Comparing Vancomycin Area Under the Curve With a Pharmacist Protocol that Incorporates Trough and Maximum Doses at a Children's Hospital

OBJECTIVE Updated vancomycin guidelines suggest dose adjustment based on area under the curve in a 24-hour period (AUC24). This study aims to determine whether a pharmacist managed vancomycin protocol that incorporates maximum dosing paired with trough monitoring can achieve appropriate vancomycin AUC24 exposures. METHODS A retrospective review was performed evaluating vancomycin usage from October 2018 through September 2019 at a children's hospital. Patients with less than 4 doses or lack a trough concentration were excluded. Vancomycin AUC24 were estimated using 2 calculations: 1) the Le method, incorporating age and serum creatinine, and 2) the trapezoidal method based upon population data and patient-specific trough. Target AUC24 ranges were assessed. AUC24 goals were 400 to 600 mg·hr/L, but due to known variations between calculations, a variance of 20 mg·hr/L was allowed for each end of the goal. Secondary analyses included evaluations of efficacy and toxicity. RESULTS Two-hundred twenty-three patients were included. Initial doses were estimated to meet AUC24 goals in only 63%. After trough-based dose modification, 81% achieved a therapeutic AUC24. Using the trapezoidal method, therapeutic concentrations were found in 51% of patients based on the initial dose and 77% after dose modification. Only 6.3% of patients had kidney injury with only 1 of those patients having any calculated AUC24 > 600 mg·hr/L and none above 620 mg·hr/L. No clinical failures were identified. CONCLUSIONS Increased initial dosing in infants and children is needed to result in AUC24 exposures recommended in the guidelines. Maximum dosing paired with trough monitoring may be an alternative to AUC24 monitoring in areas that are unable to perform AUC24 calculations. Prospective data are needed to validate these conclusions.

Comparison of dose modification strategies to address expected hematologic toxicities in treatment-naïve higher-risk (HR) MDS patients treated with venetoclax + azacitidine.

7041 Background: Venetoclax (Ven) is a selective, potent BCL-2 inhibitor. Ven + azacitidine (Aza) were associated with a combined complete remission (CR)/marrow CR (mCR) rate of 79% in a phase 1b study of patients (pts) with HR-MDS. Here we compared two different dose modification strategies to manage expected hematologic toxicities in two safety expansion cohorts with similar follow-up periods. Methods: Pts ≥18y diagnosed with treatment-naïve IPSS intermediate-2 or high-risk MDS with ECOG ≤2 were enrolled. Aza 75 mg/m2 (iv or subQ daily) was administered for 7 days (d) and Ven was administered at 400 mg for 14d in each 28d cycle. In both cohorts, dose modification during Cycle 1 was not recommended; dose modifications in subsequent cycles were prescribed for AEs. In Safety Expansion Cohort 1 (SE1), either Aza or Ven were initially reduced according to investigator’s choice for significant neutrophil or platelet toxicity. Dose reductions per protocol were 33% for Aza and 50% for Ven (for 14d each cycle). In subsequent cycles, Ven duration could be shortened to 9d of each cycle. In Safety Expansion Cohort 2 (SE2), dose modification guidelines recommended stepwise reductions, first in Aza dose (first to 50 mg/m2, then 36 mg/m2) and subsequently in Ven duration to 7d of each cycle (Ven 400 mg). The impact of each dose modification strategy on safety and efficacy in SE1 vs SE2 was compared. Worsening of treatment-emergent adverse events (TEAE) grades from baseline (BL) was analyzed by cycle. Responses were evaluated using IWG 2006 criteria. Analyses included all pts who received ≥1 dose of study drug. Results: We compared 22 pts in SE1 and 21 pts in SE2 with median (range) follow-up of 7.5 (1.0–8.9) and 7.9 (1.8–10.1) mos, respectively. A similar frequency of ≥ G3 hematologic TEAEs (approx %) were reported in SE1 and SE2, respectively, including anemia (14% and 33%), febrile neutropenia (46% and 48%), leukopenia (36% and 19%), neutropenia (55% and 48%) and thrombocytopenia (32% and 38%). Infections (59% and 38%) were more frequent in SE1 than SE2. In a longitudinal analysis, there were more TEAE grade increases from BL to Cycle 1 in SE2 vs SE1. This could be accounted by pts in SE1 and SE2 having unbalanced susceptibility to AEs at BL, as SE1 and SE2 pts received identical Aza + Ven doses in Cycle 1. Response rates were identical: 86% of pts in both SE1 and SE2 had CR or mCR. For pts with mCR, hematologic improvement occurred in 50% of SE1 and 46% of SE2 pts. Conclusions: No obvious hematologic differences were observed when reducing Aza before Ven (SE2) in MDS compared to investigator’s choice (SE1). Both approaches had a similar acceptable safety profile without compromising efficacy for pts with HR-MDS. Clinical trial information: NCT02942290. [Table: see text]

Cabozantinib (C) exposure-response (ER) analysis for the phase 3 CheckMate 9ER (CM 9ER) trial of nivolumab plus cabozantinib (N+C) versus sunitinib (S) in first-line advanced renal cell carcinoma (1L aRCC).

4561 Background: In the phase 3 CM 9ER trial (NCT03141177), N+C significantly improved progression-free survival (PFS; HR 0.51, 95% CI 0.41–0.64; p < 0.0001), overall survival (OS; HR 0.60, 98.89% CI 0.40–0.89; p = 0.0010), and objective response rate (p < 0.0001) vs S in 1L aRCC (Choueiri, 2020). N+C was generally well tolerated with low rates of treatment-related discontinuations, indicating successful adverse event (AE) management with dose modification to maintain tolerability. Here the impact of C exposure on efficacy and safety outcomes in CM 9ER was evaluated using ER analysis. Methods: Patients (pts, N = 320) with previously untreated aRCC received C 40 mg QD in combination with N 240 mg Q2W; dose reductions of C to 20 mg QD or 20 mg Q2D were allowed to manage AEs. Time-to-event Cox proportional hazard ER models were developed to characterize the relationship between predicted C exposure or apparent clearance (CL/F) and specified endpoints, including PFS, dose modification, and select AEs (palmar-plantar erythrodysesthesia [PPE; Gr ≥1], diarrhea [Gr ≥3], hypertension [Gr ≥3], fatigue/asthenia [Gr ≥3], and ALT/AST elevation [Gr ≥3]). C exposure was defined as the overall average concentration from time zero to the time of event or censoring (CAVG) and estimated by population pharmacokinetic modeling for a typical patient. ER analysis for OS was not done due to the low number of events at the database lock date (March 30, 2020). Results: In the ER analysis of PFS, predicted C exposure at 40-mg and 20-mg QD doses was not significantly associated with the rate of progression or death (HR 1.00, 95% CI 0.78–1.27, for 20-mg vs 40-mg dose). In the ER analysis of AEs, lower predicted C exposure was significantly associated with lower rates of PPE (HR 0.63, 95% CI 0.50–0.78, for 20-mg vs 40-mg dose) and diarrhea (HR 0.48, 95% CI 0.29–0.80) but was not significantly associated with the rates of hypertension, fatigue/asthenia, or ALT/AST elevation. Higher predicted C CL/F was associated with a lower rate of C dose modification; however, this association was not statistically significant (HR 0.80, 95% CI 0.57–1.12, for CL/F 3.2 vs 1.2 L/hr). Conclusions: In ER models of pts with 1L aRCC treated with the combination of N+C, C exposure was not significantly associated with PFS; however, higher C exposure was associated with higher rates of PPE and diarrhea. ER modeling predicts that a starting dose of 40 mg QD C in combination with N with appropriate dose modifications to manage C AEs will not adversely affect the efficacy of the combination in 1L aRCC. Clinical trial information: NCT03141177.

Gender Differences in Patients with Metastatic Pancreatic Cancer Who Received FOLFIRINOX

Background: The combination of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) is a very effective chemotherapeutic regimen for unresectable pancreatic cancer. Previous studies have reported that female gender may be a predictor of a better response to FOLFIRINOX. This study was aimed at investigating the clinical outcomes and dose modification patterns of FOLFIRINOX by gender. Methods: Patients with metastatic pancreatic cancer (MPC) who began FOLFIRINOX as the first-line therapy at Seoul National University Bundang Hospital between 2013 and 2018 were enrolled. The patients received at least four chemotherapy cycles. Local regression and a linear mixed model were used to analyze dose modification patterns by gender. Results: Ninety-seven patients with MPC (54 men; 43 women) were enrolled. In the first FOLFIRINOX cycle, there were significant differences in age and body surface area between the genders (58.8 (men) and 64.9 years (women), p = 0.005; 1.7 (men) and 1.6 m2 (women), p < 0.001, respectively). The median progression-free survival (PFS) and overall survival (OS) were 10.8 and 18.0 months, respectively. There was a trend of longer PFS (10.3 (men) and 11.9 months (women), p = 0.153) and a significantly longer OS (17.9 (men) and 25.9 months (women), p = 0.019) in female patients. During the first year of FOLFIRINOX treatment, there was a significant difference of the age-corrected dose reduction pattern by gender (a mean of 95.6% dose at the initial cycle and −0.35% of dose reduction per week in men versus a mean of 90.7% dose at the initial cycle and −0.53% of dose reduction per week in women, p-value of the slope: <0.001). There was no difference in the adverse event rates between the genders. Conclusions: Female patients showed longer OS despite a more rapid dose reduction during each cycle. Gender differences should be considered during FOLFIRINOX treatment.

Peripheral Neuropathy in the Cassiopeia Study

Introduction Peripheral neuropathy (PNP) remains one of the most common adverse events during multiple myeloma (MM) treatment. The immunomodulatory agent thalidomide and proteasome inhibitor bortezomib are particularly prone to induce PNP (Dimopoulos MA et al., Leukemia., 2010). Both agents are part of standard treatment regimens for newly diagnosed transplant-eligible MM patients. PNP varies from mild symptoms to severe disability, depending on timely dose reduction or discontinuation of treatment. Currently, incidence or severity of PNP cannot be predicted. Therefore, it is of utmost importance to monitor incidence of PNP in different treatment combinations, and in order to identify risk factors for developing PNP. Aims To investigate the incidence of PNP in patients treated in the Cassiopeia trial, to evaluate the role of CD38 antibody (daratumumab) treatment in development of PNP, and to identify risk factors for the development of PNP. Methods We retrospectively analysed incidence of PNP grade 2 to 4, scored according to common terminology criteria for adverse events version 4 (CTCAE) in the Cassiopeia study, a phase III trial conducted by IFM/HOVON, investigating the efficacy of adding daratumumab to bortezomib, thalidomide and dexamethasone (VTD). 1074 newly diagnosed MM patients were randomised. Patients received 4 induction cycles and 2 post transplantation consolidation cycles of 28 days each. Cycles included subcutaneous bortezomib (1.3 mg/m2 days 1,4,8,11), oral thalidomide (100 mg daily), dexamethasone (20-40 mg) and daratumumab intravenously (16 mg/kg and weekly during induction cycles 1 and 2 and once every two weeks during induction cycles 3,4 and consolidation). This trial was registered as ClinicalTrials.gov NCT02541383 and was supported by the French IFM and Dutch HOVON groups (Moreau et al., Lancet, 2019). Multivariate analysis was performed including sex, age, arm, body mass index (BMI), cytogenetics, ISS stage, country, diabetes mellitus (DM), creatinine clearance, liver function, ECOG, baseline PNP and disease characteristics. Results Baseline characteristics in dara-VTD and VTD arms were similar. Overall, 380/1074 (35%) patients developed grade ≥2 PNP and 102/1074 (9%) patients developed grade ≥3 PNP. Multivariate analysis indicated that the cumulative incidence of PNP grade ≥2 was significantly lower in the dara-VTD arm (33%) when compared to the VTD arm (38%) (hazard ratio (HR)=0.73, 95% confidence interval (CI) 0.59-0.91, P=0.004). Furthermore, risk factors associated with a higher cumulative incidence of PNP grade ≥2 included older age (HR=1.03; P=0.020), grade 1 PNP at baseline (HR= 2.75; P= 0.002) and higher BMI (HR=1.46, P=0.003 for BMI 25-30 to HR=2.02, P=0.004 for BMI &gt; 35). Progression free survival (PFS) from the end of induction was similar (86% vs 80% at 2 years, HR = 0.74, 95% CI 0.41-1.33, P=0.32) for patients developing grade ≥2 PNP during induction (179 pts, 17%). An unexpected finding was the difference in cumulative incidence between countries participating in this trial: in the Netherlands 68/141 (49%) of patients developed grade ≥2 PNP, while in France this was 280/846 (33%) and in Belgium 31/87 (36%) (p&lt;0.001). The protocol of the Cassiopeia trial included instructions of discontinuation and dose modification, when PNP grade ≥2 was observed. However, in a subset of patients reaching PNP grade ≥ 2 the (temporary) discontinuation or adjustment of dose as described in the treatment protocol had not been applied (respectively in 148/352 (42%) with PNP ≥ 2 and in 39/97 (40%) with PNP ≥3). Conclusions Despite bortezomib being administered subcutaneously and clear instructions on discontinuation and dose modification, we observed a clinically relevant incidence of grade ≥2 PNP (35%) and grade ≥3 PNP (9%) in patients treated in the Cassiopeia trial. Patients in the dara-VTD arm showed less grade ≥2 PNP, suggesting a possible positive effect of daratumumab. Risk factors for the development of grade ≥2 PNP included older age, PNP at baseline and BMI &gt; 25. Differences in incidence between countries were observed, however no clear explanation was found. Furthermore, standard measures for grading PNP, such as CTCAE criteria, are subject to interpretation bias of both the patient and the treating physician. Continuous screening and correct grading of PNP and strict compliance with guidelines is warranted. Disclosures Moreau: Amgen: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Honoraria; Sanofi: Consultancy, Honoraria; Novartis: Honoraria. Vermeulen:Janssen: Current Employment, Current equity holder in publicly-traded company. Broyl:Janssen, Celgene, Takeda, Amgen: Honoraria. Sonneveld:Sanofi: Consultancy; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Skyline Dx: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.