent pan-deacetylase inhibitor, demonstrating anti-tumor activities in a wide variety of preclinical models and showing promising clinical activity. This study elucidates the metabolic and elimination pathways of PAN using [14C]-PAN. Methods: Four patients with advanced cancer received a single oral 20 mg dose of [14C]-PAN (50 μCi). Whole blood, plasma, urine, and feces were collected over 7 days. Total radioactivity was measured in blood, plasma, and excreta by liquid scintillation counting. PAN and its metabolite concentrations in plasma and excreta were measured by LC-MS/MS and HPLC with radiometric detection. Patients were monitored for safety. Results: The single PAN dose was well tolerated with no clinically significant laboratory or ECG abnormalities observed. PAN had a rapid oral absorption [median Tmax 0.8 h (range, 0.5–1 h)] and moderate elimination (median t1/2 31 h). The median t1/2 for blood and plasma radioactivity was 54 and 75 hours, respectively. Mass balance was achieved with ≥87% of the administered radioactivity being recovered in the excreta of all patients after 7 days. 44–77% and 29–51% of the dose was recovered in the feces and urine, respectively. Unchanged PAN accounted for ≤3% of the administered dose in the feces, suggesting good oral absorption. The most prominent metabolic pathways involved modifications of the hydroxamic acid (HA) side chain, to form an amide via reduction, carboxylic acid via either hydrolysis or one- and two-carbon (M1) shortening of the HA side chain. Oxygenation and glucuronidation were also observed. PAN accounted for ≤9% of the total radioactivity AUC. The most abundant circulating metabolites in plasma were the glucuronide of M1 (19%) and carbamoyl glucuronide of PAN (13%). At least 40 metabolites, many at trace levels, were observed circulating in plasma. Conclusions: PAN and its metabolites are equally excreted in the urine and feces. Elimination of PAN is primarily by metabolism via reduction, hydrolysis, oxidation and glucuronidation. The balanced elimination and absence of a single major route of PAN metabolism suggest that clinical drug-drug interactions are unlikely with PAN. [Table: see text]

OBJECTIVES:Our objective was to characterize the local vascular effects of gastrin-releasing peptide in forearm resistance vessels as a biomarker to aid the clinical development of broad-spectrum neuropeptide antagonists as anticancer agents.METHODS:On different occasions, 7 healthy male volunteers received brachial artery infusions of gastrin-releasing peptide, and forearm blood flow was measured by venous occlusion plethysmography. Dose-finding studies identified a range of pharmacologically active doses of gastrin-releasing peptide (3 to 450 pmol/min) for use in dose response and tachyphylaxis studies. The nitric oxide clamp method was used for the assessment of the contribution of nitric oxide to the vasodilatory effect shown.RESULTS AND CONCLUSIONS:Gastrin-releasing peptide proved to be a potent, dose-dependent arteriolar vasodilator. The time to onset and offset of effect was rapid, within minutes, and marked tachyphylaxis was shown, with recovery by approximately 20 minutes. The contribution of nitric oxide to this vasodilatation was minimal. Forearm blood flow studies with the use of gastrin-releasing peptide may be usefully incorporated into the further clinical development of broad-spectrum neuropeptide growth factor antagonists.

PURPOSE:Arg-D-Trp-NmePhe-D-Trp-Leu-Met-NH(2) (Antagonist G), a substance P (SP 6-11) analogue, inhibits mitogenesis stimulated by a broad spectrum of neuropeptides and has demonstrated antitumor activity in vitro and in vivo with IC(50) concentrations of 10-20 microM in small cell lung cancer and other cell lines. Because neuropeptides are part of complex neurohumoral pathways, we have sought to develop novel pharmacodynamic approaches as part of the early clinical development of this potential anticancer drug.EXPERIMENTAL DESIGN:A Phase I trial was performed in two stages. In stage 1, Antagonist G was administered at 3- week intervals using an accelerated dose-escalation strategy until the target maximum plasma concentration (C(max)) of 10 microM was achieved. In stage 2, dose intensity was increased to weekly, and the inhibitory effect of i.v. Antagonist G was assessed by forearm blood flow (FBF) using SP as a vasodilator, as measured by venous plethysmography.RESULTS:In stage 1, dose was escalated from 2 to 300 mg/m(2) in 12 dose levels using only 15 patients. In stage 2, nine patients were entered at three dose levels (300, 350, and 400 mg/m(2)) and a C(max) of 45 microM was achieved. Facial flushing was the only consistent toxicity but was not dose limiting. FBF studies demonstrated that Antagonist G consistently inhibited the vasodilatory effects of SP (mean, 62 +/- 2% inhibition).CONCLUSIONS:Antagonist G can be safely administered up to 400 mg/m(2), achieving C(max)s >20 microM by weekly 6-h i.v. infusion. FBF studies in patients demonstrated that Antagonist G inhibits SP vasodilatory effects in vivo at these doses in the absence of dose-limiting toxicity.

BACKGROUND:Recurrent cutaneous breast cancer is difficult to manage, with surgery, radiotherapy and systemic therapy all having their limitations. Miltefosine is a topical cytostatic agent which may provide an alternative approach in its treatment.PATIENTS AND METHODS:Patients with previously treated progressive cutaneous lesions from breast cancer were treated with miltefosine on a named-patient compassionate supply basis. Miltefosine was applied topically to the skin at a dose of 2 drops/10 cm(2) skin area.RESULTS:Twenty-five patients were treated, most of whom had been heavily pre-treated. Treatment was continued for a median of 14 weeks (range 2-164). In 7 patients grade I skin toxicities were observed, and in 4 patients grade 3 local toxicities necessitated dose adjustments. A response was seen in 9 patients (1 complete response, 2 partial responses, 6 minor responses) giving a total response rate of 36%, with stable disease in 11 patients (44%) and progressive disease in 5 (20%). Those lesions which were superficial or < 2 cm in diameter were most likely to respond.CONCLUSIONS:Miltefosine, either used alone or in conjunction with other therapies for distant metastases, is an effective and tolerable local treatment for cutaneous breast cancer.