Dose Escalation Patterns Research Articles

Real-world evidence on levodopa dose escalation in patients with Parkinson's disease treated with istradefylline.

Istradefylline, a selective adenosine A2A receptor antagonist, is indicated in the US and Japan as adjunctive treatment to levodopa/decarboxylase inhibitors in adults with Parkinson's disease (PD) experiencing OFF time. This study aimed to observe patterns of dose escalation of levodopa over time in patients initiated on istradefylline. Using Japanese electronic health record data, interrupted time series analyses were used to compare levodopa daily dose (LDD, mg/day) gradients in patients before and after initiation of istradefylline. Data were analyzed by period relative to istradefylline initiation (Month 1): pre-istradefylline (Months -72 to 0), early istradefylline (Months 1 to 24), and late istradefylline (Months 25 to 72). Subgroup analyses included LDD before istradefylline initiation (<400, ≥400 to <600, ≥600 mg/day) and treatment with or without monoamine oxidase-B (MAO-B) inhibitors, catechol-O-methyltransferase (COMT) inhibitors, or dopamine agonists before istradefylline initiation. The analysis included 4026 patients; mean (SD) baseline LDD was 419.27 mg (174.19). Patients receiving ≥600 mg/day levodopa or not receiving MAO-B inhibitors or COMT inhibitors demonstrated a significant reduction in LDD increase gradient for pre-istradefylline vs late-phase istradefylline (≥600 mg/day levodopa, -6.259 mg/day each month, p<0.001; no MAO-B inhibitors, -1.819 mg/day each month, p = 0.004; no COMT inhibitors, -1.412 mg/day each month, p = 0.027). This real-world analysis of Japanese prescription data indicated that slowing of LDD escalation was observed in patients initiated on istradefylline, particularly in those receiving ≥600 mg/day levodopa, suggesting istradefylline may slow progressive LDD increases. These findings suggest that initiating istradefylline before other levodopa-adjunctive therapies may mitigate LDD increases, potentially reducing occurrence or severity of levodopa-induced complications in long-term istradefylline treatment.

Phase I dose escalation study and pilot efficacy analysis of LXI-15029, a novel mTOR dual inhibitor, in Chinese subjects with advanced malignant solid tumors

BackgroundThe mammalian target of rapamycin (mTOR) kinase, a central component of the PI3K/AKT/mTOR pathway, plays a critical role in tumor biology as an attractive therapeutic target. We conducted this first-in-human study to investigate the safety, pharmacokinetics (PK), and pilot efficacy of LXI-15029, an mTORC1/2 dual inhibitor, in Chinese patients with advanced malignant solid tumors.MethodsEligible patients with advanced, unresectable malignant solid tumors after failure of routine therapy or with no standard treatment were enrolled to receive ascending doses (10, 20, 40, 60, 80, 110, and 150 mg) of oral LXI-15029 twice daily (BID) (3 + 3 dose-escalation pattern) until disease progression or intolerable adverse events (AEs). The primary endpoints were safety and tolerability.ResultsBetween June 2017 and July 2021, a total of 24 patients were enrolled. LXI-15029 was well tolerated at all doses. Only one dose-limiting toxicity (grade 3 increased alanine aminotransferase) occurred in the 150 mg group, and the maximum tolerated dose was 110 mg BID. The most common treatment-related AEs were leukocytopenia (41.7%), increased alanine aminotransferase (20.8%), increased aspartate aminotransferase (20.8%), prolonged electrocardiogram QT interval (20.8%), and hypertriglyceridemia (20.8%). No other serious treatment-related AEs were reported. LXI-15029 was absorbed rapidly after oral administration. The increases in the peak concentration and the area under the curve were greater than dose proportionality over the dose range. Eight patients had stable disease. The disease control rate was 40.0% (8/20; 95% CI 21.7–60.6). In evaluable patients, the median progression-free survival was 29 days (range 29–141).ConclusionsLXI-15029 demonstrated reasonable safety and tolerability profiles and encouraging preliminary antitumor activity in Chinese patients with advanced malignant solid tumors, which warranted further validation in phase II trials.Trial registrationNCT03125746(24/04/2017),http://ClinicalTrials.gov/show/NCT03125746

EPH161 Dose Escalation Patterns in Patients with Overweight or Obesity Initiating Semaglutide 2.4mg: A 6-Month Follow-up in a Real-World Setting in the United States

Once-weekly subcutaneous semaglutide 2.4mg is approved for chronic weight management in adults with obesity (or overweight with ≥1 weight-related comorbidity). This study describes real-world treatment patterns of semaglutide 2.4mg for 6 months following medication initiation when availability of escalation and maintenance doses were limited.

Dose Escalation Patterns of Advanced Therapies in Crohn's Disease and Ulcerative Colitis: A Systematic Literature Review.

Dose escalation is one of the treatment approaches studied and suggested in advanced therapies for Crohn's disease (CD) and ulcerative colitis (UC). This study aimed to identify and characterize the dosing escalation patterns of advanced therapies in CD and UC. Two systematic literature reviews (SLRs) were conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. MEDLINE®, Embase®, and Cochrane Library were searched for articles published between January 2011 and October 2021 and limited to non-interventional studies in English language. Congress and bibliographic searches were also conducted. Articles were screened by two independent researchers. Dose escalation patterns were described and summarized considering the regional regulatory label recommendation (in North America [NA] or outside of North America [ONA]). Among 3190 CD and 2116 UC articles identified in the Ovid searches, 100 CD and 54 UC studies were included in the SLR, with more studies conducted ONA. Most studies reported an initial maintenance dose pattern aligned with the lower starting dose per local regulatory label; however, several ONA studies (n = 13 out of 14) reported ustekinumab every 8 weeks as starting maintenance pattern in CD. In ONA studies, the median within-guideline escalation rates in CD and UC were 43% in ustekinumab (CD only), 33% and 32% for vedolizumab; 29% and 39% for adalimumab; and 14% and 10% for infliximab. Evidence regarding dose escalation patterns for tofacitinib, certolizumab pegol, and golimumab was limited. Some dose escalation patterns outside of label recommendations were observed including ustekinumab every 8 weeks to every 4 weeks and vedolizumab every 8 weeks to every 6 weeks. Dose escalation strategies are widely documented in the literature. The reported dose escalation patterns and escalation rates vary by region and by CD and UC. Most escalation patterns reported were aligned with regulatory recommendations while some reported more diverse or aggressive dose escalation. CRD42021289251.

A phase 1 study of dalpiciclib, a cyclin-dependent kinase 4/6 inhibitor in Chinese patients with advanced breast cancer

BackgroundDalpiciclib (SHR6390) is a novel inhibitor of cyclin-dependent kinase 4/6 which demonstrated promising anti-tumor potency in preclinical models. This first-in-human study was conducted to evaluate the tolerability, pharmacokinetics, safety, and preliminary antitumor activity of dalpiciclib in patients with advanced breast cancer (ABC).MethodsIn this open-label, phase 1 study, Chinese patients who had failed standard therapy were enrolled to receive oral dalpiciclib in 3 + 3 dose-escalation pattern at doses of 25–175 mg. Eligible patients were given a single-dose of dalpiciclib in week 1, followed by once daily continuous doses for 3 weeks, and 1 week off in 28-day cycles. Based on the tolerability, pharmacokinetics, and activity data revealed from the dose-escalation phase, three dose cohorts were selected to expand to 8–10 patients. The primary endpoints were maximum tolerated dose (MTD) and pharmacokinetics.ResultsBetween Apr 15, 2016 and Dec 21, 2018, 40 patients were enrolled; all were diagnosed of hormone receptor-positive and HER2-negative ABC. Dalpiciclib 100 mg, 125 mg, and 150 mg cohorts were expanded to 10 patients. No dose-limiting toxicity was observed and the MTD was not reached. Adverse events (AEs) of grade 3 or 4 were observed in 22 (55.0%) of 40 patients, being neutropenia (52.5%), leukopenia (35.0%), thrombocytopenia (5.0%), and hypertension (2.5%). No serious AEs were reported. At the doses of 50–175 mg, steady state areas under the concentration-time curve and peak concentration increased almost proportionally with dose. The disease control rate (DCR) was 62.5% (25/40, 95% CI: 45.8–77.3). Two patients (5%; 125 mg and 150 mg cohorts) achieved partial response, with responses lasting 169 and 356+ days, respectively. Among the three expansion cohorts, the 150 mg cohort had the numerically highest DCR of 80.0% (95% CI: 44.4–97.5) and longest median progression-free survival of 8.4 months (95% CI: 2.1–not reached).ConclusionsDalpiciclib showed acceptable safety profile and dose-dependent plasma exposure in Chinese patients with ABC. The recommended phase 2 dose was 150 mg. Preliminary evidence of clinical activity was observed, which warrants further validation.Trial registrationClinicalTrials.gov identifier: NCT02684266. Registered Feb 17, 2016.

Patterns of Dose-Escalation in Patients with T2-4 N0-3 M0 Unresectable Esophageal Cancer, 2011-2016

Patterns of Dose-Escalation in Patients with T2-4 N0-3 M0 Unresectable Esophageal Cancer, 2011-2016

Patterns of Dose Escalation Among Patients With Esophageal Cancer Undergoing Definitive Radiation Therapy: 2006-2016

PurposeAlthough single-institution series suggest potential benefit to dose escalation in definitive radiation therapy for esophageal cancer, randomized trials including intergroup-0123 and the recently presented A Randomized Trial of Dose Escalation in definitive Chemoradiotherapy for patients with Oesophageal cancer (ARTDECO) trial showed no improvement in outcomes with higher radiation therapy dose. As such, there may be significant variation in radiation dose for definitive treatment of esophageal cancer. Methods and MaterialsThe National Cancer Database was used to identify patients who received a diagnosis of nonmetastatic T2+ esophageal cancer between 2006 and 2016 who did not receive definitive surgery and were treated with chemotherapy and radiation therapy doses between 41.4 and 74 Gy. Multivariable logistic regression defined adjusted odds ratios (AORs) of receipt of >50.4 Gy, including year of diagnosis (2006-2013 vs 2014-2016) ∗ histology (squamous cell carcinoma [SCC] vs adenocarcinoma) and year of diagnosis (2006-2013 vs 2014-2016) ∗ disease site (cervical esophagus vs noncervical esophagus) interaction terms, to assess whether the effect of diagnosis year on dose varied by histology and disease site, respectively. ResultsAmong 14,517 patients, the most common dose was 50.4 Gy, used for 6955 (47.9%) patients. Dose escalation above 50.4 Gy was observed in 4440 (30.6%) patients and declined by year, from 42.2% in 2006 to 23.5% in 2016. Patients with SCC versus adenocarcinoma had higher odds of dose escalation (39.3% vs 23.8%; AOR 1.46; P < .001), as did those with cervical esophageal primaries versus other primary sites (54.9% vs 27.4%; AOR 2.51; P < .001). The effect of later diagnosis year was greater for adenocarcinoma than for SCC (pint = 0.001, AOR 0.54, P < .001 vs AOR 0.71, P < .001) and significant for noncervical esophagus but not cervical esophagus (pint <0.001, AOR 0.56, P < .001 vs AOR 0.95, P = .616). ConclusionsDose escalation in definitive chemoradiotherapy for esophageal cancer declined over time, particularly for adenocarcinoma histology and noncervical primary site. Given the recent results of ARTDECO, our findings can serve as a benchmark from which to measure future shifts in practice patterns.

A phase I study of SHR6390, a cyclin-dependent kinase 4/6 inhibitor in patients with advanced breast cancer (ABC).

1095 Background: SHR6390 is a novel inhibitor of cyclin-dependent kinase 4/6 (CDK 4/6). This study was conducted to evaluate the tolerability, pharmacokinetics, safety, and preliminary antitumor activity of SHR6390 in patients (pts) with advanced breast cancer (ABC). Methods: In this open-label, single-arm phase I study, pts who had failed standard therapy were enrolled to receive oral SHR6390 in 3 + 3 dose-escalation pattern at doses of 25−175 mg. Eligible pts were given a single-dose of SHR6390 in week 1, followed by once daily continuous doses for three weeks, and one week off in 28-day cycle. Based on the tolerability, pharmacokinetics, and activity data revealed from the dose-escalation phase, three dose cohorts were selected to expand to 8−10 pts. The primary endpoints were maximum tolerated dose (MTD) and pharmacokinetics. Results: Between Apr 15, 2016 and Dec 21, 2018, 40 pts were enrolled. All pts were diagnosed of hormone receptor positive and HER2-negative ABC. 45.0% of pts had at least three prior chemotherapies and 55.0% had at least two prior endocrine therapies. SHR6390 100 mg, 125 mg, and 150 mg cohorts were expanded to 10 pts, respectively. No dose limiting toxicity was observed and the MTD was not reached. Adverse events (AEs) of grade ≥3 were observed in 22 (55.0%) of 40 pts, being neutropenia (52.5%), leukopenia (35.0%), thrombocytopenia (5.0%), and hypertension (2.5%). No serious AEs were reported. At the doses of 50−175 mg, median time to peak concentration was 2.5−4.0 h, and mean terminal half-life was 40.3−51.4 h with single-dose SHR6390. Following multiple dosing, steady state SHR6390 was observed on day 8. The steady state areas under the concentration and peak concentration increased slightly greater than the increase rate of dose, with steady state Cmax at day 21 of 41.1, 53.4, 87.0, 115.0, 126.0, and 155.0 ng/mL in 50, 75, 100, 125, 150, and 175 mg cohorts, respectively. The disease control rate was 62.5% (25/40, 95% CI 45.8% to 77.3%). Two pts (5%, one in 125 mg, one in 150 mg cohort) achieved partial response, with responses lasting 169 and 356+ days, respectively. Conclusions: SHR6390 showed acceptable safety profile and dose-dependent plasma exposure in pts with ABC. The recommended phase II dose was 150 mg. Preliminary evidence of clinical activity was observed, warranted further study. Clinical trial information: NCT02684266 .

Deep reinforcement learning for automated radiation adaptation in lung cancer.

To investigate deep reinforcement learning (DRL) based on historical treatment plans for developing automated radiation adaptation protocols for nonsmall cell lung cancer (NSCLC) patients that aim to maximize tumor local control at reduced rates of radiation pneumonitis grade 2 (RP2). In a retrospective population of 114 NSCLC patients who received radiotherapy, a three-component neural networks framework was developed for deep reinforcement learning (DRL) of dose fractionation adaptation. Large-scale patient characteristics included clinical, genetic, and imaging radiomics features in addition to tumor and lung dosimetric variables. First, a generative adversarial network (GAN) was employed to learn patient population characteristics necessary for DRL training from a relatively limited sample size. Second, a radiotherapy artificial environment (RAE) was reconstructed by a deep neural network (DNN) utilizing both original and synthetic data (by GAN) to estimate the transition probabilities for adaptation of personalized radiotherapy patients' treatment courses. Third, a deep Q-network (DQN) was applied to the RAE for choosing the optimal dose in a response-adapted treatment setting. This multicomponent reinforcement learning approach was benchmarked against real clinical decisions that were applied in an adaptive dose escalation clinical protocol. In which, 34 patients were treated based on avid PET signal in the tumor and constrained by a 17.2% normal tissue complication probability (NTCP) limit for RP2. The uncomplicated cure probability (P+) was used as a baseline reward function in the DRL. Taking our adaptive dose escalation protocol as a blueprint for the proposed DRL (GAN + RAE + DQN) architecture, we obtained an automated dose adaptation estimate for use at ∼2/3 of the way into the radiotherapy treatment course. By letting the DQN component freely control the estimated adaptive dose per fraction (ranging from 1-5 Gy), the DRL automatically favored dose escalation/de-escalation between 1.5 and 3.8 Gy, a range similar to that used in the clinical protocol. The same DQN yielded two patterns of dose escalation for the 34 test patients, but with different reward variants. First, using the baseline P+ reward function, individual adaptive fraction doses of the DQN had similar tendencies to the clinical data with an RMSE = 0.76 Gy; but adaptations suggested by the DQN were generally lower in magnitude (less aggressive). Second, by adjusting the P+ reward function with higher emphasis on mitigating local failure, better matching of doses between the DQN and the clinical protocol was achieved with an RMSE = 0.5 Gy. Moreover, the decisions selected by the DQN seemed to have better concordance with patients eventual outcomes. In comparison, the traditional temporal difference (TD) algorithm for reinforcement learning yielded an RMSE = 3.3 Gy due to numerical instabilities and lack of sufficient learning. We demonstrated that automated dose adaptation by DRL is a feasible and a promising approach for achieving similar results to those chosen by clinicians. The process may require customization of the reward function if individual cases were to be considered. However, development of this framework into a fully credible autonomous system for clinical decision support would require further validation on larger multi-institutional datasets.

Patterns of Dose Escalation Amongst Patients with Ulcerative Colitis and Crohnʼs Disease Treated with Vedolizumab vs. Infliximab in the United States

Patterns of Dose Escalation Amongst Patients with Ulcerative Colitis and Crohnʼs Disease Treated with Vedolizumab vs. Infliximab in the United States

High-dose-rate stereotactic body radiation therapy for postradiation therapy locally recurrent prostatic carcinoma: Preliminary prostate-specific antigen response, disease-free survival, and toxicity assessment

PurposePatients with locally recurrent adenocarcinoma of the prostate following radiation therapy (RT) present a challenging problem. We prospectively evaluated the use of “high-dose-rate-like” prostate stereotactic body RT (SBRT) salvage for this circumstance, evaluating prostate-specific antigen response, disease-free survival, and toxicity. Methods and materialsBetween February 2009 and March 2014, 29 patients with biopsy-proven recurrent locally prostate cancer >2 years post-RT were treated. Median prior RT dose was 73.8 Gy and median interval to SBRT salvage was 88 months. Median recurrence Gleason score was 7 (79% was ≥7). Pre-existing RT toxicity >grade 1 was a reason for exclusion. Magnetic resonance imaging–defined prostate volume including any suspected extraprostatic extension, comprising the planning target volume. A total of 34 Gy/5 fractions was given, delivering a heterogeneous, high-dose-rate-like dose-escalation pattern. Toxicities were assessed using Common Terminology Criteria for Adverse Events, version 3.0, criteria. ResultsTwenty-nine treated patients had a median 24-month follow-up (range, 3-60 months). A median pre-SBRT salvage baseline prostate-specific antigen level of 3.1 ng/mL decreased to 0.65 ng/mL and 0.16 ng/mL at 1 and 2 years, respectively. Actuarial 2-year biochemical disease-free survival measured 82%, with no local failures. Toxicity >grade 1 was limited to the genitourinary domain, with 18% grade 2 or higher and 7% grade 3 or higher. No gastrointestinal toxicity >grade 1 occurred. ConclusionsTwo-year disease-free survival is encouraging, and the prostate-specific antigen response kinetic appears comparable with that seen in de novo patients treated with SBRT, albeit still a preliminary finding. Grade ≥2 genitourinary toxicity was occasionally seen with no obvious predictive factor. Noting that our only brachytherapy case was 1 of the 2 cases with ≥grade 3 genitourinary toxicity, caution is recommended treating these patients. SBRT salvage of post-RT local recurrence appears clinically feasible, with longer term evaluation required to assess ultimate efficacy and late toxicity rates.

AB1077 Treatment Patterns and Persistence with Subcutaneous Biologic Therapies in Patients with Ankylosing Spondylitis

BackgroundAnkylosing Spondylitis (AS) is a chronic, systemic disease that predominantly affects the axial skeleton with sacroiliac joints involvement as its hallmark, causing characteristic inflammatory back pain and resulting in varying...

Chemical coping versus pseudoaddiction in patients with cancer pain

The purpose of this case series was to describe patients with aberrant drug-related behaviors and similar patterns of dose escalation in whom interdisciplinary assessment revealed different bases for their dose increases. During the period from December 26 to December 30, 2011, the medical records of two patients with opioid-related aberrant behaviors were reviewed. We described two patients with a significant cancer history and different comorbidities who presented with different aberrant drug-related behaviors and opioid requirements. Opioid-related aberrant behaviors can be interpreted in different ways, and two of the more common syndromes in cancer patients are chemical coping and pseudoaddiction. In advanced cancer patients, the boundaries between these conditions are not as clear, and diagnosis is often made retrospectively. Furthermore, there have been relatively limited studies describing these two syndromes. Thus, they continue to pose a diagnostic and treatment challenge that requires different approaches for effective management of symptoms. The key characteristic between the two syndromes is that the behaviors displayed in chemical coping are motivated by obtaining opioids to relieve psychosocial distress, while in pseudoaddiction these behaviors are motivated by uncontrolled nociceptive input. Close monitoring of the pain syndromes, aberrant behaviors, and opioid requirements over several visits is usually necessary to distinguish the two syndromes.

Long-term durability and dose escalation patterns in infliximab therapy for psoriasis

Infliximab often requires dose escalation to maintain response. Studies regarding long-term durability and dose escalation patterns for psoriasis are few. We sought to evaluate dose escalation patterns in psoriatic patients to identify factors of lack of optimal response to infliximab. A retrospective cohort study included 93 patients (216.3 patient-years) treated with infliximab for psoriasis. Kaplan-Meier analysis assessed drug durability. A median infliximab dose of 5.42 mg/kg/mo (range: 2.71-10.83) for a mean of 28 months was administered. Two thirds of patients received a dose escalation. Concurrent methotrexate extended duration of therapy (by a mean ± SD of 19.5 ± 8.1 months, P= .034), including time until first dose escalation (by a mean ± SD of 12.0 ± 6.1 months, P= .037), and failure (by a mean ± SD of 20.7 ± 6.7 months, P= .034). Patients who increased the infusion frequency before increasing the dose remained on infliximab 8.4 months longer than those who first increased the dose (P= .045). Four patients experienced adverse events; 2 required discontinuation. Psoriasis Area and Severity Index, infliximab levels, and antibody titers were not measured. Dose escalation optimizes durability of infliximab. The probability of maintaining response is enhanced by concomitant methotrexate and increasing the infusion frequency before increasing the dose.

Dosing patterns of three tumor necrosis factor blockers among patients with rheumatoid arthritis in a large United States managed care population

Objective:To describe dosing patterns of etanercept, adalimumab, and infliximab in rheumatoid arthritis (RA) patients in US managed care.Methods:This retrospective analysis included adult (18–64 years) RA patients in the HealthCore Integrated Research Database with ≥1 claim for etanercept, adalimumab, or infliximab between 7/1/2007 and 1/31/2010. Patients had 6 months pre-index and 12 months post-index claim eligibility. Patients without any TNF blocker claim during the pre-index period were considered new patients and patients with a TNF blocker claim during the pre-index period were considered continuing patients. Persistence, discontinuation, switch, and dose escalation patterns were evaluated. Patients with 1-year persistence were evaluated for dose escalation using two methods: (1) average weekly dose and (2) increase from 50 mg to 75 mg or 100 mg weekly of etanercept or from 40 mg every other week to 40 mg weekly of adalimumab or increase in vial or decreased infusion interval for infliximab.Results:Data from 2426 patients were analyzed (1595 etanercept; 417 adalimumab; 414 infliximab). Persistence ≥1 year on index medication was reported in 62.2% and 89.2% of new and continuing patients on etanercept, respectively, 66.0% and 94.0% on adalimumab, and 68.9% and 96.4% on infliximab. Discontinuation occurred in 19.7% and 7.9% of new and continuing patients on etanercept, respectively, 20.6% and 4.5% on adalimumab, and 18.8% and 2.1% on infliximab. Switching occurred in 12.2% and 4.3% of new and continuing patients on etanercept, respectively, 9.1% and 1.8% on adalimumab, and 10.4% and 2.1% on infliximab. Dose escalation was lower with etanercept (0.4–2.6%) than adalimumab (12.6–24.3%) or infliximab (40.0–79.5%) (P < 0.0001).Conclusions:Discontinuation and switching were common within 1 year of initiating etanercept, adalimumab, and infliximab in patients with RA in this analysis. Study limitations included the restricted patient age range; analysis of three TNF blockers; study period (prior to approval of additional agents); and missing reasons for treatment changes.

Tumor necrosis factor blocker dose escalation among biologic naïve rheumatoid arthritis patients in commercial managed-care plans in the 2 years following therapy initiation

Objective:This study uses real-world US managed-care claims data to estimate dose escalation rates over the first and second years of therapy among biologic naïve rheumatoid arthritis (RA) patients initiating tumor necrosis factor (TNF) blocker therapy with etanercept, adalimumab, or infliximab.Methods:Non-elderly adult (age 18–65 years) RA patients initiating etanercept, adalimumab, or infliximab from July 1, 2005 to April 30, 2009, were identified using the MarketScan Commercial Database. National and regional dose-escalation patterns were evaluated 12 and 24 months after initiation. In the single-instance method, dose escalation was defined as having one average weekly dose 115%, 130%, or 150% greater than the initial average weekly dose. By the two-instances method, dose escalation was defined as having two consecutive claims with an average weekly dose 115% or 130% greater than the initial average weekly dose.Results:A total of 2747 patients met the inclusion criteria (mean age 50 years [SD = 10]; 74% female). More patients initiated etanercept (44%) than adalimumab (37%) or infliximab (20%). Using the single-instance method, dose escalation at 12 months ranges were 0.8–1.5% for etanercept, 10.8–12.5% for adalimumab, and 16.4–42.5% for infliximab; ranges at 24 months were 0.8–2.1% for etanercept, 14.3–17.5% for adalimumab, and 26.4–57.6% for infliximab. The two-instances method showed a similar relationship among the treatment cohorts at both 12 and 24 months, with lower dose-escalation rates for etanercept (0.8%, 0.8%) than adalimumab (8.7%, 13.3%) or infliximab (22.9%, 37.6%) at the 130% threshold (p < 0.001). Dose-escalation rates for etanercept, adalimumab, and infliximab were consistent across US geographic regions.Conclusion:Patients initiating etanercept had lower rates of dose escalation than patients initiating adalimumab or infliximab in the first and second year following therapy initiation, as well as across US geographic regions. These results may not be generalizable to the entire US RA population.

Comparison of methods for measuring dose escalation of the subcutaneous TNF antagonists for rheumatoid arthritis patients treated in routine clinical practice

Objectives:Tumor necrosis factor (TNF) antagonists, most frequently prescribed biologics for moderate to severe rheumatoid arthritis (RA), are subject to dose escalation. Even though different methods have been employed to estimate the timing and magnitude of dose escalation, there is no consensus on which method is optimal. The purpose was to evaluate different methods for assessing dose escalation patterns for the subcutaneously delivered TNF antagonists, etanercept and adalimumab.Methods:Five different methods to describe dose escalation patterns were compared using a large administrative claims database from US health plans. RA patients age 18 and above with ≥2 claims for etanercept or adalimumab were included. These methods included last dose versus index dose (the dose of a patient’s first biologic prescription [adalimumab or etanercept]), average dose versus recommended dose, multiple (≥2) instances of subsequent doses exceeding the index dose, subsequent doses exceeding a predetermined threshold above the index dose, and the time-trend method, comparing each subsequent dose throughout the course of therapy to the index dose.Results:A total of 1369 etanercept and 461 adalimumab RA patients were evaluated for dose escalation. Estimates of dose escalation were highest for both drugs based on the average dose method (10.3% for etanercept, 33.6% for adalimumab). The time-trend method demonstrated the temporal trends in the percent of patients with dose escalation. Adalimumab patients had a higher rate of dose escalation than etanercept patients, regardless of method. The study is limited in that it could not assess the reason for or clinical outcomes associated with dose escalation.Conclusions:Different methods for evaluating dose escalation yield different numerical estimates but consistently give the same overall comparative result. The choice of method should depend on the specific research question. The average dose method may be the most useful for cost impact studies, whereas the time-trend method provides the most comprehensive information on dose patterns.

Long-term management of chronic pain with transdermal buprenorphine: A multicenter, open-label, follow-up study in patients from three short-term clinical trials

Transdermal buprenorphine is available in Europe for the treatment of moderate to severe chronic pain. It has been evaluated at doses of 35, 52.5, and 70 microg/h for the management of moderate to severe chronic cancer and noncancer pain in 3 randomized, double-blind, placebo-controlled trials, each of limited duration (approximately 14 days each). Long-term data are essential to determining the performance of an analgesic in the management of chronic pain. The purpose of this follow-up study was to obtain data on the efficacy and tolerability of long-term treatment with transdermal buprenorphine in cancer and noncancer patients with chronic persistent pain of moderate to severe intensity. This was an open-label, uncontrolled, follow-up study in patients from the 3 previous clinical trials who elected to continue treatment with transdermal buprenorphine 35 microg/h and sublingual buprenorphine tablets (0.2 mg) as needed for breakthrough pain. The patch was to be changed every 72 hours throughout the patient's course of pain therapy. At visits every 2 weeks for the first 4 weeks and every 4 weeks for the remainder of study participation, patients evaluated their pain relief retrospectively on a 4-point verbal rating scale. They also rated the ease of patch handling using a 3-point verbal rating scale. Patterns of dose escalation and dose stability were monitored over time. Adherence to therapy was determined based on the number of patients who complied with the dosing schedule. Adverse events were documented by type, intensity, location (systemic or local), and relationship to study medication. Two hundred thirty-nine patients were included in this follow-up study (120 women, 119 men; 100% white; mean [SD] age, 58 [11.3] years; mean weight, 70.8 [14.7] kg). One hundred thirty-four had cancer-related pain and 105 had pain of noncancerous origin. The mean duration of participation was 7.5 months, and 37 (15.5%) patients participated for >12 months. Maximum study participation was 3.4 years in cancer patients and 5.7 years in noncancer patients. One hundred eighty-eight (78.7%) patients were considered adherent to therapy. The majority (65.9%) of patients managed their pain with the patchalone or took no more than 1 additional sublingual tablet daily for breakthrough pain. At least satisfactory pain relief was reported by 215 (90.0%) patients, and the buprenorphine patch was generally well tolerated. The most common systemic adverse drug reactions were nausea (9.2%), dizziness (4.6%), vomiting (4.2%), constipation (3.8%), and tiredness (2.9%), whereas the most common local adverse drug reactions were erythema (12.1%), pruritus (10.5%), and exanthema (8.8%). Transdermal buprenorphine was generally well tolerated and effective for the long-term treatment of chronic cancer or noncancer pain in these patients who had previously received buprenorphine in 3 short-term clinical trials.

Feasibility Study of a Dose Dense Induction Regimen of High Dose Cytarabine (HiDAC) and Gemtuzumab Ozogamicin (Mylotarg™) for Newly Diagnosed Elderly Patients with Acute Myeloid Leukemia.

Elderly patients with acute myeloid leukemia (AML) are known to have higher relapse rates due to the failure to overcome drug resistance. In an attempt to overcome this we conducted a Phase I study of a dose dense regimen of two cycles of HiDAC and MylotargTM as sole therapy in newly diagnosed AML patient's ≥60 years. HiDAC was administered in a dose escalation pattern: 3000mg/m2 intravenously for 6 (cohort 1) and 9 (cohort 2)doses, and MylotargTM was infused at 6mg/m2 intravenously on days 1 and 8 of each cycle. All patients received G-CSF 5mcg/kg/day subcutaneously from days 11–14 until count recovery. Nine patients were enrolled, six patients in cohort 1 and three patients in cohort 2. The mean age in this study was 68 years, 90% patients were white, there were 6 male and 3 female patients. Four patients had de novo AML while 5 patients had secondary AML (four with prior MDS, one with prior alkylator therapy). Of these 9 patients, 6 patients achieved a CR or CRP i.e. overall response rate of ~ 67%. The median duration of response was 6 months. Two patients who received 9 doses of HiDAC developed neurotoxicity after the sixth dose of HiDAC and thus required to have dose of cytarabine reduced to 100mg/m2 for second cycle. All 9 patients had grade IV cytopenias as expected. Thrombocytopenia was a major issue with one patient developing hemorrhagic cystitis, two patients with broncho-alveolar hemorrhage and one patient with gastrointestinal bleeding. Only one patient died within 30 days of treatment from disseminated aspergillosis infection and multiorgan failure response was evaluable. No veno-occlusive disease was seen in any of these patents treated with two cycles of HiDAC and MylotargTM. Given the profound hematologic and neurologic toxicity in this elderly group of patients the trial has been rewritten using prolonged infusion gemcitabine at 10mg/m2/min intravenously over 6,9,or 12 hours (depending on the cohort patient will be assigned to) after MylotargTM 6mg/m2 infusion. Currently we are evaluating the possible mechanisms for drug toxicity and resistance in these nine elderly AML treated with HiDAC and will present these data. Using primary leukemic cells obtained from these patients, real-time quantitative polymerase chain reaction is being utilised to measure mRNA levels of enzymes involved in the metabolism of cytarabine namely, deoxycytidine kinase, cytidine deaminase, 5′nucleotidase, ribonucleotide reductase, DNA polymerases alpha and beta, and also for levels of hENT1 transporter protein which is responsible for the intracellular transport of cytarabine. Western Blot technique will be utilized to determine the levels of expression of four major proteins, namely, LRP, MRP, GSTP1 and MRP-1, and of proteins associated with apoptosis and cell survival, such as, bcl-2, bax, p53. GSTP1 genetic polymorphism will be determined using an allele-specific TaqMan PCR assay. Apoptosis will be quantified using the TUNEL assay and by flow cytometry following propidium iodide staining.

Dose Dense, High Intensity Therapy in Newly Diagnosed Elderly Patients with Acute Myeloid Leukemia Using Gemtuzumab Ozogamicin (Mylotarg™) and High Dose Cytarabine (HiDAC).

The failure to overcome drug resistance leads to a high rate of relapse in elderly patients with acute myeloid leukemia. We evaluated, in a Phase I study the feasibility of a dose dense regimen of HiDAC, and MylotargTM therapy for newly diagnosed elderly (≥60 years) patients with AML in terms of toxicity with two cycles of this regimen as the sole induction and consolidation therapy. HiDAC was administered in a dose escalation pattern: 3000mg/m2 intravenously given for 6, and 9 doses, and MylotargTM was administered at a dose of 6mg/m2 intravenously on days 1 and 8 of each cycle. Patients without unacceptable toxicity, defined as failure to recover counts to a minimum of ANC ≥ 500/ μl, platelets ≥ 30K and hematocrit ≥ 25%, received a second cycle of therapy, though not before day 28 following day 1 of induction. In addition, death within the first 30 days of induction (not related to disease progression) and life-threatening non-hematologic toxicity (such as cardiac or pulmonary arrest) was also considered dose-limiting. Patients with persistent disease but at least a 50% decrease in the marrow or peripheral blood blast count, or those with low blood counts and patients achieving CR without platelet recovery (CRp) at the 4–6 week examination received cycle 2 with a de-escalation of the Mylotarg dose (from 6 mg/m2 to 4 mg/m2). All patients received G-CSF 5mcg/kg/day subcutaneously from days 11–14. Eight patients (five male, three female) with a median age of 68 years (range 60–74) were enrolled. In cohort one (6 doses of HiDAC), four of six patients were able to complete both cycles of therapy and two of these have achieved CR. Two of the six patients achieved CRp with persistent thrombocytopenia and thus received a second cycle of chemotherapy off protocol. One patient in this cohort had progressive disease and persistent pancytopenia requiring transfusions and subsequently received chemotherapy using Etoposide and Cyclophosphamide. Five out of six patients are alive and remain disease free. In cohort two (9 doses of HiDAC), two patients have been enrolled thus far. One patient developed neurotoxicity after six doses of HiDAC and thus completed both cycles of therapy with six doses of HiDAC along with protocol dose of MylotargTM. The other patient was able to get all nine doses of HiDAC and both patients have achieved a CR. No unexpected hematologic toxicity was observed. All patients developed grade IV thrombocytopenia requiring platelet transfusions. One patient in cohort one died after developing aspergillus infection and multiorgan failure before he could be evaluated for response. Two patients in cohort one developed uncomplicated gram-positive bacteremia requiring antibiotics. In cohort two, one patient developed neurotoxicity and the other developed uncomplicated gram-positive bacteremia. At the time of submission of this abstract seven out of eight patients are alive with four CR and two CRp. No veno-occlusive disease was seen in these eight patients treated with two cycles of HiDAC and MylotargTM back to back. The high rate of CR and relatively good tolerance of this regimen remains encouraging.