Dose-efficacy Relationship Research Articles

Phase I/II Design for Selecting Subgroup-Specific Optimal Biological Doses for Prespecified Subgroups.

We propose a phase I/II trial design to support dose-finding when the optimal biological dose (OBD) may differ in two prespecified patient subgroups. The proposed design uses a utility function to quantify efficacy-toxicity trade-offs, and a Bayesian model with spike and slab prior distributions for the subgroup effect on toxicity and efficacy to guide dosing and to facilitate identifying either subgroup-specific OBDs or a common OBD depending on the resulting trial data. In a simulation study, we find the proposed design performs nearly as well as a design that ignores subgroups when the dose-toxicity and dose-efficacy relationships are the same in both subgroups, and nearly as well as a design with independent dose-finding within each subgroup when these relationships differ across subgroups. In other words, the proposed adaptive design performs similarly to the design that would be chosen if investigators possessed foreknowledge about whether the dose-toxicity and/or dose-efficacy relationship differs across two prespecified subgroups. Thus, the proposed design may be effective for OBD selection when uncertainty exists about whether the OBD differs in two prespecified subgroups.

A Bayesian quasi-likelihood design for identifying the minimum effective dose and maximum utility dose in dose-ranging studies.

Most existing dose-ranging study designs focus on assessing the dose-efficacy relationship and identifying the minimum effective dose. There is an increasing interest in optimizing the dose based on the benefit-risk tradeoff. We propose a Bayesian quasi-likelihood dose-ranging design that jointly considers safety and efficacy to simultaneously identify the minimum effective dose and the maximum utility dose to optimize the benefit-risk tradeoff. The binary toxicity endpoint is modeled using a beta-binomial model. The efficacy endpoint is modeled using the quasi-likelihood approach to accommodate various types of data (e.g. binary, ordinal or continuous) without imposing any parametric assumptions on the dose-response curve. Our design utilizes a utility function as a measure of benefit-risk tradeoff and adaptively assign patients to doses based on the doses' likelihood of being the minimum effective dose and maximum utility dose. The design takes a group-sequential approach. At each interim, the doses that are deemed overly toxic or futile are dropped. At the end of the trial, we use posterior probability criteria to assess the strength of the dose-response relationship for establishing the proof-of-concept. If the proof-of-concept is established, we identify the minimum effective dose and maximum utility dose. Our simulation study shows that compared with some existing designs, the Bayesian quasi-likelihood dose-ranging design is robust and yields competitive performance in establishing proof-of-concept and selecting the minimum effective dose. Moreover, it includes an additional feature for further maximum utility dose selection.

Inactivation of the NLRP3 inflammasome mediates exosome-based prevention of atrial fibrillation.

Rationale: Extracellular vesicles (EVs) from human explant-derived cells injected directly into the atria wall muscle at the time of open chest surgery reduce atrial fibrosis, atrial inflammation, and atrial fibrillation (AF) in a rat model of sterile pericarditis. Albeit a promising solution to prevent postoperative AF, the mechanism(s) underlying this effect are unknown and it is not clear if this benefit is dependent on EV dose. Methods: To determine the dose-efficacy relationship of EVs from human explant-derived cells in a rat model of sterile pericarditis. Increasing doses of EVs (106, 107, 108 or 109) or vehicle control were injected into the atria of middle-age male Sprague-Dawley rats at the time of talc application. A sham control group was included to demonstrate background inducibility. Three days after surgery, all rats underwent invasive electrophysiological testing prior to sacrifice. Results: Pericarditis increased the likelihood of inducing AF (p<0.05 vs. sham). All doses decreased the probability of inducing AF with maximal effects seen after treatment with the highest dose (109, p<0.05 vs. vehicle). Pericarditis increased atrial fibrosis while EV treatment limited the effect of pericarditis on atrial fibrosis with maximal effects seen after treatment with 108 or 109 EVs. Increasing EV dose was associated with progressive decreases in pro-inflammatory cytokine content, inflammatory cell infiltration, and oxidative stress. EVs decreased NLRP3 (NACHT, LRR, and PYD domains-containing protein-3) inflammasome activation though a direct effect on resident atrial fibroblasts and macrophages. This suppressive effect was exclusive to EVs produced by heart-derived cells as application of EVs from bone marrow or umbilical cords did not alter NLRP3 activity. Conclusions: Intramyocardial injection of incremental doses of EVs at the time of open chest surgery led to progressive reductions in atrial fibrosis and inflammatory markers. These effects combined to render atria resistant to the pro-arrhythmic effects of pericarditis which is mechanistically related to suppression of the NLRP3 inflammasome.

The Backfill i3+3 Design for Dose-Finding Trials in Oncology

We consider a formal statistical design that allows simultaneous enrollment of a main cohort and a backfill cohort of patients in a dose-finding trial. The goal is to accumulate more information at various doses to facilitate dose optimization. The proposed design, called Bi3+3, combines the simple dose-escalation algorithm in the i3+3 design and a model-based inference under the framework of probability of decisions (POD), both previously published. As a result, Bi3+3 provides a simple algorithm for backfilling patients to lower doses in a dose-finding trial once these doses exhibit safety profile in patients. The POD framework allows dosing decisions to be made when some backfill patients are still being followed with incomplete toxicity outcomes, thereby potentially expediting the clinical trial. At the end of the trial, Bi3+3 uses both toxicity and efficacy outcomes to estimate an optimal biological dose (OBD). The proposed inference is based on a dose-response model that takes into account either a monotone or plateau dose-efficacy relationship, which are frequently encountered in modern oncology drug development. Simulation studies show promising operating characteristics of the Bi3+3 design in comparison to existing designs.

A Phase 1 Trial of the Safety, Tolerability, and Biological Effects of Intravenous Enadenotucirev (EnAd), a Novel Oncolytic Virus, in Combination with Chemoradiotherapy in Locally Advanced Rectal Cancer (CEDAR)

Novel treatment combinations are required to increase response rates in rectal cancer. EnAd is an intravenous, tumor selective, oncolytic adenovirus with high affinity for malignant colorectal epithelial cells. Pre-clinical evidence of synergy with radiation warranted further clinical evaluation and assessment of safety in combination with chemoradiation (CRT), 25 × 2Gy and concurrent capecitabine. EnAd was escalated using 2 dose levels of viral particles (1 × 1012, 3 × 1012), given Monday, Wednesday, Friday over 3 schedules (pre-CRT, pre & post CRT). Toxicity and efficacy were used as dual end points in escalation decisions. A 2-parameter and 3-parameter logistic Time to Event Continual Reassessment Method (TiTE-CRM) were used estimate the dose-toxicity and dose-efficacy relationship, respectively. Results are shown as probability and 95% credible interval (Cr.I). The dose limiting toxicity (DLT) window was 13 weeks. Patients who had not completed their DLT window at the time of a dose decision were included in the safety analysis but down-weighted according to their follow-up time and amount of IMP received. Efficacy was assessed at 13 weeks using MRI Tumor Regression Grade (mrTRG), where mrTRG 1-2 equals response. The trial (NCT03916510) was conducted in 4 UK centers. A total of 13 patients were enrolled, 12 of whom were evaluable. Median age was 57 (range 31-84), and 10/13 were male. One patient had two G3 adverse events (AE); diarrhea, acute kidney injury. All other adverse events (AEs) were G1 or 2, with no G4/5 events. The most common AE by organ system was gastrointestinal (20.8%, G1). There were two observed DLTs on Dose schedule 3; leg swelling and acute kidney injury. Responses and toxicities increased with escalating schedules of EnAd (Table 1). CEDAR is the first trial to successfully combine an intravenous oncolytic adenovirus with radiation, demonstrating the feasibility and acceptability of this approach, and a new paradigm in radiosensitization in rectal cancer. Within this small Phase I study, EnAd demonstrated an acceptable safety profile with evidence of a higher-than-expected rate of response by mrTRG. Translation analysis of tissue, blood and microbiome for biological correlates of radiation synergy is underway. PsiOxus, CRUK (A24474). University of Oxford.

Population Sensitive to Lenvatinib Plus Anti-PD-1 for Unresectable Hepatocellular Carcinoma Infected with Hepatitis B Virus.

We explore the dose-efficacy relationship of lenvatinib plus anti-PD-1 in patients with unresectable hepatocellular carcinoma (u-HCC) infected with hepatitis B virus (HBV) in real-world practice. Furthermore, we identify the population sensitive to lenvatinib plus anti-PD-1 treatments. This retrospective study included 70 patients treated with lenvatinib plus at least 3 cycles of anti-PD-1 and 140 with lenvatinib alone. Stabilized inverse probability of treatment weighting (SIPTW) was used to balance clinical features between the two groups. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were analyzed. Subpopulation treatment effect pattern plot (STEPP) estimated treatment-effect differences between the two groups. The median age was 54 years, and 189 (90%) cases were male. A total of 180 (85%) patients were infected with HBV. A slowly increasing 12-month survival rate was with the cycles of anti-PD-1, and 5 cycles and more of anti-PD-1 appeared the most beneficial and stable survival rate. The lenvatinib plus at least 3 cycles anti-PD-1 group had better OS (21.4 vs 14 months, p = 0.041), PFS (8.0 vs 6.3 months, p = 0.015) than the lenvatinib alone group in unadjusted cohorts, and the SIPTW adjusted cohorts had confirmed it. For patients with portal vein trunk invasion (PVTI) or extrahepatic spread (EHS) combined with Child-Pugh class B (CPB), lenvatinib plus anti-PD-1 made the 12-month survival rate increase by 38%, while, in the other population, it did only 18%. The two groups had similar AEs (p ≥ 0.05). The lenvatinib combined with at least 3 cycles of anti-PD-1 was efficacy and safe for u-HCC patients infected with HBV. Especially, patients with PVTI or EHS combined with CPB may benefit most from the combination therapy.

Mathematical Modelling for Optimal Vaccine Dose Finding: Maximising Efficacy and Minimising Toxicity.

Vaccination is a key tool to reduce global disease burden. Vaccine dose can affect vaccine efficacy and toxicity. Given the expense of developing vaccines, optimising vaccine dose is essential. Mathematical modelling has been suggested as an approach for optimising vaccine dose by quantitatively establishing the relationships between dose and efficacy/toxicity. In this work, we performed simulation studies to assess the performance of modelling approaches in determining optimal dose. We found that the ability of modelling approaches to determine optimal dose improved with trial size, particularly for studies with at least 30 trial participants, and that, generally, using a peaking or a weighted model-averaging-based dose–efficacy relationship was most effective in finding optimal dose. Most methods of trial dose selection were similarly effective for the purpose of determining optimal dose; however, including modelling to adapt doses during a trial may lead to more trial participants receiving a more optimal dose. Clinical trial dosing around the predicted optimal dose, rather than only at the predicted optimal dose, may improve final dose selection. This work suggests modelling can be used effectively for vaccine dose finding, prompting potential practical applications of these methods in accelerating effective vaccine development and saving lives.

When Less May Be Enough: Dose Selection Strategies for Immune Checkpoint Inhibitors Focusing on AntiPD-(L)1 Agents.

Early clinical trials investigating antiPD(L)-1 agents rarely reached a maximum tolerated dose (MTD), and efficacy signals were observed even at the lowest dose levels. Most extended treatment intervals investigated indicated that these drugs do not follow a direct dose-toxicity or dose-efficacy relationship. Within this context and considering the high cost of antiPD(L)-1 agents, there is a significant debate on whether lower doses or the administration of such agents at an extended interval should be prospectively evaluated in already-approved agents, or at least be considered in novel combination trials involving antiPD(L)-1 drugs. Herein, we review the dosing, overall response rates, and incidence of treatment-related adverse events of antiPD(L)-1 agents in early dose-escalation trials and discuss the appropriateness of recommended Phase 2 dose selection as well as the final regulatory approved doses of such agents. Efficacy and safety data from randomized dose-range Phase 2 trials and real-world data (RWD) on the usage of lower doses and/or non-standard extended treatment intervals are also examined. As the accumulating evidence suggests lower doses or extended dosing intervals of antiPD(L)-1 may achieve a similar clinical benefit in comparison to the currently approved doses, we address the clinical and financial toxicity implications of using potentially higher doses than necessary. Last, we discuss ways to resolve the current dosing conundrum of antiPD-(L)1 agents such as performing near-equivalence studies and propose a framework for future development of immunotherapeutics to find the lowest efficacious dose instead of MTD.

Optimal dose of selective serotonin reuptake inhibitors, venlafaxine, and mirtazapine in major depression: a systematic review and dose-response meta-analysis

SummaryBackgroundDepression is the single largest contributor to non-fatal health loss worldwide. Second-generation antidepressants are the first-line option for pharmacological management of depression. Optimising their use is crucial in reducing the burden of depression; however, debate about their dose dependency and their optimal target dose is ongoing. We have aimed to summarise the currently available best evidence to inform this clinical question.MethodsWe did a systematic review and dose-response meta-analysis of double-blind, randomised controlled trials that examined fixed doses of five selective serotonin reuptake inhibitors (SSRIs; citalopram, escitalopram, fluoxetine, paroxetine, and sertraline), venlafaxine, or mirtazapine in the acute treatment of adults (aged 18 years or older) with major depression, identified from the Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS, MEDLINE, PsycINFO, AMED, PSYNDEX, websites of drug licensing agencies and pharmaceutical companies, and trial registries. We imposed no language restrictions, and the search was updated until Jan 8, 2016. Doses of SSRIs were converted to fluoxetine equivalents. Trials of antidepressants for patients with depression and a serious concomitant physical illness were excluded. The main outcomes were efficacy (treatment response defined as 50% or greater reduction in depression severity), tolerability (dropouts due to adverse effects), and acceptability (dropouts for any reasons), all after a median of 8 weeks of treatment (range 4–12 weeks). We used a random-effects, dose-response meta-analysis model with flexible splines for SSRIs, venlafaxine, and mirtazapine.Findings28 554 records were identified through our search (24 524 published and 4030 unpublished records). 561 published and 121 unpublished full-text records were assessed for eligibility, and 77 studies were included (19 364 participants; mean age 42·5 years, SD 11·0; 7156 [60·9%] of 11 749 reported were women). For SSRIs (99 treatment groups), the dose-efficacy curve showed a gradual increase up to doses between 20 mg and 40 mg fluoxetine equivalents, and a flat to decreasing trend through the higher licensed doses up to 80 mg fluoxetine equivalents. Dropouts due to adverse effects increased steeply through the examined range. The relationship between the dose and dropouts for any reason indicated optimal acceptability for the SSRIs in the lower licensed range between 20 mg and 40 mg fluoxetine equivalents. Venlafaxine (16 treatment groups) had an initially increasing dose-efficacy relationship up to around 75–150 mg, followed by a more modest increase, whereas for mirtazapine (11 treatment groups) efficacy increased up to a dose of about 30 mg and then decreased. Both venlafaxine and mirtazapine showed optimal acceptability in the lower range of their licensed dose. These results were robust to several sensitivity analyses.InterpretationFor the most commonly used second-generation antidepressants, the lower range of the licensed dose achieves the optimal balance between efficacy, tolerability, and acceptability in the acute treatment of major depression.FundingJapan Society for the Promotion of Science, Swiss National Science Foundation, and National Institute for Health Research.

An information theoretic phase I-II design for molecularly targeted agents that does not require an assumption of monotonicity.

SummaryFor many years phase I and phase II clinical trials have been conducted separately, but there has been a recent shift to combine these phases. Although a variety of phase I–II model‐based designs for cytotoxic agents have been proposed in the literature, methods for molecularly targeted agents (TAs) are just starting to develop. The main challenge of the TA setting is the unknown dose–efficacy relationship that can have either an increasing, plateau or umbrella shape. To capture these, approaches with more parameters are needed or, alternatively, more orderings are required to account for the uncertainty in the dose–efficacy relationship. As a result, designs for more complex clinical trials, e.g. trials looking at schedules of a combination treatment involving TAs, have not been extensively studied yet. We propose a novel regimen finding design which is based on a derived efficacy–toxicity trade‐off function. Because of its special properties, an accurate regimen selection can be achieved without any parametric or monotonicity assumptions. We illustrate how this design can be applied in the context of a complex combination–schedule clinical trial. We discuss practical and ethical issues such as coherence, delayed and missing efficacy responses, safety and futility constraints.

In vitro and in vivo activities of an antitumor peptide HM-3: A special dose-efficacy relationship on an HCT‑116 xenograft model in nude mice.

Anti-angiogenesis is an important therapy for cancer treatment. Peptide HM-3 is an integrin antagonist with anti-angiogenic and antitumor activity. Previous research found that HM-3 at an effective dose inhibited tumor growth whereas at higher doses, the inhibitory effect gradually decreased. In the present study, three human tumor cell lines, human colorectal cancer cell (HCT-116) and human hepatic cancer cell (HepG-2 and SMMC-7721), were selected and their interactions with HM-3 were compared with western blot and flow cytometric assays. The effect of HM-3 on the migration of two tumor cell lines (HCT-116 and HepG-2) was also evaluated and a bell-shaped dose-efficacy curve was found for both cell lines. Furthermore, invivo imaging in BALB/c nude mice confirmed that HM-3 had a short half-life and targeted the tumor tissue. Moreover, on an HCT-116 xenograft model in BALB/c nude mice, HM-3 at 3mg/kg inhibited tumor growth with an inhibition rate of 71.5% (by tumor mass) whereas at 12and48mg/kg, the inhibition rates were 59.2and36.0%, respectively. Immunohistochemistry analyses found that both sunitinib (60mg/kg) and HM-3 (3and48mg/kg) decreased microvascular density and increased percent of HIF-1α and VEGF expressing cells. The present study investigated the effect of tumor microenvironments on the antitumor effect of HM-3 and concluded that HM-3 inhibited angiogenesis and thereafter tumor growth by directly inhibiting HUVEC migration. The special dose-efficacy curves for antitumor effect and for cell migration inhibition were correlated. The present study also confirmed that the effective dose has to be strictly defined for better clinical applications of anti‑angiogenic drugs such as HM-3.

Treatment with high doses of pegvisomant in 56 patients with acromegaly: experience from ACROSTUDY.

To investigate the characteristics of patients who need more or less pegvisomant (PEGV) to normalize serum IGF-I. ACROSTUDY is a global noninterventional safety surveillance study of long-term treatment outcomes in patients treated with PEGV. As of June, 2014, ACROSTUDY included data on 2016 patients. All patients treated for at least 6weeks at a dose above 30mg/day and who had two consecutive normal serum IGF-I values were included in the 'high'-dose group (H; n=56; mean daily dose 44±12.5; median dose 40, 35-60 (10-90%)). Patients with two consecutive normal IGF-I values and who never received a PEGV dose above 10mg/day were included in the 'low'-dose group (L; n=368; mean daily dose 7.5±2.5; median dose 8.6, 4.3-10 (10-90%)). Patients in the H group were significantly younger (median 47 vs 52years) and had a significantly higher BMI (median 31.8 vs 26.5kg/m(2)). They had more diabetes (55% vs 21%), sleep apnea (25% vs 14 %) and more hypertension (61% vs 43%). The incidence of (serious) adverse events was low and was not different between the groups. Patients who need more PEGV to normalize IGF-I have more aggressive disease, as they are younger, have higher baseline IGF-I levels, more hypertension, more sleep apnea and diabetes and are more overweight. A better understanding of this dose-efficacy relationship of PEGV might avoid inappropriate dosing and prevent serum IGF-I levels from remaining unnecessarily uncontrolled.

An adaptive dose-finding method using a change-point model for molecularly targeted agents in phase I trials.

The paradigm of oncology drug development is expanding from developing cytotoxic agents to developing biological or molecularly targeted agents (MTAs). Although it is common for the efficacy and toxicity of cytotoxic agents to increase monotonically with dose escalation, the efficacy of some MTAs may exhibit non-monotonic patterns in their dose-efficacy relationships. Many adaptive dose-finding approaches in the available literature account for the non-monotonic dose-efficacy behavior by including additional model parameters. In this study, we propose a novel adaptive dose-finding approach based on binary efficacy and toxicity outcomes in phase I trials for monotherapy using an MTA. We develop a dose-efficacy model, the parameters of which are allowed to change in the vicinity of the change point of the dose level, in order to consider the non-monotonic pattern of the dose-efficacy relationship. The change point is obtained as the dose that maximizes the log-likelihood of the assumed dose-efficacy and dose-toxicity models. The dose-finding algorithm is based on the weighted Mahalanobis distance, calculated using the posterior probabilities of efficacy and toxicity outcomes. We compare the operating characteristics between the proposed and existing methods and examine the sensitivity of the proposed method by simulation studies under various scenarios. Copyright © 2016 John Wiley & Sons, Ltd.

Phase I/II dose-finding design for molecularly targeted agent: Plateau determination using adaptive randomization.

Conventionally, phase I dose-finding trials aim to determine the maximum tolerated dose of a new drug under the assumption that both toxicity and efficacy monotonically increase with the dose. This paradigm, however, is not suitable for some molecularly targeted agents, such as monoclonal antibodies, for which efficacy often increases initially with the dose and then plateaus. For molecularly targeted agents, the goal is to find the optimal dose, defined as the lowest safe dose that achieves the highest efficacy. We develop a Bayesian phase I/II dose-finding design to find the optimal dose. We employ a logistic model with a plateau parameter to capture the increasing-then-plateau feature of the dose-efficacy relationship. We take the weighted likelihood approach to accommodate for the case where efficacy is possibly late-onset. Based on observed data, we continuously update the posterior estimates of toxicity and efficacy probabilities and adaptively assign patients to the optimal dose. The simulation studies show that the proposed design has good operating characteristics. This method is going to be applied in more than two phase I clinical trials as no other method is available for this specific setting. We also provide an R package dfmta that can be downloaded from CRAN website.

High-Resolution Analysis of the Relationship Between Ponatinib Dose and Molecular Response in CP-CML Patients in the PACE Trial

Understanding the relationship between dose and efficacy is a critical step in optimizing the benefit-risk ratio of therapeutic agents. Ponatinib, a potent pan-BCR-ABL TKI, induced major cytogenetic and molecular responses in heavily pretreated CP-CML patients in the PACE trial. Investigation of the dose-response relationship (45mg starting dose) revealed that induction of MCyR was dose-dependent and that responses were maintained upon dose reduction (to 15 or 30mg). To further explore the dose-efficacy relationship of ponatinib, we developed a novel approach to associate drug exposure with changes in BCR-ABL transcript levels. The method, BCR-ABL Response-Dose association (BARD), enables a higher-resolution view of the dose-response relationship in CML than endpoint analyses because of the high sensitivity, broad dynamic range, and frequency of molecular response assessments.

Abstract 16451: Dose-Escalation Study Using Novel Continuous Flow Intracoronary Delivery of Allogeneic Cardiosphere-Derived Stem Cells: Is There a Threshold for Cell Therapy?

BACKGROUND: Intracoronary (IC) infusion of cardiosphere-derived stem cells (CDCs) under stop-flow conditions has proven efficacious in producing myocardial regeneration in preclinical and clinical studies. However, the minimally-effective dose is not known, nor is it clear whether benefit is straightforwardly dependent on CDC dose. OBJECTIVE: To determine the dose-efficacy relationship of allogeneic CDCs in a large-animal chronic myocardial infarction (MI) model. METHODS: Escalating doses of allogeneic CDCs (3.125M, 6.25M, 12.5M, 25M; or vehicle as a control) were infused into the left anterior descending coronary artery using a nonocclusive guiding catheter in an anterior chronic MI minipig model. Magnetic resonance imaging (MRI) was used to assess structural and functional endpoints. RESULTS: CDCs were infused in a total of 25 animals under continuous flow at a rate of 1.25M CDCs/min. An additional 5 control animals underwent continuous flow of vehicle over 10 min. No animals experienced adverse events during or after the infusions. One month post therapy, ejection fraction (EF) was preserved at doses of 6.25M, 12.5M and 25M, but not with 3.125 M allo-CDCs or control (ΔEF = -6.7±0.9% in the placebo, -5.1±1.8% in 3.125M, -1.4±0.6% in the 6.25M, -2±1.4% in the 12.5M and -2.3±1.2% in the 25M group; p=0.04 by one way ANOVA for treatment effect). All doses of CDCs (except 3.125M) led to equivalent scar mass reductions, as assessed by MRI with Gd enhancement (p=0.0037 treated vs placebo, one-way ANOVA). Provocative electrophysiology testing at the end of the study revealed no enhanced arrythmogenic potential after cell therapy. CONCLUSIONS: Allogeneic CDCs can be safely administered with a non-occlusive method, over a wide dosage range. All doses &gt;3.125M lead to enhanced preservation of left ventricular function and tissue remodeling, but to similar degrees. Our data reveal that CDCs work by a “threshold” effect that does not obey classical drug-receptor kinetics. This finding is consistent with the extraordinary ability of seemingly-homeopathic doses to exert large, lasting benefits.

Bayesian Model Averaging Continual Reassessment Method for Bivariate Binary Efficacy and Toxicity Outcomes in Phase I Oncology Trials

Many dose-finding approaches that could evaluate bivariate binary efficacy and toxicity outcomes have been proposed in recent years. In such designs, the operating characteristics with finite sample size can be greatly affected by the assumed dose–toxicity and/or dose–efficacy relationship. However, we do not have much information about a new agent we investigated at the planning stage of Phase I trials and so always face to the risk of misspecifying the true dose–toxicity and/or dose–efficacy relationship by arbitrarily and subjectively choosing skeletons. In this article, we proposed the Bayesian model averaging bivariate continual reassessment method to cope with above risk.

Dose-Response Analyses Of Momelotinib (CYT387), a JAK1 and JAK2 Inhibitor, From a Phase I/II Study (CCL09101) In Treatment Of Myelofibrosis

BackgroundMomelotinib (MMB, previously CYT387) is a selective small molecule inhibitor of JAK 1 and JAK 2 currently under investigation for the treatment of myelofibrosis (MF). Study CCL09101 is a Phase I/II, open-label, dose-escalation study of oral MMB in MF subjects. Following an initial dose escalation phase, subjects were assigned to 150 mg once-daily (QD), 300 mg QD or 150 mg twice-daily (BID) MMB capsules, in a 9 month (mos) dose expansion phase. The safety and tolerability of MMB, based on assigned dose, was previously reported with a maximum tolerated dose of 300 mg QD and dose limiting toxicities of elevated lipase and headache at 400 mg QD. Clinical efficacy included spleen response rate of 37% based on IWG criteria and suggested improvement in anemia related endpoints. As the study allowed intra-subject dose adjustments for tolerability, additional analyses based on average daily dose administered were performed. In a subset of patients, pharmacokinetics (PK) was assessed. MethodsDose-efficacy analyses were conducted using the average daily dose received over 6 mos for spleen response and 9 mos for transfusion (txn) independence response. Subjects were grouped based on tertiles of average daily dose < 200 mg, 200 to < 300 mg, > 300 mg. Spleen response at 6 mos required a ≥ 50% reduction in palpable splenomegaly. Txn response required maintaining transfusion independence for ≥12 weeks (wks) for subjects who were txn dependent at baseline and completed ≥ 12 wks on study.The incidence of hgb and platelet (plt) decline was also analyzed as a function of average daily dose received over 6 mos. Subjects evaluated for hgb decline were txn independent with hgb ≥ 8 g/dL at baseline. Hgb decline was defined as the incidence of hgb < 8 g/dL and at least a 1 g/dL decrease compared to baseline. Subjects evaluated for plt decline had baseline platelet count ≥ 100 x 109/L. Plt count decline was defined as the incidence of plt count < 100 x 109 /L and ≥ 50 x 109/L decrease compared to baseline at any point during the 6 mos. In the PK subset, dose-exposure relationship was explored. ResultsSpleen response rates were comparable across MMB average daily dose tertiles, indicating a relatively flat dose-efficacy relationship. A trend towards a higher txn response was observed at the highest MMB average daily dose. No dose dependent increase in hgb or plt decline was noted across average daily dose tertiles. 60 subjects (41%) reported peripheral neuropathy as an adverse event during the 9 mos study; 92% grade 1, 8% grade 2. Incidence was comparable across average daily dose tertiles (see table).MMB Average Daily Dose (mg/day)< 200200 to < 300≥ 300Spleen response, % at 6 mos (n = 148; spleen > 5 cm at baseline)30% (14/47)28% (12/43)31% (18/58)Transfusion response, % over 9 mos (n = 68; transfusion dependent at baseline and completed 12 wks)41% (9/22)63% (20/32)86% (12/14)Hgb < 8 g/dL and ≥ 1 g/dL decline compared to baseline, % over 6 mos (n = 93; transfusion independent and hgb ≥ 8 g/dL at baseline)17% (4/24)7% (2/27)2% (1/42)Plt count < 100 x 109/L and ≥ 50 x 109/L decline compared to baseline, % over 6 mos (n = 126; plt ≥ 100 x 109/L at baseline)28% (11/40)28% (11/40)13% (6/46)Neuropathy, % over 9 mos (n = 166)Grade 122% (9/41)40% (32/81)32% (14/44)Grade 22% (1/41)4% (3/81)2% (1/44)In the PK subset of subjects, MMB exposures were generally dose proportional between 150 mg QD and 300 mg QD (mean AUCtau: 2114 and 4424 h×ng/ml, respectively; steady state Cmax: 339 and 660 ng/ml, respectively) with limited data from the other dose levels (n ≤ 5).Of subjects receiving 300 mg total daily starting dose, > 60% of subjects maintained this dose level throughout the study; > 75% of subjects had an average daily dose of ∼250 mg to 280 mg (following 300 mg QD or 150 mg BID dosing, respectively), and the median average daily dose was 300 mg, suggesting 300 mg QD was well tolerated. ConclusionNo relationships were observed between average daily doses of MMB vs clinically relevant endpoints of spleen response rate or plt count decline compared to baseline. There was a suggested trend, albeit with limited sample size, towards improved anemia-related endpoints at MMB dose ≥ 300 mg QD. Analyses suggest no need to adjust dose based on baseline plt count. In conjunction with the previously reported primary endpoints of safety and efficacy, these analyses support selection of the 300 mg QD capsule formulation as the starting dose for all subjects in the planned Phase 3 study. Disclosures:Xin:Gilead Sciences: Employment, Equity Ownership. Shao:Gilead Sciences: Employment, Equity Ownership. Deng:Gilead Sciences: Employment, Equity Ownership. Niforos:Gilead Sciences: Employment. Kowalski:Gilead Sciences: Employment. Bavisotto:YM Biosciences: Consultancy. Kawashima:Gilead Sciences: Employment. Jun:Gilead Sciences: Employment. Collins:Gilead Sciences: Employment, Equity Ownership. Ramanathan:Gilead Sciences: Employment, Equity Ownership.

A Bayesian Dose Finding Design for Oncology Clinical Trials of Combinational Biological Agents

Treating patients with novel biological agents is becoming a leading trend in oncology. Unlike cytotoxic agents, for which efficacy and toxicity monotonically increase with dose, biological agents may exhibit non-monotonic patterns in their dose-response relationships. Using a trial with two biological agents as an example, we propose a dose-finding design to identify the biologically optimal dose combination (BODC), which is defined as the dose combination of the two agents with the highest efficacy and tolerable toxicity. A change-point model is used to reflect the fact that the dose-toxicity surface of the combinational agents may plateau at higher dose levels, and a flexible logistic model is proposed to accommodate the possible non-monotonic pattern for the dose-efficacy relationship. During the trial, we continuously update the posterior estimates of toxicity and efficacy and assign patients to the most appropriate dose combination. We propose a novel dose-finding algorithm to encourage sufficient exploration of untried dose combinations in the two-dimensional space. Extensive simulation studies show that the proposed design has desirable operating characteristics in identifying the BODC under various patterns of dose-toxicity and dose-efficacy relationships.

Study on analgesic and accompanying toxic and side effects of Euodiae Fructus based on clinical efficacy dose

To observe and study the toxic and side effects of water extracts from Euodiae Fructus accompanied with its efficacy analgesic dose and its mechanism, in order to provide experimental basis for the correlation between its "efficacy-toxicity". Mice were randomly divided into 5 groups according to weight, namely the normal group, the voltaren group, and Euodiae Fructus water extracts high, middle and low dose groups. Mice were administered with drugs for consecutively seven days, abdominally injected with acetic acid at 90 min and treated with hot plates after the last administration to establish the pain model, in order to the toxic and side effects accompanied with the efficacy. Besides toxic symptoms in mice, activities of ALT and AST, and content of BUN and Cr in serum were detected to calculate indexes in livers and kidneys. The other part of serum was collected to detect the content and activities of PGE2, MDA, SOD, NO, NOS, GSH and GSH-PX in serum. Continuous oral administration of water extracts from Euodiae Fructus of efficacy dose could significantly decrease the frequency of writhe in mice and increase the hot plate pain threshold, with good dose-efficacy relationship. During the administration, mice showed such toxic symptoms as diarrhoea, idle move, dysphoria and slow growth of weight. The activities of both ALT and AST in serum and hepatic tissues were remarkably increased and the liver size remarkably increased, without notable chance in content of BUN and CR in serum. Kidney size increased in only the high dose group. The content and activities of PGE2, SOD, GSH, GSH-PX in serum notably decreased, where the content and activities of MDA, NO, NOS in serum increased. The above-mentioned changes gradually aggravated with the rise in dose. There was significant difference compared with the model group, showing 'dose-toxicity' relationship to certain extent. Continuous oral administration of certain dose of water extracts from Euodiae Fructus to mice can generate the toxic and side effects in liver accompanying with the analgesic effect, and show dose-dependence relationship to some extent. Its analgesic mechanism is related to the reduction of PGE, content in blood, while its toxic mechanism is related to oxidative injury to some extent.