Steroid Premedication Research Articles

Incidence and Risk Factors for IVIG-Mediated Hemolysis

INTRODUCTIONHemolysis is a recognized complication of high-dose IVIG infusion, but as the majority of case reports are retrospective the actual incidence and risk factors for its occurrence are poorly understood. METHODS: Between November 2012 and October 2016, recipients of high-dose IVIG in Toronto (Canada) were prospectively monitored for hemolysis using a panel of investigations performed pre- and post-infusion and then 5-10 days later. Hemolysis was defined and graded as per the Canadian IVIG Hemolysis Pharmacovigilance Group, with both patient and product risk factors analyzed for correlation. RESULTS: After a preliminary analysis revealed a strong association with ABO group and dose, enrollment was restricted to patients with non-O blood group receiving doses ≥ 2 g/kg, adjusted for lean body mass. Within this cohort, 99 infusions to 78 patients completed the follow-up protocol, with hemolysis observed in 32 (32%) and 28 (36%) of cases, respectively. Hemolytic anemia of Grades 1, 2, 3 and 4 were observed in 10, 9, 2 and 7 patients, respectively, and an additional 4 patients hemolyzed but maintained a stable hemoglobin via reticulocytosis. Although the initial fall in hemoglobin was slightly larger in hemolytic than non-hemolytic reactions (-14.9 vs -11.1 g/L, p = 0.0091), in 84% of cases laboratory confirmation of hemolysis only manifested 5-10 days after the infusion. In contrast, while 88% of hemolyzers had a positive DAT immediately post-IVIG, this proportion had fallen to 38% by day 5-10. Amongst 49 infusions evaluated by day 5-10 monocyte monolayer assay, there was 69% correlation between the development of hemolysis and the presence of heightened phagocytic activity in patient monocytes, vs 43% correlation when testing was performed with monocytes from healthy controls. Further supporting a state of increased macrophage activation, the proportional increase in serum ferritin was greater in hemolyzers than non-hemolyzers (5.1-fold vs 2.1-fold, p = 0.033). Conversely, all positive DAT test results were for IgG only, with no evidence of complement deposition. In regards to predictors of hemolysis, univariate analysis identified a higher incidence with group AB than with other blood groups (90% vs 26%, p = 0.0001), in first-time compared to repeat recipients (50% vs 20%, p = 0.002), in patients not taking immunosuppressant medications (43% vs 23%, p = 0.0316), and in patients whose post-infusion DAT was 1+ or stronger as compared to weak or by eluate only (57% vs 19%, p = 0.0001). One of three manufacturers had a lower rate of hemolysis (0% vs 35%, p = 0.009) but was also more likely than the other two manufacturers to be given to patients on immunosuppressant medications (83% vs 24%, p=0.0001). No correlation was observed with year of treatment, patient age, sex, BMI, diagnosis, rate of infusion, steroid pre-medication, subjective symptoms or pre-infusion levels of CRP or IL1-RA. CONCLUSION: Amongst non-O blood group recipients of high-dose IVIG, hemolysis is common and appears to occur via delayed-onset phagocytosis by activated patient monocytes. The highest risk appears to be in patients with blood group AB, those who are receiving IVIG for the first time, who are not taking immunosuppressive medications, or who have a 1+ or stronger DAT immediately post-infusion. Whether specific IVIG products carry higher risk requires further study. DisclosuresLin:Pfizer: Other: advisory board; Pfizer: Honoraria; CSL Behring, Grifols: Other: unrestricted education grant; Novartis: Research Funding. Pavenski:Novartis: Honoraria; Ablynx: Other: participation in industry sponsored RCT; CSL Behring: Research Funding; Alexion Pharmaceuticals: Honoraria. Branch:CSL Behring (Bern): Research Funding; CSL Behring (Canada): Research Funding; Canadian Blood Services: Employment, Research Funding; ViroCarb Inc.: Other: Founder and stock holder.

Ninety-Minute Daratumumab Infusion Is Safe in Multiple Myeloma

▪Background: Daratumumab, an anti-CD38 monoclonal antibody, was first approved for the treatment of relapsed and refractory multiple myeloma (MM) in December of 2015. The approved initial infusion lasts at least 6.5 hours, second infusion for 4.5 hours and all subsequent infusions over 3.5 hours. The risk of infusion related reactions (IRRs) is very low after the second infusion, and the prolonged continued infusion time results in long days for patients. Because of our success infusing other monoclonal antibodies over shorter times, such as rituximab (Dotson et al Support Care Cancer, 2016), we hypothesized that shortening the daratumumab infusion from 3.5 hours to 90 minutes beginning with the third infusion would not increase the incidence of IRRs.Methods: This is a single-center safety study of an accelerated daratumumab infusion in patients receiving standard of care daratumumab therapy. Patients were eligible once they received at least 2 prior doses of daratumumab, administered per standard prescribing information. Previous IRR was not an exclusion criterion. The accelerated infusion was calculated to deliver 20% of the dose over the first 30 minutes, then the remaining 80% over 60 minutes, resulting in an estimated 90 minute infusion (Table 1). Patients who tolerated the infusion well were allowed to continue the accelerated rate. Premedication regimens were allowed to be altered based on previous tolerability. Simon's two-stage optimal design was utilized to design the study based on the incidence of grade 3 or above IRR. With 80% power the design allows 7 patients to be treated in the first stage, and if no patients experienced ≥ grade 3 IRR, an additional 21 patients would be treated. Out of all 28 patients, if 2 or more experienced ≥ grade 3 IRR, the regimen would be declared as too toxic. The protocol was approved by the cancer institutional review board.Results: Baseline characteristics are listed in Table 2. Twenty eight patients were treated with daratumumab utilizing the accelerated rate, 8 of which received the accelerated infusion with their third dose of daratumumab. The premedication regimen varied patient-to-patient and did not impact tolerability of the accelerated infusion. There were 5 patients who did not receive any steroid premedication and 3 who received reduced doses (< 12 mg) of dexamethasone. Of the 28 patients treated, there was only 1 adverse reaction - a grade 2 hypertension during which the infusion was paused for a patient that had received 10 prior infusions at standard rates. The patient received a diuretic, the infusion was resumed and subsequently increased to the accelerated rate without further incidence of hypertension. There were no grade 3 or higher IRRs. At the 4-week follow-up, all patients remaining on daratumumab treatment continued at the accelerated infusion rate.Conclusion: An accelerated infusion rate of daratumumab delivering 20% of the dose over 30 minutes and 80% over 60 minutes is feasible and well-tolerated in patients who have received 2 prior doses of daratumumab at standard infusion rates. Starting with the third dose of daratumumab therapy, the 90-minute infusion is now standard practice at our institution. [Display omitted] DisclosuresHofmeister:Janssen: Research Funding; Roche: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding; Karyopharm: Research Funding; Celgene: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Thrassos: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Phase II prospective open label study of neoadjuvant pertuzumab, trastuzumab, and nab-paclitaxel in patients with HER-2 positive advanced breast cancer.

583 Background: HER2 overexpression occurs in 20-25% of breast cancers (BC) and is associated with poor prognosis. The addition of trastuzumab (trast) to chemotherapy significantly improves disease-free (DFS) and overall survival (OS) in the adjuvant setting. Pertuzumab (pert) inhibits ligand-activated signaling and in combination with trast has synergistic inhibition of BC cells overexpressing HER2. In the neoadjuvant therapy (NT) setting, the combination of trast, pert, and docetaxel can improve the pCR rate. PCR may predict for improved DFS and OS. De-escalation with weekly paclitaxel combined with trast and pert appeared to be safe and efficacious but requires steroid premedication, whereas nab-paclitaxel (nab) does not require steroid premedication. To decrease treatment-associated toxicity in patients with HER2+ BC, we utilized a non-anthracycline regimen with pert, trast, and nab as NT. The objectives of this study were to evaluate the safety and efficacy of pert added to trast and nab in HER2+ locally advanced BC (LABC) to determine the pCR, as well as DFS and OS. Methods: A total of 45 patients with biopsy-confirmed HER2+ LABC or inflammatory BC were enrolled from 2013-2017, and were treated with 6 cycles of neoadjuvant pert (840 mg loading dose, then 420 mg IV day 1 every 21 days), weekly trast (4 mg/kg loading dose, then 2 mg/kg), and weekly nab (100 mg/m2 IV). Patient characteristics, including age, race, menopausal status, grade, stage, and prior surgery and radiation were recorded. Median treatment cycles determined, and events (AE) were identified for each arm. PCR rate, DFS and OS were calculated. Results: Median age was 56 (31-78) years. 1/45 (2%) was stage I, 30/45 (67%) were stage II, 14/45 (31%) were stage III. pCR rate was 29/45 (64.4%). The initial primary tumor size was similar in pCR and non-pCR patients (mean 4.1 cm vs. 3.2 cm, respectively). Median follow-up was 36.1 months (95% CI [27.1, 41.8]). Median treatment cycles completed was 6 (1-6). A total of 4/45 (9%) patients had &gt;1 cycle delayed, and 32/45 (71%) patients had &gt;1 cycle modified. For the patients achieving pCR, the DFS (95% CI) at 3 years was 85.9% (66.7%, 94.4%) and for those without pCR, it was 87.5% (58.6%, 96.7%). OS was not reached (95% CI [NR, NR]). Grade 3 AEs (&gt; 2 patients) included 7/45 (16%) of patients with hypertension; 4/45 (9%) with anemia; and 2/45 (4%) with diarrhea, ALT, fatigue, or rash. Conclusions: This anthracycline-free regimen which included nab achieved great pCR rate of 64.4% in HER2+ BC patients with fewer treatment-related toxicities. The pCR rate is comparable with docetaxel, carboplatin, trast, and pert (TCHP) therapy in NT setting, but without the treatment-associated toxicities. This suggests we may be able to safely avoid anthracyclines and carboplatin for NT in HER2+ BC patients. The improved pCR did not translate into DFS benefit. Clinical trial information: NCT01730833.

An open-label, pharmacokinetic study to determine the bioavailability, safety and tolerability of single dose oral docetaxel in metastatic prostate cancer (mPC) patients treated with IV docetaxel.

5050 Background: Docetaxel has poor oral bioavailability in part due to extrusion by intestinal p-glycoprotein. To improve IV solubility, it is fomulated with the nonionic surfactant polysorbate 80, requiring steroid premedication to manage hypersensitivity type reactions. Oral administration has the potential to improve tolerability, reduce day-stay utilization and improve patient convenience and allows investigation of alternative dosing schedules. Oradoxel is a new combination of oral docetaxel capsules plus the novel gut-selective P-glycoprotein inhibitor encequidar (HM30181A). Methods: Patients with mPC receiving IV docetaxel were enrolled in 3 cohorts with a dose escalation schedule of Oradoxel 75 mg/m2 in Cohort 1, 150 mg/m2 in Cohort 2, 300mg/m2 in Cohort 3. Oradoxel was given 3 weeks before or after IV docetaxel treatment. Intensive PK samples were taken on days 1-5 for Oradoxel and days 1-4 for IV docetaxel. Dose limiting toxicity (DLT) or serious adverse events (SAE) were assessed per CTCAE v4.03. Results: 3 evaluable patients in each Cohort were studied. No DLT, MTD, or drug-related SAE were observed. PK parameters of Oradoxel vs IV docetaxel are summarized in the table below. Mean absolute bioavailability of Oradoxel was 15.9% (range 8-25%). PK became non linear at 300mg/m2. Conclusions: Oradoxel was well tolerated. Based on the results of this and related studies, Oradoxel 300mg/m2 in divided doses is being further evaluated in phase 2 studies. Clinical trial information: 12616000983404. [Table: see text]

Abstract GS3-01: Additional efficacy endpoints from the phase 3 KEYNOTE-355 study of pembrolizumab plus chemotherapy vs placebo plus chemotherapy as first-line therapy for locally recurrent inoperable or metastatic triple-negative breast cancer

Abstract Background: Pembrolizumab (pembro) monotherapy showed durable antitumor activity and manageable safety in patients (pts) with metastatic triple-negative breast cancer (TNBC) in the KEYNOTE-012, -086, and -119 studies. In a prespecified interim analysis of KEYNOTE-355 (NCT02819518), pembro combined with chemotherapy (chemo) showed a statistically significant improvement in PFS versus chemo alone in pts with previously untreated locally recurrent inoperable or metastatic TNBC whose tumors expressed PD-L1 CPS ≥10 (HR for progression or death, 0.65, 95% CI, 0.49-0.86; one-sided P=0.0012 [prespecified statistical criterion was alpha=0.00411 at this interim analysis]). Additionally, pembro + chemo was generally well tolerated, with no new safety signals. Here, we examine PFS outcomes for each chemo partner and present key secondary endpoints from KEYNOTE-355. Methods: 847 pts with measurable disease per RECIST v1.1, ECOG PS 0-1, and ≥6 mo DFI were randomized 2:1 to pembro + chemo (nab-paclitaxel 100 mg/m2 days 1, 8, and 15 every 28 days; paclitaxel 90 mg/m2 days 1, 8, and 15 every 28 days; or gemcitabine 1000 mg/m2 + carboplatin AUC 2 days 1 and 8 every 21 days) or pbo + chemo for up to 35 administrations of pembro/pbo or until progression/intolerable toxicity. Steroid premedication for paclitaxel was given according to local guidelines and practices, and was not restricted by the protocol. Crossover between arms was not allowed. Pts were stratified by chemo type (taxane vs gemcitabine/carboplatin), PD-L1 status (CPS ≥1 vs &amp;lt;1), and prior (neo)adjuvant treatment with same-class chemo (yes vs no). Dual primary endpoints are PFS (RECIST v1.1, blinded independent central review) and OS in pts with PD-L1 positive tumors (CPS ≥10 and ≥1) and in all pts. Secondary endpoints include ORR, DCR (CR + PR + SD ≥24 weeks), and DOR. The PFS treatment effect was assessed in subgroups descriptively using HRs and 95% CIs; although subgroup analysis by on-study chemo were pre-specified, the trial was not powered to compare efficacy among treatment groups by different chemo regimens. Results: As of Dec 11 2019, median follow-up was 25.9 mo for pembro + chemo (n=566) and 26.3 mo for pbo + chemo (n=281). The HR for PFS favored pembro regardless of choice of chemo or CPS population (Table). Results for the key secondary endpoints of ORR, DCR, and DOR favored pembro + chemo, with the treatment effect increasing as CPS increased (Table). Conclusion: In subgroup analysis, PFS with pembro + chemo compared to pbo + chemo in pts with metastatic TNBC was improved regardless of chemo partner. A trend toward improved efficacy with PD-L1 enrichment with pembro + chemo was observed for ORR, DCR and DOR endpoints. These data further support the potential of pembro + chemo as a first-line treatment option for metastatic TNBC. CPS ≥ 10CPS ≥ 1All ptsPembro + ChemoPbo + ChemoPembro + ChemoPbo + ChemoPembro + Chemo|Pbo + ChemoN = 220N = 103N = 425N = 211N = 566N = 281PFS, mo median (95% CI)9.7 (7.6 - 11.3)5.6 (5.3 - 7.5)7.6 (6.6 - 8.0)5.6 (5.4 - 7.4)7.5 (6.3 - 7.7)5.6 (5.4 - 7.3)HR (95% CI)0.65 (0.49 - 0.86)0.74 (0.61 - 0.90)0.82 (0.69 - 0.97)PFS by on-study chemo, (n [%)) mo median(95% CI)Nab-Paclitaxel(63 [28.6%]) 9.9(36 [35.0%]) 5.5(130 [30.6%]) 6.3(74 [35.1%)) 5.3(173 [30.6%]) 7.5(95 [33.8%]) 5.4HR (95% CI)0.57 (0.34 - 0.95)0.66 (0.26 - 0.82)0.69 (0.51 - 0.93)Paclitaxel(33 [15.0%]) 9.6(11 [10.7%]) 3.6(62 [14.6%]) 9.4(22 [10.4%]) 3.8(82 [14.5%]) 8.0(32 [11.4%]) 3.8HR (95% CI)0.33 (0.14 - 0.76)0.46 (0.26 - 0.82)0.57 (0.35 - 0.93)Gemcitabine-Carboplatin(124 [56.4%]) 8.0(56 [54.4%]) 7.2(233 [54.8%]) 7.5(115 [54.5%]) 7.5(311 [54.9%]) 7.4(154 [54.8%]) 7.4HR (95% CI)0.77 (0.53 - 1.11)0.86 (0.66 - 1.11)0.93 (0.74 - 1.16)ORR, % (95% CI)53.2 (46.4 - 59.9)39.8 (30.3 - 49.9)45.2 (40.4 - 50.0)37.9 (31.3 - 44.8)41.0 (36.9 - 45.2)35.9 (30.3 - 41.9)DCR, % (95% CI)65.0 (58.3 - 71.3)54.4 (44.3 - 64.2)58.6 (53.7 - 63.3)53.6 (46.6 - 60.4)56.0 (51.8 - 60.1)51.6 (45.6 - 57.6)DOR, mo, median (range)19.3 (1.6+ - 29.8)7.3 (1.5 - 32.5+)10.1 (1.0+ - 29.8)6.5 (1.5 - 32.5+)10.1 (1.0+ - 29.8)6.4 ( 1.5 - 32.5+)"+" indicates there is no progressive disease by the time of last disease assessment. Citation Format: Hope S. Rugo, Peter Schmid, David W. Cescon, Zbigniew Nowecki, Seock-Ah Im, Mastura Md Yusof, Carlos Gallardo, Oleg Lipatov, Carlos Henrique Barrios, Jose Perez-Garcia, Hiroji Iwata, Norikazu Masuda, Marco Torregroza Otero, Erhan Gokmen, Sherene Loi, Zifang Guo, Jing Zhao, Vassiliki Karantza, Gursel Aktan, Javier Cortes. Additional efficacy endpoints from the phase 3 KEYNOTE-355 study of pembrolizumab plus chemotherapy vs placebo plus chemotherapy as first-line therapy for locally recurrent inoperable or metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS3-01.

Updates from Ongoing, First-in-Human Phase 1 Dose Escalation and Expansion Study of TTI-621, a Novel Biologic Targeting CD47, in Patients with Relapsed or Refractory Hematologic Malignancies

Updates from Ongoing, First-in-Human Phase 1 Dose Escalation and Expansion Study of TTI-621, a Novel Biologic Targeting CD47, in Patients with Relapsed or Refractory Hematologic Malignancies

A randomized clinical trial comparing physician-directed or fixed-dose steroid replacement strategies for incomplete dexamethasone dosing prior to docetaxel chemotherapy.

Prior to docetaxel chemotherapy, incomplete dosing of steroid premedication is common. The lack of standardized steroid replacement strategies can lead to variability in care and delays in starting docetaxel. This randomized trial compared physician-directed with fixed-dose dexamethasone. Patients who had missed at least one dose of steroid premedication were randomized to physician-directed replacement (any choice of steroid, dose or route) or to dexamethasone 8mg oral before starting docetaxel. The primary outcome was time from randomization to starting docetaxel. Secondary outcomes included rates of acute and delayed hypersensitivity reactions, fluid retention and skin toxicity. Of 60 eligible patients, 30 (50%) and 30 (50%) were randomized to physician-directed and fixed-dose arms, respectively. Overall tumour types: breast (42 [70%]), gastrointestinal (7 [12%]), prostate (7 [12%]) and lung (3 [7%]). Dexamethasone was most commonly incompletely taken with cycles 1 (28 [48%]) and 2 (13 [22%]) of docetaxel. Seven different replacement strategies were used in the physician-choice arm. Patients in the fixed-dose arm received docetaxel a mean of 21.2 (95% CI for the difference is 2.1 to 44.6) minutes earlier than the physician-choice arm (p = 0.033 Wilcoxon rank sum test or p = 0.073 two-sample t test). Median time to docetaxel was 47.5 vs 61min (mean 62.2 vs 83.4min) by arm, respectively. No significant difference in toxicity rates was observed. While not meeting our predefined criteria of improving the time from randomization to starting docetaxel by 30min, the fixed-dose replacement strategy reduced both the time to starting docetaxel and treatment variability. Fixed dosing with oral dexamethasone 8mg should be the preferred standard of care. REGISTRATION: www.clinicaltrials.gov NCT02815319 REGISTRATION DATE: June 28, 2016.

Absence of Iodinated Contrast Hypersensitivity and Characterization of Gadolinium Utilization in an Interventional Pain Population.

Iodinated contrast media (ICM) allergy labels pose a unique clinical problem for the interventional pain physician due to the drawbacks of gadolinium for enhancement during pain procedures, as well as the reluctance to add to the cumulative steroid burden with steroid premedication. However, the risks of ICM hypersensitivity specific to this setting have not been previously described. We aimed to describe the incidence of ICM-induced hypersensitivity during the performance of epidural injections in a large healthcare system. We also sought to characterize preexisting ICM allergy labels and how these affected consequent gadolinium utilizations in this population. 6,471 epidural pain procedures requiring contrast enhancement were performed during the 18-month study period. There were no reported contrast-induced hypersensitivity reactions in this time. 108 patients (1.6%) had a preexisting ICM allergy; a shellfish/seafood allergy was recorded in 118 patients (1.82%), and 51 charts (0.78%) were labeled with "iodine" allergy. 183 individuals received gadolinium for enhancement during epidural steroid injections. 96.7% of gadolinium utilization occurred in the context of preexisting allergy labels in the electronic medical record. Of note, 20 patients (18.5%) with ICM allergy labels also received iodinated contrast, and this was uneventful in all cases. Our results suggest that ICM-associated hypersensitivity is very rare during epidural procedures and the incidence is significantly lower than expected based on reaction rates during intravascular administration. This may be related to both dose as well as route of administration. The establishment of a protocol for safe workup of ICM allergy labels would be useful in optimizing pain procedures.

First-in-human phase I study of HPN424, a tri-specific half-life extended PSMA-targeting T-cell engager in patients with metastatic castration-resistant prostate cancer (mCRPC).

5552 Background: HPN424 is a first-in-class, prostate-specific membrane antigen (PSMA)-targeting T-cell engager designed as a small, globular protein to enable efficient solid-tumor penetration with prolonged half-life. HPN424 is derived from the TriTAC platform (Tri-specific T-Cell-Activating Construct) and engineered with three binding domains: anti-PSMA for tumor cell engagement, anti-albumin for half-life extension and anti-CD3 for T-cell engagement. Methods: This Ph I study is evaluating HPN424 in progressing mCRPC patients (pts) who have received &gt;2 prior systemic therapies. Primary endpoints are safety, tolerability and determination of MTD/RP2D. Secondary objectives are pharmacokinetics (PK), pharmacodynamics, immunogenicity, and preliminary anti-tumor activity. HPN424 is administered IV once weekly. Tumor assessments include PSA, CT, and bone scans every 9 weeks. Results: As of 1/17/20, 27 pts were dosed in 8 cohorts ranging from 1.3 to 72ng/kg. Pts received a median of 6 prior systemic regimens, including &gt;1 novel AR therapy, and 59% received prior chemotherapy for mCRPC. Median PSA at baseline was 251 ng/mL (range: 0.05 – 5000). No DLTs have been observed. The most common grade &gt;3 TRAEs were cytokine release syndrome (CRS) (3 pts) and transient elevated liver transaminases (2 pts) that occurred concurrently with CRS. All CRS events resolved and pts were successfully re-treated. Short-term steroid premedication was effective in limiting CRS and allowing long-term weekly treatment. HPN424 demonstrated dose proportional increase in Cmax and AUC with a geometric mean T1/2 of 30.5 hours. Dose-dependent, transient increases in peripheral cytokine and chemokine levels were observed. Reduction in circulating tumor cells (CTCs) was seen in 11 of 19 pts with measurable CTC at baseline. Six pts had PSA decreases from baseline ranging from -3.8% to -76%, including 2 pts with PSA decline ≥50%. Ten of 20 pts (50%) with &gt; 18 weeks follow-up remained on study beyond week 18 and includes 8 pts on study &gt; 24 weeks. Conclusions: HPN424 represents a novel half-life extended PSMA-targeting T-cell engager that can be safely administered once weekly. AEs have been transient and manageable. Cytokine increases indicate T-cell activation. CTC reductions in subset of pts suggest target engagement. Early signs of clinical activity include PSA reductions and time on study, including 8 pts on study &gt; 24 weeks. Dose escalation is ongoing, including exploration of step dosing. Clinical trial information: NCT03577028 .

Pharmacokinetics, safety, and early activity of a nanoparticle micellar formulation of docetaxel in women with metastatic breast cancer: Results of two randomized trials (phase I and II).

3526 Background: Docetaxel micellar (DM) is a nano-sized particle formulation of docetaxel in which a retinoic acid derivative is used as solubilizer with a high drug to excipient ratio possibly resulting in reduced systemic toxicity or hypersensitivity reactions due to the excipient. DM is given without standard use of premedication, avoiding steroid-associated immunosuppression. Here we present the pharmacokinetics (PK) after a single dose of DM or polysorbate-solubilized docetaxel (D) as well as safety and early activity including overall response rate (ORR) in female patients with metastatic breast cancer. Methods: The PK study was a two-cycle, cross-over study where 30 patients were included and randomized to either DM followed by D or D followed by DM, both given as a 1-hour intravenous infusion at a dose of 100mg/m2. The phase II study was a prospective, multicenter, open-label, third-party blinded, randomized, parallel group, active-controlled study including 200 patients to compare the early activity and safety of DM and D, both given as 100 mg/m2 1-hour intravenous infusion every 21 days (1 cycle) for a total of 6 cycles. Results: Bioequivalence of total docetaxel in plasma, AUC0-last and Cmax, was demonstrated for DM compared to D. The incidence of adverse events was higher in the D arm than in the DM arm for the majority of SOCs and PTs in the phase II study. Overall, Grade 3 or 4 AEs were reported for 82.7% of patients from DM arm and 99.0% of patients from D arm. Twelve (12.2%) patients in the DM arm and 24 (24.0%) patients in the D arm needed at least one dose reduction due to AEs. The primary efficacy endpoint in the phase II study was based on the assessment according to Response Evaluation Criteria in Soldid Tumors (RECIST) 1.1 and non-inferiority was not reached based on the pre-defined non-inferiority margin. A post-hoc analysis investigating the ORR based on tumour assessment at the end of chemotherapy, and non-inferiority of DM as compared to D was shown (ITT population). Conclusions: DM is bioequivalent to D regarding total drug in plasma and provides a docetaxel formulation that spares patients steroid premedication. An improved safety profile for DM compared to D was shown while additional efficacy data is needed for future development of DM. Eudra CT: 2012-005161-12 and 2013-004889-33. Clinical trial information: 2012-005161-12 and 2013-004889-33 .

Incidence of diabetes and prediabetes unmasked by dexamethasone in women undergoing (neo) adjuvant taxane therapy.

e12526 Background: Women with early stage breast cancer receive premedication with dexamethasone prior to administration of paclitaxel and docetaxel. We undertook a retrospective chart review to determine the frequency of steroid-induced hyperglycemia in women receiving steroid premedication with paclitaxel and docetaxel. Methods: Women who were receiving paclitaxel or taxotere chemotherapy as (neo)adjuvant therapy were identified from pharmacy records. Patients were excluded if they were currently receiving insulin or hypoglycemic agents for diabetes. A Comprehensive Metabolic Panel (CMP) was performed prior to chemotherapy and the random glucose level was recorded. The highest random glucose level recorded during all cycles of treatment was used in the analysis. The threshold for diabetes is a random glucose of 200 mg/dL and levels &gt; 150 mg/dL, but less than 200 mg/dL is considered prediabetes. Between August 2017 to December 2019, 131 patients were identified and 100 met the criteria for inclusion. The study was approved by the Institutional Review Board. A single individual abstracted the data which included demographic data, BMI, comorbidities, random glucose levels prior to therapy and whether they received treatment for the elevations in blood glucose. Results: A total of 131 charts were reviewed, but 31 were excluded because 2 were male, 13 had type 2 diabetes at diagnosis, and 16 had metastatic disease. The median age of the 100 patients was 53 years (range 31 to 82 years); 45% were White/Non-Hispanic, 28% Hispanic, 18% Asian, 5% African American, 1% were Native Hawaiian or other Pacific Islander, 2% were unknown, and 1% were of mixed race. Prediabetic random glucose levels were recorded in 30% of patients and 23% had levels consistent with a diagnosis of diabetes. Out of the patients who exhibited a blood glucose above 200, 16 out of the 23 patients were White, 6 of them were Hispanic and 1 was Asian. The average BMI was 27.7. The average BMI of patients who exhibited a blood glucose of over 200 mg/dL was 28.85 and the average of those who had a blood glucose of over 150 mg/dL was 27.56. Conclusions: Diabetes and prediabetes were unmasked by taking the premedication with dexamethasone in 53% of women undergoing (neo)adjuvant docetaxel or paclitaxel. Current guidelines do not recommend additional blood work after completion of active treatment. Given our results, it is important that medical oncologist ensure that patients with elevations in random glucose be referred for appropriate endocrine workup and therapy, including lifestyle modifications.

477P - An international randomized cross-over bio-equivalence study of oral paclitaxel + HM30181 compared with weekly intravenous (IV) paclitaxel in patients with advanced solid tumours

BackgroundPaclitaxel has poor oral bioavailability due to excretion by P-glycoprotein (P-gp) on intestinal cells. Oral paclitaxel may reduce IV access, avoid risks of allergic reaction to cremophor, forego steroid premedication, reduce hospital stay, and improve patient convenience. Oraxol (Athenex, USA) is a combination of oral paclitaxel and HM30181, a novel orally active, potent and specific inhibitor of P-gp with minimal or undetectable systemic exposure. We report the results of a bio-equivalence study of Oraxol compared to IV paclitaxel. MethodsAn international randomized crossover pharmacokinetic (PK) study using HM30181 15mg plus oral paclitaxel 205mg/m2 was given on days 1-3 and compared to a single dose of IV paclitaxel (80mg/m2) in patients with advanced solid tumors. PK blood samples were taken days 1-9 for oral paclitaxel and days 1-5 for IV paclitaxel. Results44 patients were randomized. 35 patients were evaluable. The first cohort included 6 patients as a feasibility study. The second cohort included 29 patients and showed:Table477PTableOraxol 205mg/m2 days 1-3Paclitaxel 80mg/m2 IVAUC0-∞ (hr*ng/mL)5001.185589.70Cmax (ng/mL)366.39 (0-24hr), 324.26 (24-48hr), 296.10 (48-72hr)2710.48AUC0-t4797.085425.59GMR (%, 90% CI)89.10 (83.53, 95.03)Intra-subject CV (%)16.05 ConclusionsOraxol (oral paclitaxel + HM30181) given daily for 3 days can show bio-equivalence to single dose of IV paclitaxel 80mg/m2 at 80% power with 90% CI of the GMR within the limits of 80 – 125%. Clinical trial identificationACTRN 12615000894594. Legal entity responsible for the studyAthenex. FundingAthenex. DisclosureC.G.C.A. Jackson: Travel / Accommodation / Expenses: Athenex. N.A. Hung: Shareholder / Stockholder / Stock options, Full / Part-time employment: Zentech. D. Cutler: Shareholder / Stockholder / Stock options, Full / Part-time employment: Athenex. D. Kramer: Full / Part-time employment: Athenex. J. Zhi: Full / Part-time employment: Athenex. W. Chan: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Athenex. M.R. Kwan: Leadership role, Travel / Accommodation / Expenses, Full / Part-time employment: Athenex. C. Hung: Research grant / Funding (self), Shareholder / Stockholder / Stock options, Patent: Athenex; Shareholder / Stockholder / Stock options: Zentech. All other authors have declared no conflicts of interest.

Premedication with intravenous steroids does not influence the incidence of infusion reactions following infliximab infusions in pediatric inflammatory bowel disease patients\u2014a case-control study

PurposeInfusion reactions (IR) are commonly described side effects of infliximab (IFX) infusions, often leading to discontinuation of IFX. This study aimed to investigate the influence of steroid premedication (PM) on incidence of IR in pediatric inflammatory bowel disease (PIBD) patients receiving IFX.MethodsA case-control study in two tertiary centers in Amsterdam, The Netherlands, including PIBD patients receiving IFX. PM with steroids was part of standard care in one center (PM+) but not in the other center (PM−). Acute IR were divided into mild/severe reactions and in grade 1/2/3/4 for detailed exploration. Differences between subgroups were assessed with the T or chi-square test. Multivariate logistic regression was used to assess associations between PM and IR incidence, correcting for co-medication usage.ResultsWe included 226 patients (91 PM+, 50% male, mean age at onset of IBD 12.7 years), receiving 3433 infusions. There was no difference between the PM+ and PM− subgroups in incidence of IR (14.3% vs. 17.0% of patients, p = 0.58) and in percentage of infusions followed by IR (1.4% in both subgroups). The OR of developing IR when using PM was 1.06 (95% CI 0.49–2.27, p = 0.89), and the OR of developing a grade 3 or 4 IR when using PM was 0.90 (95% CI 0.24–3.39, p = 0.88) when correcting for co-medication usage.ConclusionThe incidence of IR was low, and premedication with steroids did not decrease the incidence of IR in this cohort of PIBD patients receiving IFX. Our results indicate that PM with steroids is not indicated in PIBD to prevent IR.

A phase II feasibility study of nab-paclitaxel and carboplatin in chemotherapy naïve epithelial neoplasms of the uterus

Objective: Few effective treatment options exist for women with advanced or recurrent endometrial cancer (EC). To explore a modification of the standard systemic treatment for advanced or recurrent EC, we sought to determine the feasibility of completing 6 cycles of nab-paclitaxel (Nab-P) and carboplatin. Unlike paclitaxel, Nab-P does not require any steroid or other premedication, an important consideration for patients with diabetes mellitus and in the investigation of combinations with immunotherapy. We prospectively evaluated safety and efficacy of a day 1, 8-dose schedule of Nab-P in combination with carboplatin day 1 q3weeks in patients with chemotherapy naïve EC.

A randomized study comparing physician-directed or fixed-dose dexamethasone replacement following incomplete steroid premedication for docetaxel chemotherapy.

6610 Background: Prior to receiving docetaxel-based chemotherapy patients often incorrectly take all or part of their steroid-premedication. The lack of standardised steroid-replacement strategies can lead to variability in care and delays in starting chemotherapy while nursing/pharmacy/physicians establish an individualized patient plan, which can use up valuable chemotherapy chair time. A randomised controlled trial comparing a fixed-oral dose of dexamethasone and physician-directed replacement was performed. Methods: Patients who missed at least one dose of steroid-premedication were randomised to either standard replacement with dexamethasone 8mg orally or physician-directed replacement (any steroid, dose or route). The primary outcome was time from randomisation to starting docetaxel. Secondary outcomes included rates of acute and delayed hypersensitivity reactions, fluid retention and skin rashes. Results: Sixty patients were randomized. Most patients were enrolled during cycle 1 (47.5%) and cycle 2 (22%) of docetaxel. The most frequent total doses of dexamethasone omitted were 24 mg (27%), 12 mg (20%), and 8 mg (19%). There were 7 different replacement strategies used by physicians. The most frequently used strategies were: dexamethasone 8mg IV (34.5%), 12mg IV (17.2%) and 20mg IV (13.8%). Patients in the fixed-dose arm received docetaxel earlier than patients in the physician-choice arm, at a median of 47.5 and 61 minutes after randomization (mean = 62.2 vs 83.4 minutes) (p = 0.033). No significant difference in rates of acute (0 vs 2)/delayed allergic reactions (1 vs 0), fluid retention (2 vs 1), or skin rashes (1 vs 0) was observed between the fixed-dose and physician-choice arms respectively. Conclusions: This is the first randomised trial to compare steroid-replacement strategies in this patient population. Fixed-dose replacement with dexamethasone 8 mg PO should be the preferred standard of care, as it reduces both the time to starting docetaxel and treatment variability, with no apparent increase in toxicity. Clinical trial information: NCT02815319.

Patients with a history of hypersensitivity reaction to iodinated contrast medium and given iodinated contrast during an interventional pain procedure

In patients with a history of a hypersensitivity reaction to iodinated contrast medium, iodinated contrast medium is avoided, antihistamine and steroid premedication are given, or a gadolinium-based contrast agent is...

A Phase I, First-in-Human Study Evaluating the Safety and Preliminary Antileukemia Activity of IMGN632, a Novel CD123-Targeting Antibody-Drug Conjugate, in Patients with Relapsed/Refractory Acute Myeloid Leukemia and Other CD123-Positive Hematologic Malignancies

A Phase I, First-in-Human Study Evaluating the Safety and Preliminary Antileukemia Activity of IMGN632, a Novel CD123-Targeting Antibody-Drug Conjugate, in Patients with Relapsed/Refractory Acute Myeloid Leukemia and Other CD123-Positive Hematologic Malignancies

Drug Monitoring of Asparaginase Activity to Detect Silent Inactivation in Pediatric Acute Lymphoblastic Leukemia Patients Receiving Peg-Asparaginase

BackgroundAsparaginase is a key component of pediatric therapy for Acute lymphoblastic leukemia (ALL). Two formulations available in the USA are pegylated E. coli asparaginase (PEG) and Erwinia chrysanthemi asparaginase (Erwinaze). Hypersensitivity reactions have been observed in ~ 20% of patients receiving PEG. Patients with overt symptoms of hypersensitivity are typically switched to Erwinaze. In cases of hypersensitivity, anti-asparaginase antibodies may be present that neutralize circulating asparaginase and in some cases may present without clinical signs, a phenomenon known as silent inactivation. Few studies have prospectively evaluated the incidence of silent inactivation in pediatric ALL patients. In this prospective study, we performed therapeutic drug monitoring of asparaginase levels on newly diagnosed pediatric ALL patients to determine the incidence of silent inactivation and to switch patients to Erwinaze, if silent inactivation was detected.MethodsA prospective study was conducted at CHOC Children's Hospital on patients with newly diagnosed ALL or lymphoblastic lymphoma between 2016 to 2018. Patients designated as high or very high risk B-ALL post induction, T-ALL and B/T lymphoblastic lymphoma were enrolled. Patients received therapy on or according to a COG protocol with PEG (2500 IU/m2) administered via 2-hour i.v. infusion without antihistamine or steroid premedication. Asparaginase activity was measured days 7 and 14 after each of the two PEG doses during Consolidation. Serum asparaginase level of >0.1 IU/ml and >0.02 IU/ml was considered therapeutic at 7 or 14 days post PEG, respectively. Silent inactivation was defined as serum asparaginase levels below these values without signs of overt allergy. Any patient found to have silent inactivation was immediately switched to Erwinaze. Patient characteristics, common adverse events associated with asparaginase and serum asparaginase levels were analyzed. Descriptive statistics and Pearson's coefficient was used for analysis.ResultsThirty-nine patients were enrolled with a mean age of 9.8 years (range, 1-23) with the majority being B-ALL (87.2%) of which 3 were Ph-like (Table 1). Twelve patients (30.7%) had overt hypersensitivity and one patient (2.6%) had silent inactivation. One patient had overt hypersensitivity after completion of the PEG infusion with a measured asparaginase level 7 days post that was therapeutic. One-hundred fifteen drug levels were collected, for an average of 2.9 levels per patient (maximum 4 levels). There was a difference in mean asparaginase activity in patients without hypersensitivity compared to those with hypersensitivity (1.110 IU/mL versus 0.737 IU/mL, respectively, p=.0095). There were no significant differences in asparaginase levels based on age, gender or BSA. The highest asparaginase level observed was 7 days post the 2nd dose of asparaginase in Consolidation. Overall, the incidence of patients with CTCAE grade ≥2 transaminitis was 51.3% (n=20), hyperglycemia 2.6 % (n=1), hyperbilirubinemia 5.1% (n=2), and thrombosis 2.6% (n=1). Pancreatitis of any grade was not observed in this cohort.DiscussionWe detected silent inactivation in a single patient who had an asparaginase level of 0.01 seven days after the first dose of PEG and showed no signs of overt allergic reaction. This patient was switched to Erwinaze and an asparaginase level drawn 48 hours post Erwinaze was therapeutic at 0.719. Another patient developed a hypersensitivity reaction 12-hours after PEG and had a serum asparaginase level of 1.29 7-days post PEG. This suggests that not all anti-asparaginase antibodies are neutralizing since this patient continued to demonstrate therapeutic drug levels. The incidence of allergic reactions to PEG at our institution appears higher than reported in prior studies. Our data shows a statistically significant difference between serum asparaginase levels in patients with and without hypersensitivity. Our study also shows that silent inactivation exists in a very small proportion of patients. Additionally, patients who develop late allergic reactions to PEG may still have therapeutic asparaginase levels. Thus, monitoring of asparaginase levels may be warranted to detect silent inactivation and to monitor asparaginase levels in patients who develop delayed hypersensitivity. A larger prospective study is needed to confirm these results. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

440P - A multicenter prospective study on the efficacy and safety of denosumab in gastrointestinal cancer patients receiving short-term periodic steroid premedication for prevention of chemotherapy-induced nausea and vomiting (ESPRESSO-02/HGCSG1602)

Background: We previously reported that short-term periodic premedication of glucocorticoids (GCs) used with chemotherapy for gastrointestinal cancer (GIC) caused the reduction of bone mineral densities (BMD) (ESPRESSO-01 study; Oncologist 2017). We conducted this study to evaluate the efficacy and safety of denosumab for prevention of chemotherapy-induced BMD decrease. Methods: The eligibility criteria were as the follows: 1) Histologically confirmed GIC, including esophageal, gastric, pancreatic, and biliary cancer; 2) a schedule of periodical intravenous steroid administration as premedication that was weekly, biweekly, or triweekly, and in which >4-week steroid-free intervals were not allowed; 3) high-risk patient with steroid-induced secondary osteoporosis; 4) no prior treatment for osteoporosis. The dose of denosumab is 60mg administered as a single subcutaneous injection within a week before the induction of chemotherapy. All participants should receive adequate calcium and vitamin D supplementation. The primary endpoint was to investigate the BMD change on lumbar spine between baseline and 16 weeks after induction of chemotherapy. Results: From April 2017 to Feb 2018, 49 cases were enrolled. Two patients did not meet the inclusion criteria. One patient died before treatment and one patient refused just after enrollment. One case was not measured for BMD at baseline and three patients were not measured for BMD at 16 weeks, due to patient refusal, discontinuation of treatment, death and so on (41 cases were the full analysis set). In 30 cases (73.2% of FAS), the levels of BMD at 16w were significantly increased compared with baseline and the average percent change of BMD of lumbar spine was 2.767% (n = 41, 95% CI: 1.308% to 4.225%, p < 0.0001). No one suffered any bone fracture in FAS population. Conclusions: We found that denosumab administration could prevent the reduction of BMD and bone fracture. Clinical trial identification: UMIN000023855. Legal entity responsible for the study: Hokkaido Gastrointestinal Cancer Study Group (HGCSG). Funding: Has not received any funding. Disclosure: M. Nakamura: Honoraria: AstraZeneca, Bayer Yakuhin, Chugai, Daiichi Sankyo, Merck Serono, Nippon Boehringer Ingelheim, Taiho, Takeda. Y. Tsuji: Honoraria: Merck Serono, Eli Lilly Japan, Chugai, Taiho, Ono, Daiichi Sankyo, Yakult Honsha, Eisai, Medicon. Y. Komatsu: Honoraria: Bayer Yakuhin, Chugai, Taiho, Takeda, Eli Lilly Japan; Research expenses: Ono, MSD, Eli Lilly Japan, Taiho, Daiichi Sankyo, Chugai. All other authors have declared no conflicts of interest.

Pain flare, complexity and analgesia in bone oligometastases treated with stereotactic body radiation therapy.

The aim of our study was to assess the incidence of pain flare and the effectiveness of stereotactic body radiotherapy (SBRT) in pain management of patients with bone oligometastases. We evaluated 48 patients accounting for 54 treatments. The Edmonton Classification System for Cancer Pain (ECS-CP) was applied to identify indicators of treatment-resistant pain, in patients with active pain (NRS≥2) at baseline. Statistical analysis was performed to identify predictors of pain flare and pain control. Pain flare occurred in 38% of treated patients (n=18/48): No correlation was found between pain flare and patient- or treatment-related variables. In the subset of patients with active pain at baseline (n=23), pain control was obtained in 62% of patients at 1year; median time to pain progression after SBRT was 29months (CI95% 6-52months). Presence of ≥2ECS-CP features was correlated with earlier pain progression (4 vs. 30months, p=0.012). Pain flare occurred in 38% of cases irrespectively of steroid premedication and dose regimen. In patient with baseline active pain, durable pain control was obtained. Presence of ≥2 complexity indicators at the ECS-CP assessment was correlated with impaired pain control and may deserve future investigation in prospective studies.