Starting Dose Research Articles

Fluoropyrimidine chemotherapy: recommendations for DPYD genotyping and therapeutic drug monitoring of the Swiss Group of Pharmacogenomics and Personalised Therapy.

Fluoropyrimidines (FPs), mainly 5-fluorouracil (5-FU) and its oral prodrug capecitabine (Cap), remain the backbone of the treatment of many different solid tumors. Despite their broad use in clinical routine, 10–40% of patients experience severe, and in rare cases (0.2–0.5%) even lethal, FP-related toxicity in early chemotherapy cycles. Today, there is a plethora of evidence that genetic variants in the gene encoding for the 5-FU catabolising enzyme dihydropyrimidine dehydrogenase (DPD, encoded by DPYD) are predictive of severe FP-related toxicities, and international clinical practice recommendations for DPYD genotype-guided FP dosing and therapeutic drug monitoring (TDM) are available. In spite of this strong evidence and DPYD genotyping becoming standard practice in other countries, it is has not been widely adopted in Switzerland to date. Here, we discuss current guidelines on genotype-guided FP dosing and TDM, and propose recommendations tailored to the situation in Switzerland to facilitate their clinical uptake for the further individualisation of FP chemotherapy. We recommend preemptive testing of four DPYD variants (c.1905+1G>A (rs3918290), c.1679T>G (rs55886062), c.2846A>T (rs67376798) and c.1129-5923C>G (rs75017182, c.1236G>A/HapB3)) in patients with an indication for FP-based chemotherapy, with the costs reimbursed through the compulsory health insurance in Switzerland. Carriers of these variants (6.5% in the Swiss population) have a 40–50% risk of developing severe early-onset toxicity when treated with standard FP doses. In these patients, we therefore recommend the use of a reduced starting dose, based on a dose adjustment scheme provided herein. Furthermore, we recommend the use of infusional 5-FU in patients with a DPYD risk genotype in order to enable TDM-based dose escalation. Only if the use of an infusional 5-FU regimen is not feasible should a slow titration of Cap, starting with the recommended reduced dose and basing further doses on monitoring of toxicity, be considered. Given that several studies have shown that TDM in 5-FU treatment improves not only the therapy’s safety, but potentially also its efficacy, we also include detailed TDM-based dosing guidelines and discuss the pre-analytical aspects of 5-FU TDM.

Outcome By Mutation Status and Line of Treatment in Optic, a Dose-Ranging Study of 3 Starting Doses of Ponatinib in Patients with CP-CML

Outcome By Mutation Status and Line of Treatment in Optic, a Dose-Ranging Study of 3 Starting Doses of Ponatinib in Patients with CP-CML

Efficacy and Safety of Ponatinib (PON) in Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML) Who Failed One or More Second-Generation (2G) Tyrosine Kinase Inhibitors (TKIs): Analyses Based on PACE and Optic

Efficacy and Safety of Ponatinib (PON) in Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML) Who Failed One or More Second-Generation (2G) Tyrosine Kinase Inhibitors (TKIs): Analyses Based on PACE and Optic

Oral Roxadustat Demonstrates Efficacy in Anemia Secondary to Lower-Risk Myelodysplastic Syndrome Irrespective of Ring Sideroblasts and Baseline Erythropoietin Levels

Background: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates iron metabolism. In Phase 3 trials, roxadustat increased hemoglobin (Hb) levels and reduced the number of red blood cell (RBC) transfusions vs placebo in patients with anemia of non-dialysis-dependent chronic kidney disease (CKD). In anemia of dialysis-dependent CKD, roxadustat achieved greater mean Hb increase vs epoetin alfa, and reduced IV iron use and RBC transfusions (Coyne, et al. Poster SA-0228 American Society of Nephrology (ASN) 2019; Charytan, et al. Poster SA-0227 ASN 2019) Low-risk myelodysplastic syndrome (LR-MDS), characterized by symptomatic anemia, is treated with RBC transfusion, erythropoiesis-stimulation agents (ESAs), or luspatercept. Suboptimal response and response durability across MDS subpopulations demonstrates an unmet medical need in LR-MDS. We report a 52-week update of the open-label (OL) phase of a study of roxadustat in anemia in primary MDS patients that determined the starting dose of the ongoing double-blind study phase (NCT03263091). Methods: The OL phase (N=24) used 3 sequential dose cohorts (1.5, 2.0, and 2.5 mg/kg) thrice weekly (TIW). Eligible patients had very low- to intermediate-risk primary MDS patients per International Prognostic Scoring System-Revised classification, with < 5% bone marrow blasts; baseline Hb < 10.0 g/dL; had low transfusion burden, defined as receiving 1-4 RBC units within 8 weeks before randomization; endogenous EPO levels ≤ 400 mIU/mL; and no 5q(del) cytogenetic abnormality. Red blood cell transfusion was allowed per institutional criteria. Roxadustat doses were titrated every 8 weeks based on Hb response and RBC transfusions. The primary endpoint was transfusion independence (TI) for ≥ 56 consecutive days during the first 28 treatment weeks; follow-up was at 52 weeks. Secondary endpoints included TI ≥ 56 consecutive days anytime during the study, proportion of patients who achieved ≥ 50% reduction in number of RBC transfusion over any 8 weeks vs baseline (BL), cumulative number of patient-exposure-week of TI, cumulative number of pRBC packs transfused, proportion of patients who achieved TI for > 20 weeks. Safety was assessed via adverse events monitoring and patients (%) who progressed to acute myeloid leukemia (AML). Patients with and without ring sideroblasts (RS+/RS-) and BL EPO ≤ 200 mIU/ml and > 200 mIU/ml were assessed for the primary endpoint. Results: In the OL phase, 24 transfusion-dependent LR-MDS patients were enrolled in 3 starting dose cohorts (Table). Nine patients (38%) achieved TI for ≥ 56 consecutive days within the first 28 and 52 weeks, 3 in cohort 1 (1.5 mg/kg), 1 in cohort 2 (2.0 mg/kg), and 5 in cohort 3 (2.5 mg/kg). When TI was achieved, 78% were receiving 2.5 mg/kg dose, 11% were receiving 2.0 mg/kg dose (started with 1.5 mg/kg) and 11% were receiving 1.5 mg/kg. Four patients (16.7%) remained TI for > 20 weeks (1 at 1.5 mg/kg dose level and 3 at 2.5 mg/kg dose-level) at 52 weeks. The 50% reduction in number of transfusion compared with BL occurred in 13 patients (54.2%) at 28 weeks and 14 (58.3%) at 52 weeks. In patients with TI duration ≥ 56 days (n = 9), the mean (SD) TI duration was 182.9 (153.66) days. In patients with TI duration ≥ 140 days (n = 4), the mean (SD) TI duration was 324.5 (121.22) days. Subgroups met the primary endpoint at week 28 (23.1% and 54.5% MDS-RS+ and -RS-, respectively, and 38.9% and 33.3% BL EPO ≤ 200 mIU/ml and > 200 mIU/ml, respectively); all subgroups maintained TI response to week 52. The overall safety profile was consistent with this patient population. Eight patients reported 8 treatment-emergent serious AEs; none were fatal. No patient progressed to AML. Conclusion: In this 52-week update, roxadustat 2.5 mg/kg TIW was effective in LR-MDS patients, based on observed response (TI and transfusion reduction), safety profile, and durable 52-week response. The ongoing, 156-patient, double-blind study phase uses a 2.5 mg/kg starting dose. Preliminary data in OL subgroups RS-/RS + and BL EPO ≤ 200 mIU/ml and >200 mIU/ml suggest roxadustat may be effective in these subgroups. These data await confirmation in the ongoing double-blind, placebo-controlled study. Table 1 Disclosures Carraway: Abbvie: Other: Independent Advisory Committe (IRC); ASTEX: Other: Independent Advisory Committe (IRC); Takeda: Other: Independent Advisory Committe (IRC); Stemline: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; BMS: Consultancy, Other: Research support, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Bradley:FibroGen, Inc.: Current Employment. Saha:FibroGen, Inc.: Current Employment. Bartels:FibroGen, Inc.: Current Employment. Leong:FibroGen Inc.: Current Employment, Current equity holder in private company. Yu:FibroGen, Inc.: Current Employment.

The Effect of Crizanlizumab on the Number of Days Requiring Opioid Use for Management of Pain Associated with Vaso-Occlusive Crises in Patients with Sickle Cell Disease: Results from the Sustain Trial

The Effect of Crizanlizumab on the Number of Days Requiring Opioid Use for Management of Pain Associated with Vaso-Occlusive Crises in Patients with Sickle Cell Disease: Results from the Sustain Trial

Efficacy and safety of beta-blockers and prolonged bronchodilators in patients with heart failure with coronary artery disease and moderate to severe COPD

Abstract Purpose To compare clinical efficacy and safety of various treatment regimens with the inclusion of beta-blockers, RAAS antagonists (ACE inhibitors or ARBs), prolonged bronchodilators (LABA, LAMA) in heart failure patients with CAD and COPD. Methods 385 patients (292 men and 93 women), aged 66.3±4.1 years, with CHF classes II to III (NYHA) combined with moderate to severe COPD (GOLD) and with LVEF less than 45% were randomized into nine groups: enalapril + LAMA (control group), nebivolol + enalapril + LAMA, nebivolol + losartan + LAMA, nebivolol + losartan + LABA, nebivolol + losartan + LAMA/LABA, carvedilol + enalapril + LAMA, carvedilol + losartan + LAMA, carvedilol + losartan + LABA, carvedilol + losartan + LAMA/LABA. Patients of all groups received complex CHF treatment comprising diuretics, nitrates, cardiac glycosides (if necessary). Clinical examination, TTE, 6-minute walk test (6MWT), 24-hour electrocardiogram and blood pressure monitoring, respiratory function test were assessed at baseline and after 6 months of treatment. The quality of life was evaluated by MYHFQ, SGRQ and mMRC scale. Results After 6 months of therapy the improvement of clinical condition and quality of life were marked in all groups. At the end of observation period there was a significant improvement of patients clinical condition, quality of life, reduction of mean CHF FC and dyspnea severity, increase of exercise tolerance, slowing of progression of CHF and COPD, improvement of the parameters of intracardiac hemodynamics, structural and functional parameters of the left and right heart (a decrease in the size of the atria, LV volumes and internal dimension at end-diastole and end-systole, cardiac index, LVMMI, an increase of LVEF, a significant decrease in systemic vascular resistance and the pulmonary hypertension grade, significant improvement in systolic and diastolic function of the ventricles, regression of pathological remodeling of the heart, reduction of heart rate, duration and frequency of myocardial ischemia episodes (including its “silent” form). The best results were obtained in groups using a beta-blocker (nebivolol or carvedilol), a RAAS antagonist, and a combination of long-acting bronchodilators (indacaterol and tiotropium) – group 5 and 9. It is worth noting that beta-blockers, LABA and LAMA were well tolerated in all observation groups and serious adverse events were absent. Conclusions The appointment of 3-generation beta-blockers to patients with CHF on the background of CAD and COPD can significantly increase the effectiveness of treatment and does not cause a deterioration in spirometry in patients with such cardiopulmonary pathology. In our opinion, the most important point in the appointment of beta blockers to patients with moderate to severe COPD is low start dose and slow titration of the dose at the beginning of the therapy. It is advisable to include in the complex therapy of such patients a combination of LABA and LAMA as a basic bronchodilator support. Funding Acknowledgement Type of funding source: None

Impact of age on sorafenib outcomes in hepatocellular carcinoma: an international cohort study

BackgroundThere is no consensus on the effect of sorafenib dosing on efficacy and toxicity in elderly patients with hepatocellular carcinoma (HCC). Older patients are often empirically started on low-dose therapy with the aim to avoid toxicities while maximising clinical efficacy. We aimed to verify whether age impacts on overall survival (OS) and whether a reduced starting dose impacts on OS or toxicity experienced by the elderly.MethodsIn an international, multicentre cohort study, outcomes for those aged <75 or ≥75 years were determined while accounting for common prognostic factors and demographic characteristics in univariable and multivariable models.ResultsFive thousand five hundred and ninety-eight patients were recruited; 792 (14.1%) were aged ≥75 years. The elderly were more likely to have larger tumours (>7 cm) (39 vs 33%, p < 0.01) with preserved liver function (67 vs 57.7%) (p < 0.01). No difference in the median OS of those aged ≥75 years and <75 was noted (7.3 months vs 7.2 months; HR 1.00 (95% CI 0.93–1.08), p = 0.97). There was no relationship between starting dose of sorafenib 800 mg vs 400 mg/200 mg and OS between those <75 and ≥75 years. The elderly experienced a similar overall incidence of grade 2–4 sorafenib-related toxicity compared to <75 years (63.5 vs 56.7%, p = 0.11). However, the elderly were more likely to discontinue sorafenib due to toxicity (27.0 vs 21.6%, p < 0.01). This did not vary between different starting doses of sorafenib.ConclusionsClinical outcomes in the elderly is equivalent to patients aged <75 years, independent of dose of sorafenib prescribed.

An Evaluation of Continuous Infusion Rocuronium for Sustained Neuromuscular Blockade in Critically Ill Adults.

Recent medication shortages of the neuromuscular blocking agent (NMBA) cisatracurium have forced the prescribing of aminosteroidal agents such as rocuronium. There are limited data on the use and dosing of continuous infusion (CI) rocuronium in critically ill patients outside of the operating room. We sought to describe the use of CI rocuronium for sustained neuromuscular blockade in intensive care unit (ICU) patients by characterizing the dosing, utilization, and safety profile in patients with multiple organ failure (MOF) and non-MOF. This was a retrospective review of patients in mixed ICUs from 2 tertiary medical centers who received CI rocuronium between January 2018 and July 2019. A total of 46 unique rocuronium infusions were utilized for 40 patients during the evaluation period. Of these, 37% had MOF, and 41% had at least 1 organ fail during the rocuronium infusion. The median starting and maximum dose was 8 µg/kg/min. Overall, 64% of train of 4 (TOF) measurements were a TOF 0 (T0) or TOF 1 (T1), with a higher percentage of T0 or T1 in the MOF group compared with the non-MOF group (75% vs 50%). The median time to recovery was more than twice as long for the MOF compared with the non-MOF group (10 vs 4.6 hours). ICU-acquired weakness was diagnosed in 27% of survivors. In ICU patients with MOF, continuous rocuronium infusions were associated with deep levels of paralysis and prolonged recovery times. If neuromuscular blockade is required for critically ill patients, alternative strategies could be considered.

Systematic review of recommendations on the use of methotrexate in rheumatoid arthritis.

Most recommendations for the use of methotrexate (MTX) in rheumatoid arthritis (RA) are issued by developed countries. It is unknown whether they are relevant globally. We reviewed existing recommendations on the use of MTX for the treatment of RA and summarized areas of agreement that could be relevant for least developed countries (LDCs). Electronic databases and registries were searched for recommendations on MTX use in RA, duplicates were eliminated, and the most updated version adopted when there were several versions on the same recommendation. Reviewers used the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument for study quality assessment. Similarities and discrepancies of recommendations are reported. After deduplication, 1693 unique citations were found; 25 full texts were screened and 12 included in the narrative synthesis. Average scores for the AGREE II domains ranged from 33.3 to 83.3%. Recommendations targeted rheumatologists and health care providers involved in RA care. Most covered some but not all of the following areas: baseline "pre-MTX" assessment (7/12;58%), prescription of MTX (10/12;83.3%), management of MTX side effects (6/12;50%), and special considerations (e.g., peri-operative management) (8/12; 66.7%). Recommendations agreed on baseline tests prior to starting MTX, monitoring, and need for folic acid supplementation. These aspects can serve as the foundation for the development of MTX recommendations relevant to LDCs. Recommendations disagreed on the MTX starting dose, optimal route, titration, and intervals to monitor toxicity. Existing recommendations do not uniformly address all aspects related to the use of MTX and disagree in relevant aspects of MTX use. Adaptations to these recommendations are needed to facilitate their implementation in LDCs. Key Points • This paper summarizes current recommendations on the use of methotrexate for the treatment of rheumatoid arthritis. • Areas of agreement between recommendations include the following: pre-methotrexate patient assessment, need for folic acid supplementation, and toxicity monitoring. • Areas of disagreement relate to methotrexate starting and maximal dose, titration, and frequency of assessments.

1366P Efficacy and safety of apatinib plus EGFR-TKI in advanced non-small cell lung cancer with EGFR-TKI resistance (date updated)

Treatment failure frequently occurs in patients with EGFR-mutant non-small cell lung cancer (NSCLC) who respond to EGFR-TKI initially. Previous studies have shown that apatinib (a TKI against VEGFR-2) combined with EGFR-TKI might prevent progression of the disease. We conducted this trial to investigate the efficacy and safety of apatinib (a TKI against VEGFR-2) plus EGFR-TKIs (including erlotinib, gefitinib, icotinib, afatinib and osimertinib) compared with chemotherapy for EGFR-TKI resistant NSCLC patients. From Mar 2017 to Nov 2019, this study enrolled 42 advanced NSCLC patients who acquired resistance to the EGFR-TKI therapy. 27 patients received apatinib plus EGFR-TKI (apatinib in start dose of 250 mg plus original EGFR-TKI dose), 15 patients received chemotherapy (pemetrexed or vinorelbine with platinum). In the apatinib group, 24/27 patients were available evaluated. The objective response rate was 21% (5/24) and the disease control rate was 96% (24/27). The most common adverse events in the apatinib group were diarrhea (63%, 17/27), hypertension (63%, 17/27) and hand-foot syndrome (41%, 11/27). The most common grade 3 or 4 toxicity was proteinuria (11%, 3/27). Most of adverse events were grade 1 or 2, as well as controllable and tolerable. Six patients with brain metastases in the apatinib group got long median progressive-free survival (PFS) of 15.7 months. In the chemotherapy group, 12/15 patients were available evaluated. The objective response rate was 25% (3/12) and the disease control rate was 92% (11/12). No new adverse event occured. The median PFS of apatinib group was 10.5 months, and chemotherapy group was 4.5 months. The longest PFS in the apatinib group was 29.8 months. Apatinib plus EGFR-TKI shown a good clinical efficacy in patients with acquired EGFR-TKI (1st, 2nd or 3rd generation) resisitance. Patient's quality of life and the compliance of therapy had been increased by oral drugs. Besides, we found that patients’ PFS tended to be prolonged who with EGFR 21 mutation (15.7 months), or male (17 months).

DIFFERENTIAL OVARIAN RESPONSE TO GONADOTROPIN PREPARATIONS DESPITE SIMILAR OVARIAN RESERVE: MENOPUR IN GNRH (GONADOTROPIN RELEASING HORMONE) ANTAGONIST SINGLE EMBRYO TRANSFER - HIGH RESPONDER (MEGASET-HR) TRIAL ANALYSIS

Assess possible interactions between treatment group [highly-purified human menopausal gonadotropin (HP-hMG) or recombinant follicle stimulation hormone (r-FSH)] and ovarian reserve as indicated by baseline levels of anti-Müllerian Hormone (AMH) on the number of oocytes retrieved. Post-hoc analysis of a randomized, open-label, assessor-blind, non-inferiority trial conducted at 31 U.S. trials sites. 620 ovulatory women aged 21-35y with BMI 18-30 kg/m2 and serum anti-Müllerian hormone (AMH) ≥5 ng/mL were randomized 1:1 to a 150 IU start dose of HP-hMG (N=311) or rFSH (N=309) in a GnRH antagonist cycle with dose adjustments based upon response from day 6 onward. Human chorionic gonadotropin (hCG) was used to trigger oocyte maturation (GnRH agonist if at high risk of ovarian hyperstimulation syndrome [OHSS]). Central laboratory serum hormone measurements were measured at baseline and stimulation days: 6, day of/after trigger. Fresh transfer of a single blastocyst was performed in hCG-triggered cycles; all embryos were frozen if the risk of OHSS was high. Live births resulting from all fresh and any frozen transfers occurring within 6 months of randomization were collected. A normal regression model was used to explore interactions between treatment group and baseline AMH on the number of oocytes retrieved. Demographics across treatment arms were similar (mean patient age: 30 years for both; HP-hMG, rFSH mean [SD] BMI: 24.4 [3.3], 24.3 [3.4] kg/m2; AMH: 7.8 [3.6], 7.5 [2.4] ng/mL; antral follicle count: 30.5 [15.5], 31.0 [12.2]). The average number of oocytes per patient in the rFSH arm (22.2 [11.54]) was significantly higher than in the HP-hMG arm (15.1 [10.12]) as were serum estradiol levels at stimulation days 6 and trigger and OHSS rates, described previously.1 Cumulative live birth rates were similar between treatment groups at 51.5% and 50.6% in rFSH and HP-hMG arms respectively. A positive effect of baseline AMH levels on the number of oocytes retrieved was identified and differed statistically by treatment group (p value=0.032); subjects with higher baseline level of AMH had a larger ovarian response to rFSH versus HP-hMG. For every 1.6 ng/ml (11.1 pmol/L) increase in baseline AMH, rFSH stimulation results in one extra oocyte versus HP-hMG in predicted high-responders. Increasing baseline AMH was associated with higher oocyte yields but no difference in cumulative live birth rates in rFSH vs HP-hMG treated patients, with an accompanying increase in OHSS rates also observed in the rFSH arm. This unexpectedly exaggerated ovarian response, which is positively correlated with increasing ovarian reserve based upon the well-established biomarker AMH, highlights a key distinction between the gonadotropin preparations evaluated, creating opportunities for further optimization of stimulation.

Abstract 578: Pharmacokinetic proprieties of a locked nucleic acid oligonucleotide targeting miR-221

Abstract MiR-221 is overexpressed in several malignancies where it promotes tumor growth and survival by interfering with gene transcripts, including p27Kip1, PUMA, PTEN, and p57Kip2. We previously demonstrated that a novel 13-mer miR-221 inhibitor (LNA-i-miR-221) exerts antitumor activity against human cancer with a pilot favorable pharmacokinetics and safety profile in mice and non-naive monkeys. Next we performed and here report a non-GLP/GLP dose-finding investigation of LNA-i-miR-221 in Sprague Dawley rats. The safety of the intravenous dose (125 mg/kg/day) for four consecutive days, two treatment cycles, was investigated by a first non-GLP study. Toxicokinetics profile of LNA-i-miR-221 was next explored in a GLP study at three different doses (5, 12.5 and 125 mg/kg/day). Slight changes in blood parameters and histological findings in kidney were observed at the highest dose. These effects were reversible and consistent with in vivo ASO class effect. Based on these findings the NOAEL was established at 5 mg/kg/day. The plasma exposure of LNA-i-miR-221, based on C0 and AUC, suggested no differential sex effect. Slight accumulation occurred between cycles one and two but was not observed after four consecutive administrations. These findings demonstrate a safety profile of LNA-i-miR-221 in Sprague Dawley rats and provide a reference translational framework and path for the development of other LNA miR inhibitors in Phase I clinical study. In addition to understand the pharmacokinetics properties of this new agent, including unbound/total clearance, we investigated the LNA-i-miR-221 protein binding in three different species including rat (Sprague Dawley), monkey (Macaca fascicularis) and human. To this aim, we generated a suitable ultrafiltration method to study the binding of LNA-i-miR-221 to plasma proteins. We identified that the fraction of LNA-i-miR-221 (at concentration of 1 and 10 µM) bound to rat, monkey and human plasma proteins is high and ranges from 98.2 to 99.05%. This high protein binding of LNA-i-miR-221 to plasma proteins in all the species tested translates into a pharmacokinetic advantage by preventing rapid renal clearance. The integration of these results into multiple allometric interspecies scaling methods have been then used to draw inferences about LNA-i-miR-221 pharmacokinetics in humans, therefore providing a framework for definition of safe starting and escalation doses toward a first-in-human clinical trial of LNA-i-miR-221. This work was supported by the Italian Association for Cancer Research (AIRC), PI: PT. “Special Program Molecular Clinical Oncology - 5 per mille" n. 9980, 2010/15 and its Extension Program 2016/17 n.9980. Citation Format: Maria Teresa Di Martino. Pharmacokinetic proprieties of a locked nucleic acid oligonucleotide targeting miR-221 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 578.

How much synthetic oxytocin is infused during labour? A review and analysis of regimens used in 12 countries

To compare synthetic oxytocin infusion regimens used during labour, calculate the International Units (IU) escalation rate and total amount of IU infused over eight hours. Observational study. Twelve countries, eleven European and South Africa. National, regional or institutional-level regimens on oxytocin for induction and augmentation labour. Data on oxytocin IU dose, infusion fluid amount, start dose, escalation rate and maximum dose were collected. Values for each regimen were converted to IU in 1000ml diluent. One IU corresponded to 1.67μg for doses provided in grams/micrograms. IU hourly dose increase rates were based on escalation frequency. Cumulative doses and total IU amount infused were calculated by adding the dose administered for each previous hour. Main Outcome Measures Oxytocin IU dose infused. Data were obtained on 21 regimens used in 12 countries. Details on the start dose, escalation interval, escalation rate and maximum dose infused were available from 16 regimens. Starting rates varied from 0.06 IU/hour to 0.90 IU/hour, and the maximum dose rate varied from 0.90 IU/hour to 3.60 IU/hour. The total amount of IU oxytocin infused, estimated over eight hours, ranged from 2.38 IU to 27.00 IU, a variation of 24.62 IU and an 11-fold difference. Current variations in oxytocin regimens for induction and augmentation of labour are inexplicable. It is crucial that the appropriate minimum infusion regimen is administered because synthetic oxytocin is a potentially harmful medication with serious consequences for women and babies when inappropriately used. Estimating the total amount of oxytocin IU received by labouring women, alongside the institution's mode of birth and neonatal outcomes, may deepen our understanding and be the way forward to identifying the optimal infusion regimen.

Therapeutic effects of regorafenib after sorafenib monotherapy with advanced hepatocellular carcinoma including Child-Pugh classification B: A retrospective observational study.

The therapeutic effect of regorafenib was previously demonstrated in patients with advanced hepatocellular carcinoma (HCC) and Child–Pugh classification A (CP-A) whose disease progressed during sorafenib treatment in a phase III trial. However, treatment options are limited for patients with advanced HCC other than CP-A. In this study, we aimed to evaluate the therapeutic effect of regorafenib on advanced HCC patients including those with Child–Pugh classification B (CP-B).We retrospectively analyzed the medical records of 21 patients with advanced HCC who were treated with regorafenib after sorafenib monotherapy at our hospital from July 2017 to April 2018 and were followed up until September 2019. Patients were classified according to liver function and adverse events experienced during sorafenib treatment and were started on regorafenib with a pre-defined reduced starting dose along with a dose reduction and schedule change based on the judgement of the attending physician.At regorafenib initiation, 13 and 8 patients were classified as CP-A and CP-B, respectively. In all patients with CP-B, the starting dose of regorafenib was reduced, and the pre-defined starting-dose sets were applied to 17 (81%) patients. The median duration of regorafenib treatment in patients with CP-A and CP-B were 4.1 months and 2.0 months, respectively, with no significant difference. The median overall survival from regorafenib initiation (OS-r) and sorafenib initiation (OS-s) was 13.2 months and 30.9 months, respectively. In subgroup analysis, OS-r was 16.3 months in patients with CP-A and 10.1 months with CP-B with no significant difference (P = .44), whereas OS-r was 16.3 months in patients with modified albumin-bilirubin Grade 1/2a and 13.2 months in patients with Grade 2b, with no significant difference. There was no clear difference in the incidence rate of ≥grade 3 adverse events between CP-A and CP-B. OS-r and OS-s were significantly correlated.Even patients with impaired liver function achieved the desired therapeutic effects by safely reducing the starting dose of regorafenib according to both impaired liver function and adverse events during pretreatment. Regorafenib may be considered to be an effective treatment after sorafenib monotherapy in patients with impaired liver function.

Patients With Fibrotic Interstitial Lung Disease Receive Supportive and Palliative Care Just Prior to Death.

Fibrotic interstitial lung diseases (f-ILDs) are often progressive and incurable. As patients experience significant symptoms and have a poor prognosis, early palliative care referral is recommended. To examine the care delivered to patients with f-ILD during the terminal hospital admission and the past 2 years of life. A retrospective audit was performed for consecutive patients who died from f-ILD at 2 Australian teaching hospitals between January 1, 2012, and December 31, 2016. Of 67 patients, 44 (66%) had idiopathic pulmonary fibrosis. Median age was 78 years. Median respiratory function: forced expiratory volume in 1 second 69.0% predicted (interquartile range [IQR]: 58.0%-77.0%), forced vital capacity 64.0% predicted (IQR = 46.8%-74.3%), and diffusing capacity of carbon monoxide 36.0% predicted (IQR = 31.0%-44.0%). In the 2 years prior to the terminal admission, 38 (57%) patients reported severe breathlessness and 17 (25%) used opioids for symptom relief. Twenty-four (36%) patients received specialist palliative care (SPC) and 11 (16%) completed advance care planning. During the terminal admission, 10 (15%) patients were admitted directly under SPC. A further 33 (49%) patients were referred to SPC, on average 1 day prior to death. Sixty-three (94%) patients received opioids and 49 (73%) received benzodiazepines for symptom management. Median starting and final opioid doses were 10 and 23 mg oral morphine equivalent/24 hours, respectively. Opioids were commenced on average 2 (IQR 1-3) days prior to death. Although most patients were identified as actively dying in the final admission, referral to SPC and use of palliative medications occurred late. Additionally, few patients accessed symptom palliation earlier in their illness.

OP0024 USE OF HYDROXYCHLOROQUINE AND RISK OF HEART FAILURE IN PATIENTS WITH RHEUMATOID ARTHRITIS

Background:Hydroxychloroquine (HCQ) is a disease-modifying anti-rheumatic drug (DMARD) used as a long-term treatment for rheumatoid arthritis (RA) patients. Cardiotoxicity is a rare but potentially life-threatening side effect of HCQ and may present as conduction disorders, cardiomyopathy, and resulting heart failure (HF). The evidence of cardiotoxicity associated with the use of HCQ largely relies on case reports and case series while large cohort studies on the subject are lacking.Objectives:To examine the relationship between the use of HCQ and risk of developing HF in RA.Methods:In this nested case-control study, cases were Olmsted county, Minnesota residents with incident RA (based on 1987 ACR criteria) in 1980-2013 who developed HF after RA incidence. Each case was matched on year of birth, sex and year of RA incidence with an RA control who did not develop HF. Each non-HF control was assigned an index date corresponding to the HF diagnosis date of the case. Controls were allowed to later become cases to avoid bias. HF was defined using the Framingham criteria. Data on HCQ use including start and stop dates and dose changes was manually abstracted via medical record review, and used to calculate HCQ duration and cumulative dose. Age-adjusted logistic regression models were used to examine the association between HCQ and HF.Results:From a cohort of 1078 subjects, the study identified 143 RA cases diagnosed with HF (mean age 65.8, 62% females) and 143 non-HF RA controls (mean age 64.5, 62% female). Cases and controls had similar RA duration, proportion of patients positive for rheumatoid factor (RF) and/ or cyclic citrullinated antibody (CCP), body mass index, and smoking status (Table). The duration of HCQ use prior to the diagnosis of HF was 2.8 years in cases and 2.6 years in controls. A total of 71 cases and 69 controls used HCQ at some time before index date. Among these, the median (interquartile range) duration of HCQ use was 2.8 (0.6, 10.0) years for cases and 2.5 (0.7, 8.2) for controls. The median cumulative dose of HCQ was 371 g and 302 g in cases and controls, respectively, with 55% of cases receiving a cumulative dose of ≥ 300 g compared to 54% in controls. HCQ cumulative dose was not associated with HF (Odds Ratio [OR]: 0.96 per 100g increase in cumulative dose, 95% confidence interval [95% CI]: 0.90-1.03). Likewise, no association was found for patients with a cumulative dose ≥300g (OR 0.92, 95% CI 0.41-2.08). The duration of use of HCQ prior to index was not associated with HF (OR 0.98, 95% CI 0.91-1.05). Retinal toxicity rates were similar in cases and controls.Table 1.Characteristics of patients with rheumatoid arthritis with and without heart failure.VariableHFnon-HFAge at RA diagnosis (years)65.8 ± 12.364.5 ± 12.5Female62%62%RA duration at baseline (years)11.3 ± 8.510.3 ± 8.2RF positive66%65%CCP positive46%53%RF/ CCP positive68%66%BMI (at RA diagnosis)28.6 ± 6.527.7 ± 5.4Smoking status at RA incidenceFormer45%41%Current22%22%Conclusion:Use of HCQ was not associated with development of HF in patients with RA in this study. While there was no statistically significant association between the cumulative dose of HCQ and HF, the confidence interval for HCQ dose ≥300 g was wide suggesting that more studies are needed to understand the impact of higher doses of HCQ on development of HF in RA.Disclosure of Interests:Ahmed Sorour: None declared, Youssef Shahin: None declared, Cynthia S. Crowson Grant/research support from: Pfizer research grant, Reto Kurmann: None declared, Sara Achenbach: None declared, Rekha Mankad: None declared, Elena Myasoedova: None declared

Starting dose selection and dose escalation for oncology small molecule first-in-patient trials: Learnings from a survey of approved drugs.

e15648 Background: The ideal starting dose (SD) for an oncology first-in-patient (FIP) trial should be low enough to be safe but not too far removed from therapeutically relevant doses. A low SD combined with small dose increments could lead to a lengthy dose escalation (DE) and could expose patients unnecessarily to sub-therapeutic dosing. Over the past decade, the SD selection for oncology FIP trials was predominantly based on ICH S9 Guidance. This work attempts to assess the performance of current approaches in SD selection and DE methods for small molecule oncology drugs (SMOD), with an aim to identify potential opportunities for more efficient FIP DE methods and to minimize patients receiving sub-therapeutic dosing. Methods: A systematic review of the FIP trials of USFDA approved SMODs from 2010 to early 2019 was performed. The data sources included the FDA “USPI”, relevant “Summary basis of approval” documents, and published articles. The review focused on FIP trial data including the SD, DE design, the number of cohorts to the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D), and the number of subjects in each cohort. These data were analyzed to evaluate the efficiency and appropriateness of current approaches for FIP SD selection and DE. Results: Of 53 SMODs approved between 2010 and early 2019, ~ 65% were kinase inhibitors and ~74% were approved for solid tumor indications. All SMODs appeared to follow ICH S9 Guidance for SD selection and none of SMODs had more than doubling for dose increments in the escalation. The median MTD to SD ratio was 8 (1 to 125). A majority (57%) of the trials used a 3+3 design for DE and had a median of 4 cohorts (0 to 11) to reach MTD or RP2D from the SD. About 30% of the FIP trials had ≥ 6 DE to reach the MTD or RP2D, and in this subset, greater than 55% of the trial participants received subtherapeutic dosing. Conclusions: The ICH S9 Guidance-based SD and the DE methods for SMODs have generally performed well in most cases; the SD was well tolerated and the MTD or RP2D were achieved with reasonable efficiency. However, for a portion of SMODs the SD appeared to be too low or the DE was too conservative, suggesting opportunities for improvement to minimize the number of patients dosed at sub-therapeutic doses.

A single institution retrospective study of the effect of starting doses in patients with ER-positive metastatic breast cancer on CDK 4/6 inhibitors.

e13056 Background: CDK4/6 inhibitors (CDKi) have become part of standard of care in the treatment ER-positive, Her2Neu negative of metastatic breast cancer (MBC). Hematologic toxicity from CDKi are common which can lead to dose interruption or dose reduction. There is limited data to compare those who started on full dose and those who started on a reduced dose CDKi. We sought to investigate the impact of reduced starting dose of CDKis. Methods: We conducted a single institution retrospective study on patients (pts) who were treated with CDKi from 2015 to 2019. In this subgroup analysis, we sought to determine the percentage of pts that started on reduced dose CDKi. Pts who were started on reduced dose were compared to those started on standard FDA dose CDKi. Rates of hematologic toxicities, dose interruptions, further dose reductions, progression-free survival and overall survival were compared between the two groups. Data from absolute neutrophil count, hemoglobin and platelet count on Days 1 and 15 of the first 2 cycles were graded for hematologic toxicity according to CTCAE v 5.0. Results: Out of 220 pts, 175 (79.6%) pts started on standard starting dose CDKi and 45 (20.5%) pts started on reduced dose CDKi. 30.86% of pts on the standard dosing group and 28.9% of pts on the reduced starting dose group had a dose interruption. The association between starting dose and dose interruption is not statistically significant (p &lt; 0.86). The estimated 12-month survival rate is 95% (95% CI: 89% - 97%) for the pts on standard dose CDKi and 85% (95% CI: 67% - 93%) for the group reduced dose group. The estimated 12-month progression-free survival rate is 72% (95% CI: 64% - 78%) for the standard dosing group and 35% (95% CI: 21% - 50%) for the reduced dose group. Conclusions: Our study showed a significant survival rate and progression-free survival rate difference between patients who were started on standard FDA starting dose compared to those started on reduced dose CDKi.

An international cohort study investigating the impact of age on clinical outcome in patients with hepatocellular carcinoma treated with sorafenib.

12049 Background: There is no consensus on the effect of sorafenib dosing on efficacy and toxicity in elderly patients with hepatocellular carcinoma (HCC). Older patients are often empirically started on low dose therapy with the aim to avoid toxicities whilst maximising clinical efficacy. We aimed to verify whether age impacts on overall survival (OS) of patients with HCC, and whether a reduced starting dose of sorafenib impacts on OS or rates of toxicity experienced by the elderly. Methods: In this international, multicentre cohort study, patients with a confirmed diagnosis of advanced-stage HCC receiving sorafenib were recruited from seven specialist centres. Demographic and clinical data including development and grade of sorafenib toxicity and sorafenib starting dose were collected prospectively. Survival time (months) was recorded prospectively. Outcomes for those &lt; or &gt; 75 years were determined Results: A total of 5598 patients were recruited; 792 (14.1%) were over the age of 75. The elderly were more likely to have larger tumours ( &gt; 7cm)(39 vs 33%, p = 0.07) with Child-Pugh A liver function(67 vs 57.7%) and less portal vein thrombosis compared to those &lt; 75years(22.1 vs 29.4)(p &lt; 0.001). They were more likely to be commenced on lower starting dose of sorafenib i.e 400mg/200mg (38.7 vs 37.2%, P &lt; 0.01). In terms of OS, there was no difference in the median OS of those &gt;75 years and patients &lt; 75 (7.3months vs 7.2months; HR 0.98 (95% CI 0.90–1.06), p = 0.63). There was no relationship between starting dose of sorafenib, 800mg vs 400mg/200mg, and OS between those &lt; or &gt; 75years. The elderly experienced a similar incidence of grade 2-4 sorafenib-related toxicity compared to &lt; 75years(74.3 vs 61.7%, p = 0.051)(except for anorexia (14.0 vs 7.2%, p &lt; 0.01) and rash (3.1 vs 6.3%, p &lt; 0.05), irrespective of the dose prescribed. The elderly were more likely to discontinue sorafenib due to toxicity (27.0 vs 21.6%, p &lt; 0.01). This did not vary between different starting doses of sorafenib. The mean duration of treatment was similar between those &lt; and &gt; 75 and, again, the starting dose of sorafenib did not affect treatment duration in the elderly. Conclusions: The median OS in the elderly is the same for that of patients under 75 years and is independent of the dose of sorafenib prescribed. Therefore, sorafenib should be offered to elderly patients and they should not be excluded from therapy

Efficiency: Minimizing dose escalation steps by calculating human dosing preclinically.

e15622 Background: Historically, oncology drug development can take years to accomplish the goal of bringing new agents to patients. Scientific knowledge is evolving rapidly, transforming our understanding of the diseases at a rapid pace. This necessitates expedited drug development and approval to allow benefit for cancer patients. First-in-human administration to accelerated approval worthy data can efficiently occur in approximately two years, often in small very specific populations (individualized [precision medicine] therapy). The pre-clinical time period solidifies basic knowledge of mechanism of action, dosing, schedule, safety and efficacy both in vitroand in vivo, but adds to the development timeline of these products. Determining the correct dose has been identified by us and others as a critical issue that often leads to prolonged Phase 1 dose escalation in very expensive human testing environments.To optimize development timelines, we have targeted identification of dose (safe vs toxic and no benefit vs effective) as a critical area to define in these pre-clinical experiments. Methods: Tumor cell killing concentrations are essential to understanding the required lower limits and optimal amounts of drug available at the target cell (cancer or immune cell), with cognizant regard to toxicity in normal tissue, both a key focus of preclinical testing. Determining these concentrations in vivo are important data sources for this concept of “therapeutic index”. Defining the concentration for killing range and concentrations in total body water can then be used to calculate human starting dose that is within or near the beneficial anti-cancer concentration, but not at the predicted toxic concentration for normal human tissues. Results: By using a mathematical algorithm, we have developed a set of formula’s that can translate micro-molar or similar concentrations in vitro, and animal studies to human optimized dose escalation trials. This often involves predicting maximum tolerated dose (MTD) or optimal biologic dosing (OBD) for efficacy and safety rather than forcing the appearance of Dose Limiting Toxicities (DLT). Conclusions: This pre-clinical work has the potential to be able to decrease the in-human dose escalation time period and lead to more efficient development of novel therapeutics.