Dose-finding Strategy Research Articles

Challenges and Lessons Learned in Autologous Chimeric Antigen Receptor T-Cell Therapy Development from a Statistical Perspective.

Chimeric antigen receptor (CAR) T-cell therapy is a human gene therapy product where T cells from a patient are genetically modified to enable them to recognize desired target antigen(s) more effectively. In recent years, promising antitumor activity has been seen with autologous CAR T cells. Since 2017, six CAR T-cell therapies for the treatment of hematological malignancies have been approved by the Food and Drug Administration (FDA). Despite the rapid progress of CAR T-cell therapies, considerable statistical challenges still exist for this category of products across all phases of clinical development that need to be addressed. These include (but not limited to) dose finding strategy, implementation of the estimand framework, use of real-world data in contextualizing single-arm CAR T trials, analysis of safety data and long-term follow-up studies. This paper is the first step in summarizing and addressing these statistical hurdles based on the development of the six approved CAR T-cell products.

Effective doses of ciprofol combined with alfentanil in inhibiting responses to gastroscope insertion, a prospective, single-arm, single-center study

BackgroundCiprofol is a novel intravenous sedative and anesthetic. Studies have shown that it features a rapid onset of action, a fast recovery time, slight inhibition of respiratory and cardiovascular functions, and a low incidence of adverse reactions. This study aims to explore the median effective dose (ED50) and the 95% effective dose (ED95) of ciprofol in inhibiting responses to gastroscope insertion when combined with a low dose of alfentanil, and to evaluate its safety, to provide a reference for the rational use of ciprofol in clinical practices.MethodsWe included 25 patients aged 18–64 years of either sex who underwent gastroscopy under intravenous general anesthesia, with a Body Mass Index (BMI) 18–28 kg/m2, and an American Society of Anesthesiologists (ASA) grade I or II. In this study, the dose-finding strategy of ciprofol followed a modified Dixon’s up-and-down method with an initial dose of 0.30 mg/kg and an increment of 0.02 mg/kg. Ciprofol was administered after intravenous injection of 7 µg/kg of alfentanil, and 2 min later a gastroscope was inserted. When the insertion response of one participant was positive (including body movement, coughing, and eye opening), an escalation of 0.02 mg/kg would be given to the next participant; otherwise, a de-escalation of 0.02 mg/kg would be administered. The study was terminated when negative response and positive response alternated 8 times. A Probit model was used to calculate the ED50 and ED95 of ciprofol in inhibiting responses to gastroscope insertion when combined with alfentanil. Patients’ recovery time, discharge time, vital signs and occurrence of adverse reactions were recorded.ResultsThe ED50 of single-dose intravenous ciprofol injection with 7 µg/kg of alfentanil in inhibiting gastroscope insertion responses was 0.217 mg/kg, and the ED95 was 0.247 mg/kg. Patients’ recovery time and discharge time were 11.04 ± 1.49 min and 9.64 ± 2.38 min, respectively. The overall incidence of adverse reactions was 12%.ConclusionThe ED50 of ciprofol combined with 7 µg/kg of alfentanil in inhibiting gastroscope insertion responses was 0.217 mg/kg, and the ED95 was 0.247 mg/kg. Ciprofol showed a low incidence of anesthesia-related adverse events.Trial registrationhttp://www.chictr.org.cn (ChiCTR2200061727).

Dose selection for biological enzyme replacement therapy indicated for inborn errors of metabolism.

This paper summarizes key features of the dose-finding strategies used in the development of 11 approved new molecular entities that are first-in-class enzyme replacement therapy (ERT), with a goal to gain insight into the dose exploration approaches to inform efficient dose-finding in future development of biological products for Inborn Errors of Metabolism (IEM). Dose exploration should preferably begin in invitro studies, followed by testing multiple doses in an appropriate animal disease model, when available, which can provide important information for dose assessment in humans. Performing adequate dose-finding in early phase clinical studies in a well-defined study population, including pediatric subjects, is generally critical to inform dose selection for pivotal trials; alternatively, additional dose exploration can be incorporated as part of a pivotal trial. Two important considerations for successful dose selection include (1) identifying appropriate disease-specific endpoints, including pharmacodynamic (PD) end points and intermediate clinical end points or clinical end points, and (2) designing a study with adequate treatment durations for evaluating these end points. Appropriately selected PD biomarkers is useful for dose selection, and early development of these biomarkers can facilitate the overall clinical development program. Optimization of ERT doses, as well as evaluations of patient intrinsic factors and/or immune tolerance strategies may be necessary to overcome antibody responses or increase efficacy in IEM.

A Multi-Arm Two-Stage (MATS) design for proof-of-concept and dose optimization in early-phase oncology trials

The Project Optimus initiative by the FDA's Oncology Center of Excellence is widely viewed as a groundbreaking effort to change the status quo of conventional dose-finding strategies in oncology. Unlike in other therapeutic areas where multiple doses are evaluated thoroughly in dose ranging studies, early-phase oncology dose-finding studies are characterized by the practice of identifying a single dose, such as the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D). Following the spirit of Project Optimus, we propose an Multi-Arm Two-Stage (MATS) design for proof-of-concept (PoC) and dose optimization that allows the evaluation of two selected doses from a dose-escalation trial. The design assesses the higher dose first across multiple indications in the first stage, and adaptively enters the second stage for an indication if the higher dose exhibits promising anti-tumor activities. In the second stage, a randomized comparison between the higher and lower doses is conducted to achieve PoC and dose optimization. A Bayesian hierarchical model governs the statistical inference and decision making by borrowing information across doses, indications, and stages. Our simulation studies show that the proposed MATS design yield desirable performance. An R Shiny application has been developed and made available at https://matsdesign.shinyapps.io/mats/.

Targeting Hedgehog Signaling with Glasdegib in Patients with Refractory Sclerotic Chronic Graft vs. Host Disease: A Report of Two Phase I/II Trials

Introduction Sclerotic chronic graft vs. host disease (scGVHD) is characterized by progressive skin fibrosis that often causes limited mobility and poor quality of life. Aberrant activation of hedgehog signaling leading to the differentiation of dermal fibroblasts into collagen-releasing myofibroblasts has been implicated in scGVHD. Targeted inhibition with hedgehog pathway inhibitors ameliorate fibrosis in experimental models. Our objective was to determine the safety and efficacy of glasdegib, an oral antagonist of the hedgehog signalling transducer Smoothened (SMO) in adult patients (pts) with refractory scGVHD. Methods Two independent, single-arm, open-label, phase I/II investigator-initiated studies [NCT03415867, Spanish Transplantation and Cellular Therapy Cooperative Group (GETH); NCT04111497, Fred Hutchinson Cancer Center/Huntsman Cancer Institute/Duke University Medical Center (FHD)] were performed. Adults with active scGVHD after ≥1 (FHD) or ≥2 (GETH) lines of prior therapy were enrolled. The GETH trial followed a 3+3 dose-finding strategy, whereas the FHD trial employed a fixed-dose design. Primary endpoints were dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) in the GETH trial, and safety and tolerability in the FHD trial. Secondary endpoints included efficacy, patient-reported outcomes and biological correlates of response. Glasdegib was administered once daily in continuous 28-day cycles. Individual organs were scored per 2014 NIH cGVHD criteria. A scGVHD partial response (PR) was defined as skin and/or joints score improvement (≥1 point for body surface area [BSA], skin features or joints/fascia scores; ≥2 points for skin/joints tightening or total P-ROM scores) in the absence of worsening in those scores or an increase ≥2 points in the global severity score. Data cut-off was at 12 months from time of glasdegib initiation. Results Twenty (GETH) and 15 (FHD) pts were enrolled who received a median of 4 (range 2-10) and 4 (1-16) prior lines of therapy. The median age was 47 years (range 27-73) and 64 (33-74) in the GETH and FHD studies, respectively. In the GETH trial, 3 pts were included in cohort 1 (50 mg), 3 in cohort 2 (100 mg) and 16 in the expansion cohort (50 mg). All pts in the FHD trial received glasdegib at an initial dose of 50 mg. Frequent treatment-emergent grade (G) ≥2 adverse events (AEs) in the GETH trial included muscle cramps (85%), alopecia (50%) and dysgeusia (35%). Two pts in cohort 2 experienced a DLT (G3 muscle cramps) that resulted in establishment of the MTD at 50 mg. Similarly, G3 muscle cramps were the most frequently reported adverse event (AE) occurring in 33% of pts in the FHD trial. In the FHD study, a pre-specified trial stopping rule was triggered by the emergence of G3 muscle cramps AEs in 5 pts. In the GETH trial, glasdegib dose reductions were undertaken in 10 pts, and 8 pts stopped glasdegib before completion of 12 cycles of therapy. Ten pts remained on treatment beyond 12 months. In the FHD trial, the glasdegib dose was reduced in 5 pts; 12 pts stopped glasdegib before 12 cycles. Two pts remained on treatment for longer than 12 months and one pt remains on glasdegib at 10 months. At the 12-month data cut-off, 9 (45%) pts in the GETH trial achieved a skin BSA score and/or sclerotic features score PR, and 9 (45%) pts had obtained a joints/fascia score response (6 PRs, 3 complete responses). Corresponding findings in the FHD trial were 4 pts (27%; 3 PRs, 1 CR) and 3 pts (20%; 2 PRs, 1 CR). An improvement ≥2 points in the total P-ROM score was observed in 11 (55%) pts in the GETH study and 4 (27%) pts in the FHD study, Additionally, an improvement ≥2 points in the 0-10 skin and/or joint tightening severity scale was reported in 13 (65%) and 4 (31%; 2 pts with missing data) pts in the GETH and FHD trials, respectively. Overall, 13 (65%) pts obtained a scGVHD PR in the GETH trial, with a median time of 2.4 months to response. Likewise, 7 (47%) pts had a scGVHD PR in the FHD group, with a median time of 0.9 months to response. Preliminary correlative studies did not show changes in the distribution of T-cell subpopulations or TCR diversity in the GETH trial. Conclusions Glasdegib demonstrated high rates of clinical activity in heavily pretreated pts with scGVHD, but tolerability was hampered by the emergence of treatment-related muscle cramps. Yet, selected pts derived a sustained benefit from treatment in the absence of limiting toxicities. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Optimal target saturation of ligand-blocking anti-GITR antibody IBI37G5 dictates FcγR-independent GITR agonism and antitumor activity

SummaryGlucocorticoid-induced tumor necrosis factor receptor (GITR) is a co-stimulatory receptor and an important target for cancer immunotherapy. We herein present a potent FcγR-independent GITR agonist IBI37G5 that can effectively activate effector T cells and synergize with anti-programmed death 1 (PD1) antibody to eradicate established tumors. IBI37G5 depends on both antibody bivalency and GITR homo-dimerization for efficient receptor cross-linking. Functional analyses reveal bell-shaped dose responses due to the unique 2:2 antibody-receptor stoichiometry required for GITR activation. Antibody self-competition is observed after concentration exceeded that of 100% receptor occupancy (RO), which leads to antibody monovalent binding and loss of activity. Retrospective pharmacokinetics/pharmacodynamics analysis demonstrates that the maximal efficacy is achieved at medium doses with drug exposure near saturating GITR occupancy during the dosing cycle. Finally, we propose an alternative dose-finding strategy that does not rely on the traditional maximal tolerated dose (MTD)-based paradigm but instead on utilizing the RO-function relations as biomarker to guide the clinical translation of GITR and similar co-stimulatory agonists.

The clinical pharmacology and potential therapeutic applications of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT).

5‐methoxy‐N,N‐dimethyltryptamine (5‐MeO‐DMT) is a naturally occurring tryptamine that primarily acts as an agonist at the 5‐HT1A and 5‐HT2A receptors, whereby affinity for the 5‐HT1A subtype is highest. Subjective effects following 5‐MeO‐DMT administration include distortions in auditory and time perception, amplification of emotional states, and feelings of ego dissolution that usually are short‐lasting, depending on the route of administration. Individual dose escalation of 5‐MeO‐DMT reliably induces a “peak” experience, a state thought to be a core predictor of the therapeutic efficacy of psychedelics. Observational studies and surveys have suggested that single exposure to 5‐MeO‐DMT can cause rapid and sustained reductions in symptoms of depression, anxiety, and stress. 5‐MeO‐DMT also stimulates neuroendocrine function, immunoregulation, and anti‐inflammatory processes, which may contribute to changes in mental health outcomes. To date, only one clinical trial has been published on 5‐MeO‐DMT, demonstrating the safety of vaporized dosing up to 18 mg. Importantly, the rapid onset and short duration of the 5‐MeO‐DMT experience may render it more suitable for individual dose‐finding strategies compared with longer‐acting psychedelics. A range of biotech companies has shown an interest in the development of 5‐MeO‐DMT formulations for a range of medical indications, most notably depression. Commercial development will therefore be the most important resource for bringing 5‐MeO‐DMT to the clinic. However, fundamental research will also be needed to increase understanding of the neurophysiological and neural mechanisms that contribute to the potential clinical effects of 5‐MeO‐DMT and its sustainability and dissemination over time. Such studies are less likely to be conducted as part of drug development programs and are more likely to rely on independent, academic initiatives.

5MO Comprehensive dose-finding strategy for single-agent RP-3500, a highly selective inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase

Dose-finding studies typically establish a maximum tolerated dose, a recent shift from this “more is better” approach towards long-term tolerability is of interest. The ongoing RP-3500 TRESR study (NCT04497116) used a comprehensive, non-randomized, dose-finding approach, focusing on longer-term tolerability to establish a patient (pt)-specific therapeutic dose level.

Seamless Phase IIa/IIb and enhanced dose-finding adaptive design

ABSTRACTIn drug development, when the drug class has a relatively well-defined path to regulatory approval and the enrollment is slow with certain patient populations, one may want to consider combining studies of different phases. This article considers combining a proof of concept (POC) study and a dose-finding (DF) study with a control treatment. Conventional DF study designs sometimes are not efficient, or do not have a high probability to find the optimal dose(s) for Phase III trials. This article seeks more efficient DF strategies that allow the economical testing of more doses. Hypothetical examples are simulated to compare the proposed adaptive design vs. the conventional design based on different models of the overall quantitative representation of efficacy, safety, and tolerability. The results show that the proposed adaptive design tests more active doses with higher power and comparable or smaller sample size in a shorter overall study duration for POC and DF, compared with a conventional design.

Innovative considerations on a phase 2a dose-finding strategy using Bayesian methods and MCP-MOD

Early phase clinical trials in specific patient populations can often have recruitment challenges due to for example a limited disease incidence, concurrent treatment and/or stringent inclusion/exclusion criteria. Owing to this limited availability of patients they often require the use of smaller numbers of patients and more innovative statistical methods. Often single agents, developed for the same disease of interest are not sufficient and may need be used in combination to be effective. Appropriate decsisions may also have to be made for doses, treatment duration and combinations with other compounds. The plan for the twelve-week phase 2a study in one such population will involve an early futility look at week 2 based on a biomarker, using Bayesian posterior probabilities. This will be followed by using MCP-Mod at the end of study on a clinical response, in order to investigate the dose response. At week 2, a biomarker is measured to see if there is a clinically meaningful effect at the target for appropriated doses. If not then new doses may need to be added. The posterior probability of the meaningful effect will be used in the decision criteria. At the end of the study MCP-Mod will be used in order to investiagate the dose response. MCP-Mod involves pre-specifying candidate dose-reponse models followed by statistical testing for dose-response signal whilst controlling the type I error. The best fitting model is then selected, and the target dose estimated, which is then recommended for phase 2b and phase 3 studies. The method has been qualified by the EMA as an efficient method of dose finding. Simulations have been conducted to investigate the futility and dose finding decisions in phase 2a and understand the operating characteristics, and comparisons made to a traditional dose finding paradigm, which might involve fewer doses using pairwise comparisons to control.

Abstract LB-256: Optimal clinical dose-finding strategies: Translational preclinical pharmacokineitcs, pharmacodynamics, and efficacy analysis of HM61713, an orally selective EGFR mutant inhibitor

Abstract The first-generation of EGFR1 inhibitors (Gefitinib and Erlotinib) has significant clinical benefits in NSCLC caused by activating mutations, but the efficacy of these agents is often limited due to the emergence of drug resistance conferred by a gatekeeper residue, T790M. HM61713 is a third-generation EGFR tyrosine kinase inhibitor that has been evaluated as a novel therapeutic agent for the treatment of non-small cell lung cancer (NSCLC) with EGFR mutations. HM61713 is an orally active and a novel EGFR mutant selective inhibitor which is potent on resistance mutation (T790M) without affecting EGFR wild type at efficacious dose level. HM61713 showed an anti-cancer activity in several EGFR mutant lung cancer cell lines including T790M mutation harboring cell line. Integrated pharmacokinetic - pharmacodynamic - xenograft tumor model (PK-PD-XTG) was used to characterize the relationship between HM61713 plasma concentration and tumor growth inhibition (TGI) in H1975 (T790M mutation) xenograft model. Simple one-compartment model applied re-absorption compartment with first-order absorption/elimination was used to describe HM61713 plasma concentration-time profiles. Biophase distribution model with baseline inhibition Emax equation was applied to characterize the PD marker (p-EGFR) and tumor volume shrinkage was explained by michaelis-menten kinetics of p-EGFR. Estimated in vivo IC50 value of p-EGFR inhibition (%) based on plasma free concentration in xenograft mice was 1.14 ng/mL. The human PD marker response curve and the tumor growth inhibition plot were obtained by replacing the mice PK to human PK in our developed model based on the hypothesis thattranslation providesa good relationship of surrogate mice tumor PD to human tumor regression corresponding human PK. According to our simulated curves, we predicted appropriate human active dose from 300 to 800 mg/man and it would be an efficacious dose in patients with NSCLC harboring the EGFR activating and also with T790M resistant mutation. Currently, HM61713 is undergoing in clinical trial phase I/II in NSCLC (ClinicalTrials.gov, NCT01588145). Citation Format: Jooyun Byun, Taehun Song, Donghyun Kim, Junhyeng Son, Kwang-Ok Lee, Jaeho Lee, Yong Hoon Kim, Young-Mi Lee, Kwee Hyun Suh. Optimal clinical dose-finding strategies: Translational preclinical pharmacokineitcs, pharmacodynamics, and efficacy analysis of HM61713, an orally selective EGFR mutant inhibitor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-256. doi:10.1158/1538-7445.AM2015-LB-256

Modeling and Simulation of Orlistat to Predict Weight Loss and Weight Maintenance in Obesity Patients

Orlistat is used clinically worldwide as anti-obesity drug. It is a chemically synthesized hydrogenated derivative of lipstatin and is an inhibitor of gastric and pancreatic lipases. It has been found to reduce the absorption of dietary fat in the gastrointestinal tract. Modeling and simulation based on pharmacokinetic/pharmacodynamic analysis is becoming increasingly used in the design of clinical trials to assure that the trials are of high quality and are conducted efficiently. We developed a clinical trial simulation model for orlistat based on Phase III clinical study data. This innovative weight loss model includes the relationships between orlistat dose, changes in fecal fat excretion, and weight loss, and also incorporates a dropout function. The model guided the dose-finding strategy and allowed simulation of long-term clinical outcomes of orlistat.

Maximum-Tolerated Dose, Optimum Biologic Dose, or Optimum Clinical Value: Dosing Determination of Cancer Therapies

Maximum-Tolerated Dose, Optimum Biologic Dose, or Optimum Clinical Value: Dosing Determination of Cancer Therapies

Application of adaptive design and decision making to a phase II trial of a phosphodiesterase inhibitor for the treatment of intermittent claudication

BackgroundClaudication secondary to peripheral artery disease (PAD) is associated with substantial functional impairment. Phosphodiesterase (PDE) inhibitors have been shown to increase walking performance in these patients. K-134 is a selective PDE 3 inhibitor being developed as a potential treatment for claudication. The use of K-134, as with other PDE 3 inhibitors, in patients with PAD raises important safety and tolerability concerns, including the induction of cardiac ischemia, tachycardia, and hypotension. We describe the design, oversight, and implementation of an adaptive, phase II, dose-finding trial evaluating K-134 for the treatment of stable, intermittent claudication.MethodsThe study design was a double-blind, multi-dose (25 mg, 50 mg, and 100 mg of K-134), randomized trial with both placebo and active comparator arms conducted in the United States and Russia. The primary objective of the study was to compare the highest tolerable dose of K-134 versus placebo using peak walking time after 26 weeks of therapy as the primary outcome. Study visits with intensive safety assessments were included early in the study period to provide data for adaptive decision making. The trial used an adaptive, dose-finding strategy to efficiently identify the highest dose(s) most likely to be safe and well tolerated, based on the side effect profiles observed within the trial, so that less promising doses could be abandoned. Protocol specified criteria for safety and tolerability endpoints were used and modeled prior to the adaptive decision making. The maximum target sample size was 85 subjects in each of the retained treatment arms.ResultsWhen 199 subjects had been randomized and 28-day data were available from 143, the Data Monitoring Committee (DMC) recommended termination of the lowest dose (25 mg) treatment arm. Safety evaluations performed during 14- and 28-day visits which included in-clinic dosing and assessments at peak drug concentrations provided core data for the DMC review. At the time of review, no subject in any of the five treatment arms (placebo, three K-134-containing arms, and cilostazol) had met pre-specified definitions for resting tachycardia or ischemic changes on exercise ECG. If, instead of dropping the 25-mg K-134 treatment arm, all arms had been continued to full enrollment, then approximately 43 additional research subjects would have been required to complete the trial.ConclusionsIn this phase II, dose-finding trial of K-134 in the treatment of stable intermittent claudication, no concerning safety signals were seen at interim analysis, allowing the discontinuation of the lowest-dose-containing arm and the retention of the two highest-dose-containing arms. The adaptive design facilitated safe and efficient evaluation of K-134 in this high-risk cardiovascular population.Trial registrationClinicalTrials.gov: NCT00783081

An adaptive design for identifying the dose with the best efficacy/tolerability profile with application to a crossover dose‐finding study

Proof-of-concept in clinical trials has traditionally focused on the identification of a maximum tolerated dose with the assumption that the higher doses provide better efficacy. However, adverse events associated with a maximum tolerated dose may have a negative effect on efficacy. We present an efficient adaptive dose-finding strategy that concentrates patient assignments at and around the dose which has the best efficacy/tolerability profile based on a utility function. The strategy is applied within the setting of a crossover design. While the strategy may also be applied to parallel studies, a crossover design provides more power for a given sample size for comparisons between the optimal dose versus placebo and/or active control when it is reasonable to assume no carryover effects.

Survival after transcoronary ablation of septal hypertrophy in hypertrophic obstructive cardiomyopathy (TASH): a 10 year experience

Catheter-based treatment of patients with hypertrophic obstructive cardiomyopathy (HOCM) by alcohol ablation (transcoronary ablation of septal hypertrophy, TASH) leads to symptomatic and haemodynamic improvement. However, little is known regarding the survival and its evolution since the introduction of the method in 1995. Theoretically, the method may be harmful, because widening of the obstructed left ventricular outflow tract is achieved by a septal infarction and subsequently by a potentially arrhythmogenic scar. This study sought to determine the impact of TASH on the survival of all patients with HOCM treated in our institution between 1995 and 2005. Survival was assessed from the early beginning in each of 644 consecutive patients to April 2005. Group A comprises a first series of 329 patients who were treated in a dose finding strategy with decreasing amounts of ethanol until December 2001, on average, from 2.9 ml to 0.93 ml/patient. The survival of this group was analysed using Kaplan-Meier estimates, multivariate Cox regression and Log-Rank testing. Group B comprises 315 patients of the following "low alcohol dose era" (mean amount of ethanol 0.8 +/- 0.4 ml, range 0.3-1.5 ml) and their mid-term survival (period to first regular 6-month post-procedural control). All patients (age 58 +/- 15 years, 99.2% follow up, mean 1.4 years): 33 patients died (5.1% all cause mortality), including perioperative deaths. 14/33 (42%) died from cardiac reasons. Annual total (all cause) mortality was 3.2%, total in-hospital mortality 1.2% in all patients (8 of 644 patients, 6 of them with severe comorbidity) and 0.4% in low risk patients. Annual cardiac mortality after hospital discharge was 0.7% (6 patients, all with sudden death). Group A (age 58 +/- 15 years, 98.8% follow up, mean 2.1 years, maximum 6.2 years): 29 patients died (total annual mortality 4.3%), 10 of them from hypertrophic cardiomyopathy related reasons resulting in a total in-hospital mortality of 1.8% (6 deaths), a cardiac annual mortality of 1.5% (including hospital mortality) and 0.6%/year after hospital discharge. Age was identified as an independent predictor of increased overall mortality (P = 0.002) and lower alcohol dosage and the absence of atrial fibrillation as independent predictors of reduced cardiac mortality (P = 0.005 and P = 0.039, respectively). With focus on the median value of the alcohol quantity (2.0 ml), patients treated with high amounts (>2.0 ml) showed a higher total mortality than patients treated with small amounts (< or =2.0 ml) (P = 0.031) and alcohol turned out to be an independent predictor of survival (P = 0.047). The same holds true for a homogenous subset of 262 patients with respect to cardiac mortality (P = 0.018). Group B (age 57 +/- 14 years, 99.7% follow up, mean 7.3 months): Total in-hospital mortality was 0.6% (2 of 315 patients; P = 0.173, group A/B) and cardiac in-hospital mortality 0% (P = 0.016, group A/B). During follow up two patients died, both of them experienced a sudden death reflecting an annual mortality of 1.0%. These data represent the largest available database on survival after alcohol septal ablation of HOCM from a single centre with large experience, and its evolution over 10 years with increasing procedural experience including the pronounced reduction of ethanol quantity in a systematic doses finding strategy. The in-hospital mortality has become very low. Cardiac survival during follow up was excellent, however, the well-known risk of sudden death is not completely eliminated. Longer follow-up time would be desirable for definite evaluation of this relatively new therapeutic option in the management of HOCM.

Phase I study of LY573636-sodium, an acylsulfonamide anti-cancer compound with a novel mechanism of action, administered as 2-hour IV infusion in patients with advanced solid tumors

2515 Background: LY573636 -sodium (hereafter referred to as LY573636 ) is a novel anti-cancer compound that induces apoptosis by a mitochondrial-mediated mechanism. Methods: A phase I study was conducted to determine the maximum tolerated dose (MTD) and pharmacokinetic (PK) profile of LY573636 administered as an intravenous infusion over 2 hours every 21 days. Results: 53 patients (pts) were enrolled on study, 16 males, 37 females, with a median age of 58 (range: 18–83). LY573636 was dose-escalated using a flat dosing paradigm in the first 34 patients (range 100 mg to 2400 mg). PK analysis of this cohort revealed that LY573636 had a low total plasma clearance (CL = 0.02L/hr) and terminal elimination half-life of approximately 340 hours due to high-albumin binding (∼99%). The dose limiting toxicity (DLT) for the flat dose escalation was bone marrow (BM) suppression, which included CTC (ver2) grade 3/4 thrombocytopenia/neutropenia. In some patients, significant BM suppression occurred in cycle 2 and later, attributed to the accumulation of albumin-bound drug with repeated flat dosing. Based on these findings, the dose-finding strategy was modified to an idealized dosing paradigm which calculated LY573636 doses based on pt lean body weight, and used a loading/maintenance dose regimen to achieve a specific Cmax target value. All 3 pts in the first 400 μg/mL Cmax cohort completed at least 2 cycles and no DLTs were reported. Of the 16 pts enrolled to the 420 μg/mL targeted dose group: 1 pt reported a DLT, a transient grade 3 elevation of ALT/AST which did not recur in subsequent cycles; 8/16 pts received 4 or more cycles prior to disease progression and 2 remain on treatment. Overall, 23/53 pts had stable disease (SD) after 2 or more cycles. Seven pts received &gt;8 cycles (SD &gt; 6 mos), including heavily pre-treated pts with ovarian cancer, non-small cell lung cancer, soft tissue sarcoma, and thymoma. Conclusions: LY573636 is a novel anti-cancer compound with a unique mechanism of action. The most common DLT was BM suppression. The individualized, target Cmax dose of 420 μg/mL has been taken forward into phase II clinical trials. No significant financial relationships to disclose.

The clinical and economic value of lovastatin in the primary prevention of cardiovascular disease

HMGCoA-inhibitors (statins) lower plasma cholesterol through interference with the rate-limiting enzyme in the endogenous synthesis process. Since their introduction in the early 90’s, the clinical attitude towards cardiovascular (cv) risk reduction has evolved from the attention to single risk factors to a more comprehensive global risk evaluation, and thus the indications of statins have broadened from the secondary prevention in hypercholesterolemic patients to include primary prevention in mildly and moderately hypercholesterolemic, or even normocholesterolemic patients, provided their global cv risk is considered high (typically, an estimated major cv event probability greater than 20%). Italian drug utilization data show that a small proportion of patients who could benefit from statins do actually receive them, contributing to the persistence of the clinical and economical burden of cv disease, the leading cause of mortality; since statins have proved effective, and cost-effective, in cv prevention, a more widespread use appears desirable, but requires high investments in pharmaceutical costs. This article defines a clinical profile of lovastatin, a statin with a solid efficacy and safety record only recently introduced into the Italian market despite it has been the first to become clinically available abroad. Among available statin formulations appropriate for target cholesterol reductions up to 30%, which apply to a significant proportion of statin therapy candidates, lovastatin 20 mg is marketed at the lowest price. Although the individual response to the different statins is highly unpredictable, determining a mandatory empirical molecule- and dose-finding strategy on the single patient, from the societal point of view the choice to start with lower cost molecules, among options that on average are equally-effective, may limit initial drug investment and dampen the impact of resource waste secondary to treatment interruptions and switches.

Dose-finding based on feasibility and toxicity in T-cell infusion trials.

A new modality for treatment of cancer involves the ex vivo growth of cancer-specific T-cells for subsequent infusion into the patient. The therapeutic aim is selective destruction of cancer cells by the activated infused cells. An important problem in the early phase of developing such a treatment is to determine a maximal tolerated dose (MTD) for use in a subsequent phase II clinical trial. Dose may be quantified by the number of cells infused per unit body weight, and determination of an MTD may be based on the probability of infusional toxicity as a function of dose. As in a phase I trial of a new chemotherapeutic agent, this may be done by treating successive cohorts of patients at different dose levels, with each new level chosen adaptively based on the toxicity data of the patients previously treated. Such a dose-finding strategy is inadequate in T-cell infusion trials because the number of cells grown ex vivo for a given patient may be insufficient for infusing the patient at the current targeted dose. To address this problem, we propose an algorithm for trial conduct that determines a feasible MTD based on the probabilities of both infusibility and toxicity as functions of dose. The method is illustrated by application to a dendritic cell activated lymphocyte infusion trial in the treatment of acute leukemia. A simulation study indicates that the proposed methodology is both safe and reliable.

Dose finding strategies involving interim analyses and unbalanced treatment allocation.

Dose finding studies usually require the application of multiple test procedures (MTP). A variety of procedures is available for data analyses. Focusing on testing only subset hypotheses of interest requires only limited alpha-adjustment. Specific strategies based on MTP, in particular closed test procedures, which also consider dropping dose groups and unequal group sizes, lead to substantial reduction in total sample size. Of course, strategies discussed here can be extended to comparisons of more than five groups, and they may be generalized to cover equivalence tests, too. For example, one may want to demonstrate therapeutical equivalence of two dose regimens like b.i.d. and o.d. administrations of the drug.