24-hour Infusion Research Articles

1115 Ultra-slow low-dose thrombolytic therapy as an option of treatment in intracardiac thrombus: a case report

Abstract We present a case of a 57-year-old male with previously known primary severe mitral regurgitation, who was admitted to the ICU due to massive venous thromboembolism with associated right ventricle dysfunction and with two large mobile right atrial thrombi (2.4 x 1.5 cm and 3.6 x 3.7 cm). Despite of five days with a therapeutic aPTT achieved with unfractionated heparin (UFH), a TTE showed deterioration of the right ventricle systolic function, persistence of the right atrial masses with similar dimensions together with new mobile thrombi on the coronary sinus and on the right pulmonary artery. Due to deterioration of his clinical condition and given the refractoriness to the classical treatment with UFH, it was decided to administer an ultra-slow low-dose thrombolysis protocol, which consisted in a 24-hour infusion of 24 mg of alteplase at a rate of 1 mg per hour, without bolus. The treatment was continued by 48 consecutive hours, with clinical improvement and important reduction of the right atrial masses with resolution of the coronary sinus and right pulmonary artery thrombi. The patient started hypocoagulation with warfarin bridging with low molecular weight heparin (LMWH). Seven days after alteplase discontinuation there was complete resolution of the intracardiac thrombi. One month after ICU admission a successful mitral valve replacement surgery was conducted. Three months after discharge, the patient is in functional New York Heart Association (NYHA) class I with no cardiovascular events or hospitalizations. This case demonstrates that ultra-slow low-dose thrombolysis is a valid bailout treatment option in patients with large intracardiac thrombi refractory to anticoagulation. Abstract 1115 Figure. TTE showing right atrial masses

Development and validation of a high-performance liquid chromatographic method with a fluorescence detector for the analysis of epirubicin in human urine and plasma, and its application in drug monitoring

The aim of the work was to develop a simple, sensitive and accurate liquid chromatography with fluorescence detection (LC-FL) method for the determination of epirubicin in human urine and plasma. Solid phase extraction with HLB cartridges and mixture of dichloromethane:2-propanol:methanol (2:1:1, v/v/v) as the eluent, was used to prepare the samples. The chromatographic analysis was carried out on a Synergi Hydro-RP column with a mobile phase consisting of 40 mM phosphate buffer (pH 4.1) and acetonitrile (69:31, v/v). Epirubicin was monitored at 497 nm and 557 nm for excitation and emission wavelengths, respectively. Validation data confirmed that the limit of detection and limit of quantification was 0.25 ng/mL and 0.5 ng/mL in both matrices. Next, the optimized LC-FL method was applied to determine the level of epirubicin in real samples taken from a 19-year-old patient with metastatic alveolar rhabdomyosarcoma (RMA) to create a drug profile. Plasma and urine samples were collected for 24 h after the end of a 6-hour infusion of epirubicin. The obtained results confirmed that the optimized and validated LC-FL method can be successfully used in drug monitoring therapy, pharmacokinetic and clinical studies. Moreover, the current work is also drawing attention to the relatively high level of epirubicin in the patient urine, which requires compliance with the safety rules in contact with this biological fluid by both medical staff and others, e.g. family members.

Micellar paclitaxel in the treatment of patients with tumors of the female reproductive system

Background. Treatment of patients with advanced cancers of the female reproductive system is very challenging. The most common treatment scheme for such patients includes paclitaxel 135—175 mg/m 2 + carboplatin AUC 5—6 or cisplatin 75 mg/m 2 . However, lengthy treatment with this regimen is limited by adverse events, such as neuropathy, allergic reactions, nephropathy, etc. The new micellar form of paclitaxel has demonstrated better tolerability compared to conventional paclitaxel and, considering the increased safe effective dose (up to 250 mg/m 2 ) it should ensure higher efficacy and better progression-free survival. The use of cremophor EL free paclitaxel is recommended in patients with concomitant extragenital diseases (including diabetes and neurological deficit), in elderly patients, and in patients with allergic reactions, as well as in cases when additional steroids should be avoided. Objective : to summarize the experience of using the new form of paclitaxel in patients with tumors of the female reproductive system and concomitant diseases. Materials and methods . We analyzed both world and our own experience in using micellar paclitaxel at a dose of200—250 mg/m 2 administered as a 1-hour intravenous infusion every 21 days for 3—6 treatment cycles in patients with solid tumors of the female reproductive system. Results. The polymeric micellar composition of cremophor EL free paclitaxel can be used in higher therapeutic doses with a lower risk of hypersensitivity and peripheral neurotoxicity. Fatigue and neuropathy were the most common dose-dependent adverse events of this drug. Nonew adverse reactions unknown for paclitaxel have been registered. Conclusions. The possibility of administration of micellar paclitaxel without premedication with steroids or at a minimum dose* makes it a promising candidate for further studies in combination with new targeted drugs and immunotherapy.

Vincristine-Induced Peripheral Neuropathy in Pediatric Oncology Patients Receiving Vincristine through Push Injections or One-Hour Infusions: Results of a Randomized Clinical Trial

Purpose Vincristine (VCR) is frequently used for the treatment of pediatric cancer. However, it can lead to dose-limiting vincristine-induced peripheral neuropathy (VIPN). This study aimed to investigate if prolonging the duration of VCR administration (1-hour infusions instead of push injections) reduces VIPN in children with cancer during the first year of treatment. Methods The VINCA trial is an international multicenter randomized controlled trial. Participants were randomized to receive all VCR administrations through push injections or 1-hour infusions. Dose of VCR was 1.5-2 mg/m2 with a maximum of 2 mg. VIPN measurements were performed at baseline and 1-3 times during treatment, depending on the number of VCR administrations and the total treatment time, using 4 items of the common toxicity criteria of adverse events (CTCAE version 4.03): constipation, peripheral sensory neuropathy, peripheral motor neuropathy and neuralgia. Individual item scores range from zero (no complaints) to five (death). The primary outcome of this trial was total sum CTCAE score during first year of treatment. For the current analysis, patients treated for acute lymphoblastic leukemia (ALL) or Hodgkin's lymphoma were included. All included patients were analyzed according to the intention-to-treat principle. Besides VIPN measurements, data on all relevant co-medication during treatment were collected, including data of concurrent azole therapy (as azole treatment is known to interact with VCR treatment). Descriptive data were analyzed using either chi-square tests or t-tests. Longitudinal data were analyzed using repeated measures mixed model analysis for continuous outcomes (total CTCAE sum score) and generalized estimating equations for dichotomous outcomes (having VIPN yes or no, with VIPN defined as a CTCAE score of ≥ 2 on any of the 4 CTCAE items). Patients were considered to have been treated with concurrent azole therapy when azoles were used during the week before or following VCR administration and if ≥ 50% of VCR administrations between two succeeding measurements were given with concurrent azole therapy. Results were corrected for concurrent azole therapy, cumulative VCR dose, disease, age, gender, ethnicity and time since diagnosis. Results In total 90 children (n=45 one hour infusions group, n=45 push injections group) participated in the study, 58 (64%) with ALL and 18 (20%) with HL. Participants in the two randomization groups did not significantly differ regarding gender, age, ethnicity, diagnosis, or cumulative VCR dose. Overall results showed no effect of randomization on total CTCAE score (β=0.07, 95% confidence interval (CI) -0.42-0.56, p=0.78). However, concurrent azole treatment appeared to be an effect modifier in this analysis and therefore results are reported separately for measurements with (n=24) and without concurrent azole therapy (n=226). Among patients who received concurrent azole therapy, total CTCAE sum score was significantly higher in the push group compared to the 1-hour group (β=1.95, 95% CI 0.49-3.41, p=0.01), while among those without concurrent azole therapy, these CTCAE sum scores did not differ between the two randomization groups (β=-0.17, 95% CI: -0.67-0.34, p=0.52). The risk of developing VIPN (no/yes) did not significantly differ between both randomization groups, irrespective whether concurrent azole treatment was given or not (with azole: OR (95% CI)=4.92 (0.60-40.37), p=0.14; without azole: OR (95% CI)=0.97 (0.51-1.82, p=0.92). Conclusions Overall, administration method of VCR given as push injection or 1-hour infusion did not seem to affect the risk of developing VIPN in children treated for ALL or HL when using the current dosing regimen. However, when concurrent azole treatment is given, total CTCAE scores are significantly lower in children in the 1-hour infusion group compared to the push injection group, demonstrating less VIPN. These results indicate that for children treated with VCR and concurrent azole therapy for the prevention or treatment of fungal infections, administration of VCR by 1-hour infusions instead of push injections is recommended. Figure Disclosures Kaspers: Helsinn Healthcare: Consultancy; Boehringer Ingelheim Pharma: Other: Member of a DSMC. van der Sluis:medac: Consultancy; jazz farmaceuticals: Consultancy.

Combining CDK2/9 Inhibitor CYC065 with Venetoclax, a BCL2 Inhibitor, to Treat Patients with Relapsed or Refractory AML or MDS

Cyclin dependent kinases (CDKs) are critical for cell cycle regulation and transcriptional elongation. Dysregulated CDKs have been linked to the cancer hallmarks of uncontrolled proliferation and increased survival. CYC065 is a potent and orally‐available inhibitor of CDK2 and CDK9. CDK9 regulates transcription of genes through phosphorylation of RNA polymerase II (RNAP II) C-terminal domain (CTD). Through inhibition of CDK9, CYC065 suppresses CDK9-dependent gene expression and reduces the level of MCL1, a key anti-apoptotic protein. In the first-in-human study, CYC065 was administered by 4-hour infusion every 3 weeks in patients with advanced cancers. Biomarkers related to CYC065 target inhibition, e.g. phosphorylation of RNAP II CTD Ser2, a direct substrate of CDK9, and protein levels of downstream targets, such as MCL1, were determined in patient's peripheral blood mononuclear cells (PBMCs). Durable MCL1 suppression was observed after a single dose in 11 out of 13 patients treated at the recommended phase 2 dose (RP2D) of 192 mg/m2. Five of these 13 patients achieved stable disease lasting ≥ 6 cycles (Do, KT et al, AACR Annual Meeting 2018 Abs CT037). Acute myeloid leukemia (AML) frequently relapses after initial treatment by intensive or low-intensive therapy. Drug resistance has been attributed to dysregulation in apoptotic pathways. AML cells often upregulate pro-survival members of the BCL2 family, such as BCL2 and MCL1, to avoid apoptosis (Grundy M et al, Oncotarget, 2018). Suppression of MCL1 triggered rapid apoptosis in AML, and cured AML-afflicted mice (Glaser SP et al, Genes Dev. 2012). Preclinically, CYC065 has demonstrated potent anti-tumor effect in various AML cell lines, including those with MLL rearrangements, and xenograft models (Frame S et al, AACR, 2010 Abs 3886; Frame S et al, SOHO, 2014 Abs 209). Venetoclax has modest single agent activity in AML. MCL1 dependence appeared to correlate with resistance to venetoclax (Konopleva M et al, Cancer Discovery, 2016). Preclinical study confirmed synergy of CYC065 and venetoclax, suggesting that the suppression of both BCL2 and MCL1 may be more beneficial than inhibiting either one alone (MacKay C et al. AACR-NCI-EORTC 2015 Abs B182). Based on the above rationale, a clinical study (NCT04017546) has been initiated to evaluate a combination of CYC065 with venetoclax in relapsed/refractory AML and MDS. CYC065 will be administered intravenously via 4-hour infusion on Day 1 and Day 15 in combination with daily venetoclax every 4 weeks. Initial dose escalation is 33% and then 25% upon occurrence of the first dose limiting toxicity (DLT). RP2D is the highest dose level at which less than one-third of at least 6 patients experience a DLT during the first treatment cycle. Eligible patients are ≥18 years with previously treated AML or MDS and ≥10% blasts in bone marrow or peripheral blood; adequate bone marrow, renal and liver functions are required. All patients will be asked to participate in the pharmacokinetic and pharmacodynamic studies. Plasma levels of CYC065 and its metabolites as well as venetoclax will be determined. PBMCs will be collected to assess MCL1 levels and the phosphorylation and protein levels of other downstream targets of CDK9 inhibition. Treatment will continue until progression of disease, unacceptable toxicity or changes in patient condition that renders patients ineligible for further treatment. Laboratory tests and bone marrow aspirate/biopsy will be performed to assess response according to standard criteria. Disclosures Borthakur: AbbVie: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; GSK: Research Funding; Polaris: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Incyte: Research Funding; Cyclacel: Research Funding; Janssen: Research Funding; Bayer Healthcare AG: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Oncoceutics, Inc.: Research Funding; Strategia Therapeutics: Research Funding; PTC Therapeutics: Consultancy; BMS: Research Funding; Oncoceutics: Research Funding; Eisai: Research Funding; NKarta: Consultancy; Xbiotech USA: Research Funding; Cantargia AB: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Eli Lilly and Co.: Research Funding; Agensys: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Arvinas: Research Funding. Kadia:BMS: Research Funding; Bioline RX: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees. Al Azzawi:Cyclacel LTD: Research Funding. Zheleva:Cyclacel Ltd: Employment, Equity Ownership, Patents & Royalties. Blake:Cyclacel Ltd: Employment, Equity Ownership, Patents & Royalties. Chiao:Cyclacel Ltd: Employment, Equity Ownership, Patents & Royalties.

A Phase I Study Combining CDK2/9 Inhibitor CYC065 with Venetoclax, a BCL2 Inhibitor, to Treat Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

Cyclin dependent kinases (CDKs) are critical for cell cycle regulation and transcriptional elongation. Dysregulated CDKs have been linked to the cancer hallmarks of uncontrolled proliferation and increased survival. CYC065 is a potent and orally‐available inhibitor of CDK2 and CDK9. CDK9 regulates transcription of genes through phosphorylation of RNA polymerase II (RNAP II) C-terminal domain (CTD). Through inhibition of CDK9, CYC065 suppresses CDK9-dependent gene expression and reduces the level of MCL1, a key anti-apoptotic protein. In the first-in-human study, CYC065 was administered by 4-hour infusion every 3 weeks in patients with advanced solid cancers. Biomarkers related to CYC065 target inhibition, e.g. phosphorylation of RNAP II CTD Ser2, a direct substrate of CDK9, and protein levels of downstream targets, such as MCL1, were determined in patient peripheral blood mononuclear cells (PBMCs). Durable MCL1 suppression was observed after a single dose in 11 out of 13 patients treated at the recommended phase 2 dose (RP2D) of 192 mg/m2. Five of these 13 patients achieved stable disease lasting ≥6 cycles (Do, KT et al, AACR Annual Meeting 2018 Abs CT037). Chronic lymphocytic leukemia (CLL) is a disease that depends upon the overexpression of anti-apoptotic proteins (MCL1, BCL2) for survival. Venetoclax, a BCL2 inhibitor, is one of the most active agents against CLL. However upregulation of MCL1 is associated with resistance to venetoclax (Oppermann S et al., Blood, 2016). Preclinical studies have demonstrated that CYC065 and venetoclax are synergistic in primary CLL cells, inducing apoptosis (Chen R et al, AACR Annual Meeting 2018 Abs 3905). This synergy may arise from targeting parallel anti-apoptotic mechanisms in the intrinsic apoptotic pathway that promote survival in CLL cells. The above findings support the conduct of an ongoing clinical study (NCT03739554) investigating a combination of CYC065 with venetoclax in CLL. CYC065 will be administered intravenously via 4-hour infusion on Day 1 and Day 15 in combination with daily venetoclax. One cycle is 28 days. Initial dose escalation is 33% and then 25% upon occurrence of the first dose limiting toxicity (DLT). RP2D is the highest dose level at which less than one-third of at least 6 patients experience a DLT during the first treatment cycle. Eligible patients are ≥18 years with CLL relapsed or refractory to standard treatment(s) including those with Richter transformation; adequate bone marrow, renal and liver functions are required. All patients will be asked to participate in the pharmacokinetic and pharmacodynamic studies. Plasma levels of CYC065 and its metabolites as well as venetoclax will be determined. PBMCs will be collected to assess MCL1 levels and phosphorylation and protein levels of other downstream targets of CDK9 inhibition. Treatment will continue until progression of disease, unacceptable toxicity or changes in patient condition that renders patients ineligible for further treatment. Laboratory tests and CT scans will be performed regularly to assess response according to standard criteria. Disclosures Wierda: Pharmacyclics LLC: Research Funding; AbbVie: Research Funding; GSK/Novartis: Research Funding; Gilead Sciences: Research Funding; KITE pharma: Research Funding; Sunesis: Research Funding; Genentech: Research Funding; Xencor: Research Funding; Janssen: Research Funding; Loxo Oncology Inc.: Research Funding; Cyclcel: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Miragen: Research Funding; Juno Therapeutics: Research Funding; Acerta Pharma Inc: Research Funding. Chen:Cyclacel Ltd: Research Funding. Zheleva:Cyclacel Ltd: Employment, Equity Ownership, Patents & Royalties. Blake:Cyclacel Ltd: Employment, Equity Ownership, Patents & Royalties. Chiao:Cyclacel Ltd: Employment, Equity Ownership, Patents & Royalties. Plunkett:Cyclacel Ltd: Research Funding.

Pharmacokinetic and Pharmacodynamic Profiles of Cefiderocol, a Novel Siderophore Cephalosporin.

Cefiderocol, a novel parenteral siderophore cephalosporin, exhibits potent in vitro activity and in vivo efficacy against most gram-negative bacteria, including carbapenem-resistant strains of Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia. In phase 1 studies, cefiderocol demonstrated linear pharmacokinetics, primarily urinary excretion, an elimination half-life of 2–3 hours, and a protein binding of 58% in human plasma. Cefiderocol is a time-dependent cephalosporin; the probability of a target attainment at ≥75% of the dosing interval during which the free drug concentration exceeds the minimum inhibitory concentration (ƒT/MIC) for bacterial strains with an MIC of ≤4 μg/mL is likely to be achieved at the therapeutic dose of 2 g over 3-hour infusion every 8 hours in most patients. As expected, renal function markers were the most influential covariates for the pharmacokinetics of cefiderocol for patients with renal impairment or augmented renal clearance (ARC). Dose adjustment is recommended for patients with impaired renal function, and additionally, in ARC patients with creatinine clearance >120 mL/minute, a more frequent dosing regimen (ie, 2 g every 6 hours) was predicted to achieve the target fT > MIC. The single and multiple doses of cefiderocol tested were well tolerated in both healthy subjects and those with renal impairment. Furthermore, neither QT interval prolongation nor drug–drug interaction via organic anion transporters was demonstrated in healthy subjects. Cefiderocol is being investigated in phase 3 clinical studies for the treatment of infections caused by carbapenem-resistant bacteria.

Methotrexate and Cytarabine for Adult Patients with Newly Diagnosed Langerhans Cell Histiocytosis: A Single Arm, Single Center, Prospective Phase 2 Study

Backgroud: Langerhans cell histiocytosis (LCH) is a rare, heterogeneous histiocytic disorder occurring in patients of all ages from neonates to the elderly. The features of LCH are well described in children, however, they remain poorly defined in adults. There is no standard first-line treatment for adult LCH. The current standard treatment protocol for children is vinblastine plus prednisone, which has never been proven effective for adults in a prospective study. Considering the relatively high frequency of pituitary involvement and late onset of neurodegenerative symptoms, patients may benefit from the combination of cytarabine and methotrexate as both these drugs cross the blood-brain barrier. Methods: This phase 2, prospective, single-center study enrolled 83 newly diagnosed adults multisystem (MS)-LCH or LCH with multifocal single system (SS-m) involved between January 2014 and March 2019 (NCT 02389400). The methotrexate (1g/m2by 24-hour infusion on day 1) and cytarabine (100 mg /m2by 24-hour infusion for 5 days) was administered every 35 days for a cycle and 6 cycles totally. The primary endpoint was event-free survival (EFS). Events were defined as a poor response to chemotherapy, reactivation after chemotherapy or death from any cause. Results: The median age was 33 years (range 18-65 years). Forty-nine patients were male (59.0%). Six patients were SS-m LCH (7.2%), 77 patients were MS LCH (92.8%). The most common organ involved in the total cohort was bone (78.3%), followed by lung (67.5%), pituitary (62.7%) and lymph nodes (38.6%). Twenty-three patients had liver involvement (27.7%), 11 patients with spleen involvement (13.3%), no patients had hematologic involvement. All patients received at least one course of chemotherapy, with median 6 (1-6) courses. Overall 69 patients (83.1%) completed protocol treatment, 14 patients (16.9%) went off protocol (13 patients' decision, 1 poor response). The overall response rate was 87.9%. including 43 patients (51.8%) as having non-active disease and 30 patients (36.1%) as active disease (AD)/better. After a median of 23 months (range 7-79 months) follow-up, one patient died of disease progression and 25 patients had reactivation of the disease. The estimated 3-year OS and EFS were 97.7% and 68.0% separately (Figure 1). To evaluate the prognostic factors of EFS using univariate analysis, liver, spleen, lung and skin involvement at baseline had significantly shorter EFS. EFS were also evaluated using multivariate Cox regression model, liver involvement remained predictive of poorer EFS (P = 0.012; HR 0.339, 95% CI 0.146-0.784). The most common toxicity was hematologic adverse events. All patients experienced neutropenia and thrombocytopenia. Thirty-five patients (42.2%) had grade 4 neutropenia, 43 patients (51.8%) had grade 3 neutropenia. Fourteen patients (16.9%) had grade 4 thrombocytopenia, 13 patients (15.7%) had grade 3 thrombocytopenia. No patients received prophylactic antimicrobial treatment during any of the cycles. Forty patients (48.2%) experienced febrile neutropenia, including 38 (45.8%) grade 3 and 2 (2.4%) grade 4. The most common non-hematological toxicities were gastrointestinal complications. Two patients developed grade 3 nausea. Grade 3 alanine aminotransferase increased occurred in in two patients. No treatment related death. One patient had secondary primary malignancy (oral squamous cell carcinoma), 56 months after the last course of MA regimen. Fifty-two of 82 surviving patients experienced sequelae to the disease that were not influenced by therapy. Forty-eight patients had diabetes insipidus and 4 presented with hypothyroidism. Conclusion: Methotrexate and cytarabine is an efficient and safe regimen for newly diagnosed adult LCH. The involvement of liver at baseline indicates a worse prognosis in adult LCH. Disclosures No relevant conflicts of interest to declare.

Study Design of an Open-Label, Single-Arm, Multicenter, Phase 2 Study to Evaluate the Safety and Efficacy of Defibrotide in Adult Patients with Transplant-Associated Thrombotic Microangiopathy

Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is an uncommon, but well-recognized, hematopoietic cell transplant (HCT) complication associated with high morbidity and mortality. TA-TMA may result from microvascular endothelial cell (EC) damage induced by HCT conditioning regimens, immunosuppressive drugs, and infections, and it may be mediated by complement activation in some cases. Although there is no consensus on optimal TA-TMA treatment, common interventions include withdrawal, replacement, or dose modification of calcineurin inhibitors (CI) and/or mammalian target of rapamycin (mTOR) inhibitors (ie, CI/mTORi changes). When increased complement activity is present, terminal complement cascade inhibition has been used. Defibrotide (DF) is approved for adult and pediatric patients (pts) with hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) with renal or pulmonary dysfunction post-HCT in the US and Canada and for pts aged >1 month with severe hepatic VOD/SOS post-HCT in the EU. DF reduces EC activation, promotes fibrinolysis, and may be a novel therapy for TA-TMA. This prospective, open-label, single-arm, multicenter, phase 2 study (EUDRACT: 2018-001101-90) is designed to assess the efficacy and safety of DF for treating pts with high-risk TA-TMA (defined as definite TMA per Postalcioglu M, et al. Biol Blood Marrow Transplant. 2018;24(11):2344-2353) who have failed to respond to CR/mTORi changes. Study Design and Methods: Diagnostic criteria for "definite" TA-TMA include lactate dehydrogenase (LDH) >2 × the upper limit of normal, thrombocytopenia (platelet count <50 × 109/L or ≥50% decrease from peak platelets post-HCT), schistocytes ≥2 per high-power field in peripheral blood, serum creatinine increase >50% from baseline, and a negative Coombs test. Allogeneic HCT pts (aged ≥18 years) who have definite TA-TMA with persistent or progressive disease after 7 or 3 days, respectively, following CI/mTORi changes are eligible (Figure). Pts will be excluded if they relapse after HCT, have grade 4 acute graft-versus-host disease or VOD/SOS, or clinically significant bleeding within 24 hours of enrollment. Planned enrollment is 30 to 40 pts. Pts will receive a 2-hour intravenous infusion of DF 25 mg/kg/day (6.25 mg/kg every 6 hours) for a recommended duration of 21 days (up to 60 days). Pts will be followed for 180 days from DF start (Day 1). The study has 2 co-primary efficacy endpoints: hematologic response by Day 45 (relative to DF start) and renal response by Day 45. Hematologic response is defined as normalization of LDH and platelet count ≥50 × 109/L without platelet transfusion for 7 days (if baseline count was <50 × 109/L) or ≥50% increase in platelet count (if baseline count was ≥50 × 109/L). Renal response is defined as <25% increase or decrease in serum creatinine versus baseline at DF start (renal function stabilization) or ≥25% decrease in serum creatinine versus baseline at DF start or independence from dialysis (if pt was dialysis dependent at baseline or started dialysis after baseline) (renal function improvement). Secondary efficacy endpoints are overall survival, duration of hematologic or renal response, proportion of pts achieving hematologic or renal (measured by serum creatinine or estimated glomerular filtration rate) response by Days 60, 90, and 180, independence from dialysis at Days 60, 90, and 180 for pts with dialysis dependence, and neurologic improvement (defined as any increase in Mini-Mental Status Examination score versus baseline or resolution of TA-TMA seizure activity) at Days 7, 14, 21, and 45. Safety endpoints include incidence of treatment-emergent adverse events (AEs), treatment-emergent serious AEs, and AEs of interest (eg, hemorrhage and hypotension) occurring up to 30 days after the last DF dose. Analysis of the co-primary efficacy endpoints will be evaluated in pts who receive ≥1 DF dose. For each co-primary endpoint, a reference background rate, based upon data from literature and/or registries or research databases, will be established to represent the Day 45 hematologic and renal response rates in a similar pt population in the setting of currently available therapy without DF treatment. A clinically meaningful benefit from DF will be inferred if the lower bounds of the 95% confidence interval of the co-primary endpoints are greater than their respective reference background rates. Disclosures Ho: Jazz Pharmaceuticals: Consultancy. Keshelava:Jazz Pharmaceuticals: Employment, Equity Ownership. Swann:Jazz Pharmaceuticals: Employment, Equity Ownership. Tappe:Jazz Pharmaceuticals: Employment, Equity Ownership. OffLabel Disclosure: The abstract contains a description of off-label product use. Defibrotide is approved for treatment of hepatic VOD/SOS post-HCT (as described in the background) and this study is evaluating its use in patients with TA-TMA.

A Phase 1a/1b Trial of ST-001, a Fenretinide Phospholipid Suspension for 4-Hour Intravenous Infusion in Relapsed/Refractory T-Cell Non-Hodgkin's Lymphoma

A phase 1a/1b trial is planned for specific types of T-cell non-Hodgkin's lymphoma (T-NHL) using a new formulation of fenretinide for intravenous (IV) administration (ST-001, IND# 135475). Despite documented anticancer properties, clinical development of fenretinide has been hampered by poor bioavailability of the oral preparations and poor water solubility for IV infusion although some progress has been made. A phase 1 clinical trial of a 20% soy oil-in-water emulsion containing 2mg/mL of fenretinide, administered via 24-hour daily infusions x5 q3wks, demonstrated activity in mycosis fungoides /Sézary syndrome (MF/SS) and in angioimmunoblastic T-cell lymphoma (AITL) (Mohrbacher et al 2017). However, all doses exhibiting disease activity were associated with grade 4 hypertriglyceridemia. ST-001 from SciTech Development, LLC is a second generation, triglyceride-free, phospholipid-based nano-dispersion formulation of higher potency fenretinide (12.5mg/mL) suitable for IV infusion. The SciTech Delivery Vehicle (SDV) is composed of 4 clinically acceptable phospholipids (DPPC, DOPC, DMPC, and DMPG) which, in the presence of fenretinide, form lamellar bilayer structures <200nm in diameter. Pharmacokinetic (PK) studies showed that IV administration of ST-001 in the Sprague-Dawley rat model achieved fenretinide blood levels required for in vitro cytotoxicity to human cancer cell lines (including T- and B-NHL). The planned US multicenter phase 1a trial utilizes an Accelerated Titration (Simon) 4B design, with 100% dose escalation in single-patient cohorts until first instance of grade 3 or higher toxicity is encountered, at which point the trial reverts to a 'standard', 3 patient-cohort approach and 40% dose escalation. To maximize each patient's chance to be treated at a potentially active dose, intrapatient dose escalation is allowed for patients who remain on study and have no evidence of toxicity once the safety of the next dose level is established in a drug-naïve patient. The primary study objective is determining the maximum tolerated dose (MTD) of ST-001 in adult patients with T-NHL. Secondary objectives are to describe the toxicity profile of ST-001, observe and record anti-tumor activity of ST-001 in patients with T-NHL, describe the PK of ST-001 when given at the specified dose/schedule in this study, and evaluate potential mechanisms of action of ST-001 using pharmacodynamic (PD) biomarkers. Eligible patients will be 18 years or older with histologically confirmed diagnosis of MF/SS (stages IB-IV according to TNMB system), or Ann Arbor stage II-IV non-cutaneous peripheral T-cell NHL (PTCL), AITL, or follicular T-NHL (FTCL) as defined in the 2016 WHO classification of lymphoid malignancies. Patients must have received at least 2 prior systemic therapies, have good performance status, and acceptable organ function. The drug will be administered IV over 4 hours daily for 5 consecutive days as outpatient starting at a dose of 1.25mg/m2/day. Treatment will be repeated every 3 weeks for up to 8 cycles. Once MTD is determined, an expanded cohort (phase 1b) will be conducted at MTD for diseases that demonstrate efficacy signals in phase 1a; however, patients must have at least one measurable disease site to be eligible for 1b. Up to 44 patients are projected to be enrolled (24 for phase 1a, and 20 for 1b). All patients who receive at least one dose of ST-001 will be evaluated for safety and toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.03. Patients with at least one measurable site of disease and have received at least one full cycle (5-day infusion) of ST-001 are eligible for response evaluation. Descriptive statistics will be used for PK analysis to characterize the range, median and mean of calculated values of clearance, volume of distribution, and half-lives of distribution and elimination phases across all evaluable patients. PD analysis will use each patient's baseline value as the control and normalize PD values as % change from baseline. Effect of ST-001 on specific immune functions including cytokines and immune effector cell function will be evaluated at baseline and after therapy. It is anticipated that ST-001 will demonstrate activity in T-NHL in the absence of excipients that contribute to triglyceride elevations. Disclosures Kuzel: SciTech Development, LLC: Membership on an entity's Board of Directors or advisory committees. Parchment:SciTech Development, LLC: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Regional intra-arterial polychemotherapy to increase the effectiveness of conservative treatment of locally invasive oral squamous cell carcinoma

The objective is using a clinical example to demonstrate the possibilities of intra-arterial polychemotherapy (PCT) in the combined treatment of oral squamous cell carcinoma.Clinical case. A 43-year-old oral squamous cell carcinoma patient with metastases to cervical lymph nodes, left side (T3N2bM0, stage IV) underwent 2 courses of regional neoadjuvant intra-arterial PCT (docetaxel at a dose of 105 mg, cisplatin at a dose of 105 mg), accessed through a. lingualis. A total dose of 6,800 mg of 5-fluorouracil was administered as a 96-hour infusion. PCT induced oral mucositis of grade 2, no hematological side effects were observed. Clinical examination revealed that tumor volume decreased by 60 %. Ultrasound detected no changes in lymph nodes. Second step included resection of oral cavity bottom tissues, atypical tongue resection, marginal resection of the lower jaw on the left, radical neck dissection on the left. Histological study of the surgical material of primary tumor region as well as metastases of the cervical lymph nodes on the tumor side revealed pathomorphism of 4 grade. In the postoperative period, oral cavity and neck were irradiated from 2 sides. No signs of the disease were detected within 9 months after the combined treatment.Conclusion. The clinical case demonstrates the high efficiency of regional intra-arterial PCT in patients with locally invasive oral squamous cell carcinoma. It seems relevant to further study its possibilities in the combined treatment of locally invasive forms of oral squamous cell carcinoma.

1555. Risk of Developing Acute Kidney Injury in Patients Receiving Piperacillin–Tazobactam and Vancomycin Compared with Those on Piperacillin–Tazobactam and Telavancin

BackgroundThe combination of piperacillin–tazobactam (PIP-TAZO) and vancomycin is associated with an increased frequency of acute kidney injury (AKI) in patients when compared with either agent alone. Like vancomycin, telavancin is also used for gram-positive infections and has been reported to cause AKI, but there is a paucity of data regarding the development of AKI with the combination of PIP-TAZO and telavancin. The purpose of this study was to compare the incidence of AKI in patients receiving PIP-TAZO with concomitant vancomycin or telavancin.MethodsThis retrospective cohort study included patients admitted between November 2016 and March 2019 who received at least 2 days of either vancomycin or telavancin in combination with PIP-TAZO. Patients were excluded if they had a baseline calculated creatinine clearance of less than 20 milliliters per minute or were receiving renal replacement therapy. Any cases of AKI were defined as a serum creatinine increase of 0.3 milligrams per deciliter (mg/dL) or an increase in creatinine of 1.5 times baseline when observed within 7 days of the studied antibiotic combinations. Statistical analysis was performed to compare baseline characteristics and the development of AKI between the two groups.ResultsNinety-four patients with an average age of 55 years met the inclusion criteria. Forty-seven patients were included in both treatment arms. There were no statistically significant differences observed between study group baseline characteristics. All patients received PIP-TAZO 3.375 grams every 8 hours as a 4-hour infusion and the average telavancin dose was 7.5 mg/kg. Seventeen of 94 (18%) patients developed AKI, 8(17%) in the vancomycin and PIP-TAZO group and 9 (19%) in the telavancin and PIP-TAZO group (P = 1.0). No patients required dialysis.ConclusionThe development of AKI appears to be similar when comparing vancomycin and PIP-TAZO to telavancin and PIP-TAZO in our population. It is noteworthy that PIP-TAZO was given as an extended infusion and telavancin dosing was lower than the manufacturer recommendations in this evaluation. Additional studies are warranted to further examine the occurrence of AKI with these antibiotic combinations.Disclosures All authors: No reported disclosures.

2280. Bloodstream Klebsiella pneumonia Infection and Carbapenem Combination Treatment Regimen in High-Dose Vasopressor-Dependent Septic Shock

BackgroundThe clinical effectiveness of the double-carbapenem combination therapy in mechanically ventilated patients with carbapenemase-producing carbapenem-resistant Enterobacteriaceae bloodstream septic shock infection is not well studied.MethodsOver a 4-year period (2013–2017), critically ill with high-dose vasopressor-dependent septic shock patients due to infections from Enterobacteriaceae were included in a single-center retrospective study. The clinical presentation of septic shock was defined in accordance with the international guidelines. Clinical characteristics and the presence of clinical success by the 3rd-day of treatment and 28-day outcome were evaluated. Clinical success was defined as the complete elimination of the vasopressors along with the absence of bacteria regrowth in blood cultures of Enterobacteriaceae. The combination therapy consisted of 1-hour ertapenem (1 g/day) infusion followed immediately by meropenem (6 g/day) in a prolonged 3-hour infusion. The therapeutic regimen was also included gentamicin (7 mg/kg) once daily for 3 total days because of the severity of shock.ResultsA total of 16 ICU patients with bloodstream infection causing septic shock included in the study. The bacterial strain of Enterobacteriaceae was exclusive of Klebsiella pneumonia isolated after the second week of ICU admission. Antibiotic resistance profile was carbapenem 16/16 (100%), colistin 16/16 (100%), tigecycline 14/16 (87%) aminoglycosides 10/16 (62.5%). Patients were comparable in terms of age, comorbidities, APACHE II score, and presence of concomitant ventilator-associated pneumonia. Klebsiella pneumonia bloodstream infection was catheter-related in 5/16 (31%), and the source was not identified in 11/16 (69%). Overall, complete microbiological eradication of Klebsiella pneumonia regrowth in blood cultures performed 72 h after therapy was observed in 14/16 (87%) patients, and complete shock resolution in 12/16 (75%). Death at day 28 occurred in 5/16 (31%) patients attributable to multiple organ failure.ConclusionThe double-carbapenem regimen in critically ill patients suffering high-dose vasopressor-dependent septic shock due to bloodstream infections from Klebsiella pneumonia is an effective therapeutic option.Disclosures All authors: No reported disclosures.

LB3. Exebacase (EXE) Reduced Length of Stay and 30-Day Readmission Rates for US Patients with Methicillin-Resistant Staphylococcus aureus (MRSA) Bacteremia Including Endocarditis Compared with Standard of Care Antibiotics (SoC) Alone in a Phase 2 Study

BackgroundExebacase, a lysin (cell wall hydrolase), is the first direct lytic agent to report Phase 2 study results in Staphylococcus aureus bacteremia including endocarditis. Among MRSA patients enrolled in this randomized, double-blind, placebo, controlled study, EXE used in addition to standard of care antibiotics (SoC), had 42.8% higher clinical responder rates (CRRs) compared SoC alone. We sought to determine whether these differences in CRRs translated into reductions in health resource utilization (HRU) in this population of critically ill, hospitalized patients.MethodsThe microbiological intent-to-treat population included 116 patients (71 EXE, 45 SoC) with documented S. aureus who received a single 2-hour infusion of blinded study drug dosed based on target attainment. The primary efficacy endpoint was CRR at Day 14. Diagnoses and clinical outcomes were determined by a blinded Adjudication Committee. HRU including length of stay (LOS), and 30-day hospital readmission rates (HRR) for all causes (AC) and for S. aureus (SA) were evaluated in MRSA patients who were alive at the time of discharge.ResultsThe average patient was white, male and ~56 years old (67.8%). Twenty-seven EXe patients (38.0%) and 16 SoC patients (35.6%) had MRSA. All but 2 MRSA patients (1 EXE, 1 SoC) were enrolled in the United States. The Day 14 CRR were 70.4% for EXE and 60.0% for SoC groups (p=0.314) overall. In a prespecified analysis of MRSA patients, the CRR with EXE was 74.1% vs. 31.3% with SoC (P = 0.010). Among MRSA patients who received study drug, incidence of treatment emergent adverse events (TEAEs) was balanced between groups (24 (88.9%) in EXE and 15 (98.3%) in SoC) as were serious TEAEs (17(63.0%) in EXE, 12 (75%) in SoC). 1 EXE and 2 SoC US MRSA patients died in hospital. Among US MRSA patients discharged alive from the hospital, the median LOS after study drug was 6 vs. 10 days for EXE and SoC, respectively. Thirty-day AC HRR were 16% vs. 30.8%, for EXE vs. SoC, respectively, and 30-day SA HRR were 8% vs. 15.4%, respectively.ConclusionsExebacase used in addition to SoC was associated with a reduction in length of hospital stay and 30-day readmission rates for all causes and for S. aureus compared with SoC alone in patients being treated for MRSA bacteremia/endocarditis.DisclosuresCara Cassino, MD, ContraFect Corporation (Employee), Hemal Shah, PharmD, Boehringer Ingelheim (Consultant), ContraFect Corp (Consultant), DBV Technologies (Consultant), Mylan specialty (Consultant), Nabriva (Consultant), Joy Lipka-Diamond, MS, ContraFect Corporation (Consultant), Anita F. Das, PhD, Achaogen (Consultant), AntiobioTx (Consultant), Boston Pharmaceuticals (Consultant), Cempra (Consultant), ContraFect Corporation (Consultant), Iterum Therapeutics (Consultant), Nabriva (Consultant), Paratek (Consultant), Tetraphase (Consultant), UTILITY (Consultant), Wockhardt (Consultant).

Pharmacokinetics and Pharmacodynamics of Extended-Infusion Cefepime in Critically Ill Patients Receiving Continuous Renal Replacement Therapy: A Prospective, Open-Label Study.

To evaluate extended-infusion (EI) cefepime pharmacokinetics (PK) and pharmacodynamic target attainment in critically ill patients receiving continuous venovenous hemofiltration (CVVH) or continuous venovenous hemodialysis (CVVHD). Prospective, open-label, PK study. Intensive care units at a large, academic, tertiary-care medical center. Ten critically ill adults who were receiving cefepime 2g intravenously every 8hours as a 4-hour infusion while receiving CVVH (eight patients) or CVVHD (two patients). Two sets of five serum cefepime concentrations were collected for each patient to assess pharmacokinetics before and during presumed steady state. Concurrent serum and CRRT effluent samples were collected at hours 1, 2, 3, 4, and 8 after the first cefepime dose and after either the fourth, fifth, or sixth (steady-state) cefepime doses. Reversed-phase high-performance liquid chromatography was used to determine free cefepime concentrations. PK analyses included CRRT clearance, half-life, and sieving coefficient or saturation coefficient. Cefepime peak (4 hrs) concentrations, trough (8 hrs) concentrations (Cmin ), and minimum inhibitory concentration breakpoint of 8µg/ml for the pathogen (MIC8 ) were used to evaluate attainment of pharmacodynamic targets: 100% of the dosing interval that free drug remains above MIC8 (100% fT>MIC8 ), 100% fT>4×MIC8 (optimal), percentage of time fT>4×MIC8 (%fT>4×MIC8 ) at steady state, and ratio of Cmin to MIC8 (fCmin /MIC8 ). Total CRRT effluent flow rate was a mean±SD of 30.1±5.4ml/kg/hr, CRRT clearance was 39.6±9.9ml/min, and half-life was 5.3±1.7hours. Sieving coefficient or saturation coefficient were 0.83±0.13 and 0.69±0.22, respectively. First and steady-state dose Cmin were 23.4±10.1µg/ml and 45.2±14.6µg/ml, respectively. All patients achieved 100% fT>MIC8 on first and steady-state doses. First and steady-state dose 100% fT>4×MIC8 were achieved in 22% (2/9 patients) and 87.5% (7/8 patients) of patients, respectively. The mean %fT>4×MIC8 at steady state was 97.5%. The fCmin /MIC8 was 2.92±1.26 for the first dose and 5.65±1.83 at steady state. Extended-infusion cefepime dosing in critically ill patients receiving CRRT successfully attained 100% fT>MIC8 in all patients and an appropriate fCmin /MIC8 for both first and steady-state doses. All but one patient achieved 100% fT>4×MIC8 at steady state. No significant differences were observed in PK properties between first and steady-state doses among or between patients. It may be reasonable to initiate an empiric or definitive regimen of EI cefepime in critically ill patients receiving concurrent CRRT who are at risk for resistant organisms. Further research is needed to identify the optimal dosing regimen of EI cefepime in this patient population.

685TiP - A phase II basket study of MCLA-128, a bispecific antibody targeting the HER3 pathway, in NRG1 fusion-positive advanced solid tumours

685TiP - A phase II basket study of MCLA-128, a bispecific antibody targeting the HER3 pathway, in NRG1 fusion-positive advanced solid tumours

716P - FOLFOXIRI versus FOLFIRINOX in first-line chemotherapy in patients with advanced pancreatic cancer: A propensity score analysis

BackgroundAdvanced pancreatic ductal adenocarcinoma (aPDAC) remains a challenging, non-curable disease. FOLFIRINOX regimen is the standard in first-line chemotherapy (L1) in this setting. FOLFOXIRI, a similar schedule with a lower dose of irinotecan and no bolus 5-fluorouracil, has demonstrated efficacy and good tolerance in metastatic colorectal cancer. We aimed to compare clinical outcomes of this two regimens in patients with aPDAC in routine clinical practice. MethodsAnalyses were derived from all consecutive aPDAC patients treated in L1, between 2011 and 2017 in two French institutions, with FOLFOXIRI (n=165) or standard (n=124) regimens. FOLFOXIRI consisted of irinotecan (165mg/m2), oxaliplatin (85mg/m2), leucovorin (200mg/m2) and 5-fluorouracil (3200mg/m2 as a 48-hour continuous infusion) every two weeks. One hundred pairs of patients were selected through propensity score matching (PSM) analysis and clinical outcomes of the two treatments were compared. ResultsAfter a median follow up of 44.1 months, median overall survival (OS) was 11.1 months (95% confidence interval [CI], 9.8 to 13.1) in the FOLFOXIRI group and 11.6 months (95% CI, 10.8 to 15.5) in the FOLFIRINOX group. Median progression free survival (PFS) was 5.8 months (95% CI, 3.9 to 6.9) in the FOLFOXIRI group and 6.7 months (95% CI, 6.0 to 7.7) in the FOLFIRINOX group. After PSM, the survival of patients remained similar between the two regimens in OS (hazard ratio [HR], 0.79; 95% CI, 0.58 to 1.08; P=0.137) and PFS (HR, 0.80; 95% CI, 0.60 to 1.08; P=0.139). The objective response rate was 33.3% in the FOLFOXIRI group versus 47.2% in the FOLFIRINOX group, while disease-control rates were 62.8% and 75.3%, respectively (P=0.129). The grade 3 or 4 toxicities were occurring in 29.0% of patients in FOLFOXIRI group versus 21.3% in FOLFIRINOX group (P=0.216). FOLFOXIRI was associated with a higher incidence of grade 3 or 4 digestive adverse events compared to FOLFIRINOX group (11.0% versus 5.0%, respectively) but was similar to the safety profile of FOLFIRINOX previously reported in the PRODIGE 4/ACCORD 11 trial. ConclusionsFOLFOXIRI is feasible in L1 in patients with aPDAC but does not confer any therapeutic benefit as compared with FOLFIRINOX regimen. Legal entity responsible for the studyBesançon University Hospital. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure

Experimental data suggest that intravenous vitamin C may attenuate inflammation and vascular injury associated with sepsis and acute respiratory distress syndrome (ARDS). To determine the effect of intravenous vitamin C infusion on organ failure scores and biological markers of inflammation and vascular injury in patients with sepsis and ARDS. The CITRIS-ALI trial was a randomized, double-blind, placebo-controlled, multicenter trial conducted in 7 medical intensive care units in the United States, enrolling patients (N = 167) with sepsis and ARDS present for less than 24 hours. The study was conducted from September 2014 to November 2017, and final follow-up was January 2018. Patients were randomly assigned to receive intravenous infusion of vitamin C (50 mg/kg in dextrose 5% in water, n = 84) or placebo (dextrose 5% in water only, n = 83) every 6 hours for 96 hours. The primary outcomes were change in organ failure as assessed by a modified Sequential Organ Failure Assessment score (range, 0-20, with higher scores indicating more dysfunction) from baseline to 96 hours, and plasma biomarkers of inflammation (C-reactive protein levels) and vascular injury (thrombomodulin levels) measured at 0, 48, 96, and 168 hours. Among 167 randomized patients (mean [SD] age, 54.8 years [16.7]; 90 men [54%]), 103 (62%) completed the study to day 60. There were no significant differences between the vitamin C and placebo groups in the primary end points of change in mean modified Sequential Organ Failure Assessment score from baseline to 96 hours (from 9.8 to 6.8 in the vitamin C group [3 points] and from 10.3 to 6.8 in the placebo group [3.5 points]; difference, -0.10; 95% CI, -1.23 to 1.03; P = .86) or in C-reactive protein levels (54.1 vs 46.1 μg/mL; difference, 7.94 μg/mL; 95% CI, -8.2 to 24.11; P = .33) and thrombomodulin levels (14.5 vs 13.8 ng/mL; difference, 0.69 ng/mL; 95% CI, -2.8 to 4.2; P = .70) at 168 hours. In this preliminary study of patients with sepsis and ARDS, a 96-hour infusion of vitamin C compared with placebo did not significantly improve organ dysfunction scores or alter markers of inflammation and vascular injury. Further research is needed to evaluate the potential role of vitamin C for other outcomes in sepsis and ARDS. ClinicalTrials.gov Identifier: NCT02106975.

Safety and efficacy of trabectedin when administered in the inpatient versus outpatient setting: Clinical considerations for outpatient administration of trabectedin.

BackgroundThe results of the randomized, phase 3 ET743‐SAR‐3007 trial demonstrated that trabectedin had a significantly longer progression‐free survival (PFS) compared with dacarbazine in patients with advanced leiomyosarcoma/liposarcoma after the failure of prior chemotherapy. Patients randomized to trabectedin received a 24‐hour intravenous infusion either in an inpatient or outpatient setting. Herein, the authors reported the safety, efficacy, and patient‐reported outcomes based on first infusion site of care.MethodsPatients were randomized 2:1 to trabectedin (at a dose of 1.5 mg/m2) or dacarbazine (1 g/m2 over 20‐120 minutes) with overall survival (OS) as the primary endpoint and PFS, time to disease progression, objective response rate, duration of response, safety, and patient‐reported symptom scoring as secondary endpoints. The setting of the trabectedin infusion was based on institutional preference and categorized based on the setting of the first infusion.ResultsOf the 378 patients who were treated with trabectedin, 100 (27%) and 277 (73%), respectively, first received trabectedin in the inpatient and outpatient setting. No differences were observed with regard to PFS or OS based on site of care. The median PFS was 4.1 months versus 4.2 months (hazard ratio, 0.90; P = .49) for inpatients versus outpatients, respectively, and the median OS was 14.3 months versus 13.7 months (hazard ratio, 0.89; P = .40), respectively. Grade 3/4 adverse events (classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]) were reported in 87 inpatients (87%) compared with 219 outpatients (79%); grade 3/4 serious adverse events were reported in 43 inpatients (43%) and 92 outpatients (33%). Extravasation occurred in 0 inpatients and 5 outpatients (2%), whereas the incidence of catheter‐related complications was similar between groups (16% vs 15%).ConclusionsAlthough the majority of patients who were randomized to trabectedin received outpatient therapy, the outcomes of the current study suggested equivalent safety and efficacy in either setting.

STUDY OF VEGF-A AND TGF-Β LEVELS IN BIOPTATES OF SQUAMOUS CELL CARCINOMA OF THE TONGUE AND MOUTH FLOOR MUCOSA IN POLYCHEMOTHERAPY WITH MONOCLONAL ANTIBODIES – CETUXIMAB

Aim. Study of VEGF-A and TGF-β growth factors in tumor tissue bioptates in patients with squamous cell carcinoma of the tongue and floor of the oral cavity depending on the effectiveness of polychemotherapy targeted therapy with cetuximab. Patients and methods. The study included 30 patients with squamous cell carcinoma of the tongue and mouth floor mucosa (T3-4N0-1M0). All patients received 2 cycles of therapy: cisplatin 100 mg/m2 , intravenously, day 1, 5-fluorouracil 1000 mg/m2 /day, intravenously, 96-hour continuous infusion in combination with targeted therapy (cetuximab 400 mg/ m2 on day 1 in a loading dose, then 250 mg/m2 on days 8 and 15). Patients were divided into two subgroups: target sensitivity of patients (partial regression and stabilization) n = 17 and target resistance (progression) n = 13. Levels of growth factors VEGF-A and TGF-β were determined in tumor tissue bioptates by ELISA using standard test systems (Bender Med System, Austria). Statistical processing of results was performed using the Statistica 6.0 program (Stat-Soft, 2001). Results. Polychemotherapy with cetuximab in some patients (n = 13), antitumor therapy with cetuximab did not result in statistically significant changes in levels of VEGF-A, TGF-β and the VEGF-A/TGF-β ratio compared to the initial values. In other patients (n = 17), the studied markers in tumor tissue bioptates were statistically significantly different from the initial values: VEGF-A was decreased by 1.46 times, TGF-β by 2.96 times, while the VEGF-A/TGF-β ratio was twice elevated. Conclusions. The results on levels of growth factors VEGF-A and TGF-β, as well as the VEGF-A/TGF-β ratio, are of a certain prognostic value and can be used as criteria for evaluating the efficacy of antitumor therapy in patients with squamous cell carcinoma of the tongue and mouth floor mucosa.