Aims This study was designed to investigate the biochemical and physiological covariates or comedications that affect the pharmacokinetics of imatinib mesylate in patients with chronic‐phase chronic myeloid leukaemia (CP CML). Methods Pharmacokinetic data were analyzed in 371 patients receiving 400 mg imatinib once daily during a phase III trial of imatinib vs interferon‐alfa plus cytarabine for the treatment of newly diagnosed CP CML. Covariates included age, weight, sex, ethnicity, haemoglobin (Hb) concentration, white blood cell (WBC) count, liver function, and creatinine concentration. Blood samples for imatinib analysis were taken on treatment days 1 and 29. Nonlinear mixed effects modelling was used for the population pharmacokinetic analysis. Results Population mean estimates (95% confidence interval) at day 1 for apparent clearance (CL) and apparent volume of distribution ( V ) of imatinib were 14 (13‐15) l h −1 and 252 (237‐267) l, respectively. Modelling suggested that CL decreased by 4 (3‐5) l h −1 from day 1 to day 29, whereas V remained unchanged. Interindividual variability in CL and V was 32% and 31%, respectively. Weight, Hb, and WBC count demonstrated small effects on CL and V . Doubling body weight or Hb or halving the WBC count was associated with a 12%, 86% and 8% increase in CL, respectively, and a 32%, 60% and 5% increase in V , respectively. Comedications showed no clear effects on imatinib CL. Conclusions Population covariates and coadministered drugs minimally affected imatinib pharmacokinetics in newly diagnosed CP CML patients.
5572 Background: The reported risk of HSR during carboplatin retreatment is 18-44% and increases with repeated carboplatin exposure. We aimed to prospectively study the effect of an extended incremental infusion of carboplatin on the rate of HSR. Methods: Eligible patients (pts) with recurrent ovarian cancer were consented to an IRB-approved phase II randomized study from 01/2011-01/2015. Pts were randomly assigned 1:1 to standard 30-minute or an incremental 3-hour (1% in 1st hour, 9% in 2nd hour and 90% in 3rd hour) carboplatin infusion. Pts were stratified for concomitant taxane. Based on historical estimates the study was powered to detect a reduction in HSR from 20% to 5% with the extended infusion. All pts were prescribed premedication with montelukast 10 mg nocte x 3 days, dexamethasone 20 mg the night before and morning of, as well as famotidine 20 mg (or ranitidine) and diphenhydramine 50 mg (or hydroxyzine) prior to carboplatin. Pts were deemed evaluable for the study endpoint if they completed ≥ 5 cycles of carboplatin-based treatment or had carboplatin HSR. CTCAE criteria were used. Results: A total of 143 pts with recurrent ovarian cancer were enrolled. Median age was 62 years (35-82). 104 pts (52 in each arm) were evaluable for the study endpoint. Among these pts, 72 (69%), 27 (26%), 2 (1.9%) and 3 (2.9%) pts had 1, 2, 3 and 4 prior platinum-based regimens, respectively. 27 pts (26%) received carboplatin single agent and the remainder a platinum-doublet (46 liposomal doxorubicin, 24 gemcitabine, 7 paclitaxel). There were 15 HSR (14% of pts); 9 HSR in standard arm (9/52, 17%) and 6 HSR in the extended arm (6/52, 12%). There was 1 grade 3 HSR in the extended arm. No pt required hospitalization or epinephrine for HSR. The other 14 HSR were grade 1 or 2. HSR occurred on cycle #1 (1 pt); #2 (5 pts); #3 (4 pts); #4 (2 pts); #5 (2 pts) and #6 (1 pt). 2/9 HSR pts in standard arm were able to complete therapy with an extended infusion without further HSR. Conclusions: We did not demonstrate a statistically significant reduction in carboplatin HSR with use of an extended carboplatin infusion. However, the relatively low frequency of severe HSR in both arms suggests there may be a role for prophylactic premedication prior to carboplatin retreatment. Clinical trial information: NCT01248962.
5590 Background: Although AIs are sometimes used in selected patients with uLMS, there are few data assessing the efficacy of AIs in this setting. Methods: A retrospective electronic medical record review of patients (pts) with uLMS treated with an AI at Memorial Sloan-Kettering Cancer Center between 1998–2008 was performed. The primary endpoint was progression free survival (PFS), defined as time from the start of AI until death, progression or last follow-up. PFS was estimated by Kaplan-Meier method. Best response using RECIST was also assessed. Results: 34 pts with advanced, measurable uLMS were treated with AIs. Median age was 53 yrs (range 35–74); median body mass index 28.1 kg/m 2 (range 16.1–52.1); LMS grade low: 5, high: 29; hormone receptor status: 19 ER+, 9 ER-, 6 ER unknown, 9 PR+, 9 PR-, 16 PR unknown; low volume of disease (no lesion >2 cm): 19 pts(56%), high volume: 15 pts (44%). 23 pts (68%) had had prior chemotherapy (1 regimen: 29%, 2 regimens: 18%, 3 regimens: 15%, >4 regimens: 6%); 12 pts (35%) had had prior pelvic radiotherapy. AIs used were: letrozole 74% (9% with leuprolide if premenopausal), anastrozole 21%, exemestane 6%. Median PFS was 2.9 months (95% CI: 1.8–5.1). 8 pts (23.5%) had a PFS >6months. Among pts with ER or PR + uLMS, median PFS was 5months (95% CI: 1.8–9.4) versus 1.9months (95% CI: 0.9–3.2) with ER and PR negative uLMS. Best response was partial response in 3 pts (8.8%) (all of whom were ER+), stable disease in 12 (35%), and progressive disease in 19 (56%). Common toxicities were grade 1–2 asthenia (30%), hot flashes (30%), and arthralgias (27%). Conclusions: In this highly selected population of pts with uLMS AIs fail to achieve objective response. While relatively prolonged PFS was observed among ER and/or PR+ uLMS pts, in the absence of a no-treatment control group this outcome cannot be attributed solely to the activity of the AI treatment. No significant financial relationships to disclose.
