Safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of Exendin-4-IgG4-Fc in healthy subjects: A phase 1, single-centre, randomized, double-blind, dose escalation study.

AIM: Novel long-acting drugs for type 2 diabetes mellitus may optimize patient compliance and glycaemic control. Exendin-4-IgG4-Fc (E4F4) is a long-acting glucagon-like peptide-1 receptor agonist. This first-in-human study investigated the safety, tolerability, pharmacokinetic, pharmacodynamic and immunogenicity profiles of a single subcutaneous injection of E4F4 in healthy subjects. METHODS: This single-centre, randomized, double-blind, placebo-controlled phase 1 clinical trial included 96 subjects in 10 sequential cohorts that were provided successively higher doses of E4F4 (0.45, 0.9, 1.8, 3.15, 4.5, 6.3, 8.1, 10.35, 12.6 and 14.85 mg) or placebo (ChinaDrugTrials.org.cn: ChiCTR2100049732). The primary endpoint was safety and tolerability of E4F4. Secondary endpoints were pharmacokinetic, pharmacodynamic and immunogenicity profiles of E4F4. Safety data to day 15 after the final subject in a cohort had been dosed were reviewed before commencing the next dose level. RESULTS: E4F4 was safe and well tolerated among healthy Chinese participants in this study. There was no obvious dose-dependent relationship between frequency, severity or causality of treatment-emergent adverse events. Cmax and area under the curve of E4F4 were dose proportional over the 0.45-14.85 mg dose range. Median Tmax and t1/2 ranged from 146 to 210 h and 199 to 252 h, respectively, across E4F4 doses, with no dose-dependent trends. For the intravenous glucose tolerance test, area under the curve of glucose in plasma from time 0 to 180 min showed a dose-response relationship in the 1.8-10.35 mg dose range, with an increased response at the higher doses. CONCLUSION: E4F4 exhibited an acceptable safety profile and linear pharmacokinetics in healthy subjects. The recommended phase 2 dose is 4.5-10.35 mg once every 2 weeks.

Safety and dose-finding trial of tadalafil administered for fetus in labor: A phase I clinical study.

AIM: This study aimed to investigate the safety and efficacy of tadalafil in protecting the fetus from hypoxic stress caused by repeated labor pains during delivery and preventing fetal hypoxic-ischemic encephalopathy. METHODS: The study used a three-case cohort approach. Three patients were administered 10 mg tadalafil and monitored for serious adverse events. In the absence of serious tadalafil-associated adverse events as assessed by the Safety Evaluation Committee, three new patients were added to the study and treated with 20 mg/dose. The blood levels of tadalafil were recorded before and after 2, 4, 8, and 12 h of administration and 2 h after delivery. RESULTS: A total of seven patients were enrolled, and after excluding one patient who delivered before 37 weeks, tadalafil was administered to six patients. Maternal adverse events were considered acceptable from the maternal perspective, with grade 1 headache, anorexia, and myalgia and no obstetrical complications after delivery at both doses. No serious neonatal adverse events were associated with tadalafil. Tadalafil blood levels remained stable at both doses. In addition, the level of soluble fms-like tyrosine kinase-1 did not alter, while that of the placental growth factor differed significantly before and after tadalafil administration. CONCLUSIONS: The study confirmed the safety of tadalafil administration during delivery for both mothers and newborns. The stable tadalafil blood levels confirmed the efficacy of the tested administration regime at 12 h interval. These findings would assist in conducting phase II trials to further verify the optimal dose and safety of tadalafil.

Hypofractionated Stereotactic Re-irradiation and Anti-PDL1 Durvalumab Combination in Recurrent Glioblastoma: STERIMGLI Phase I Results.

BACKGROUND: Hypofractionated stereotactic radiotherapy (hFSRT) is a salvage option for recurrent glioblastoma (GB) which may synergize anti-PDL1 treatment. This phase I study evaluated the safety and the recommended phase II dose of anti-PDL1 durvalumab combined with hFSRT in patients with recurrent GB. METHODS: Patients were treated with 24 Gy, 8 Gy per fraction on days 1, 3, and 5 combined with the first 1500 mg Durvalumab dose on day 5, followed by infusions q4weeks until progression or for a maximum of 12 months. A standard 3 + 3 Durvalumab dose de-escalation design was used. Longitudinal lymphocytes count, cytokines analyses on plasma samples, and magnetic resonance imaging (MRI) were collected. RESULTS: Six patients were included. One dose limiting toxicity, an immune-related grade 3 vestibular neuritis related to Durvalumab, was reported. Median progression-free interval (PFI) and overall survival (OS) were 2.3 and 16.7 months, respectively. Multi-modal deep learning-based analysis including MRI, cytokines, and lymphocytes/neutrophil ratio isolated the patients presenting pseudoprogression, the longest PFI and those with the longest OS, but statistical significance cannot be established considering phase I data only. CONCLUSION: Combination of hFSRT and Durvalumab in recurrent GB was well tolerated in this phase I study. These encouraging results led to an ongoing randomized phase II. (ClinicalTrials.gov Identifier: NCT02866747).

A phase I prospective, non-randomized trial of autologous dendritic cell-based cryoimmunotherapy in patients with metastatic castration-resistant prostate cancer.

Metastatic castration-resistant prostate cancer (mCRPC) is an immunologically cold disease with dismal outcomes. Cryoablation destroys cancer tissue, releases tumor-associated antigens and creates a pro-inflammatory microenvironment, while dendritic cells (DCs) activate immune responses through processing of antigens. Immunotherapy combinations could enhance the anti-tumor efficacy. This open-label, single-arm, single-center phase I trial determined the safety and tolerability of combining cryoablation and autologous immature DC, without and with checkpoint inhibitors. Immune responses and clinical outcomes were evaluated. Patients with mCRPC, confirmed metastases and intact prostate gland were included. The first participants underwent prostate cryoablation with intratumoral injection of autologous DCs in a 3 + 3 design. In the second part, patients received cryoablation, the highest acceptable DC dose, and checkpoint inhibition with either ipilimumab or pembrolizumab. Sequentially collected information on adverse events, quality of life, blood values and images were analyzed by standard descriptive statistics. Neither dose-limiting toxicities nor adverse events > grade 3 were observed in the 18 participants. Results indicate antitumor activity through altered T cell receptor repertoires, and 33% durable (> 46 weeks) clinical benefit with median 40.7 months overall survival. Post-treatment pain and fatigue were associated with circulating tumor cell (CTC) presence at inclusion, while CTC responses correlated with clinical outcomes. This trial demonstrates that cryoimmunotherapy in mCRPC is safe and well tolerated, also for the highest DC dose (2.0 × 108) combined with checkpoint inhibitors. Further studies focusing on the biologic indications of antitumor activity and immune system activation could be considered through a phase II trial focusing on treatment responses and immunologic biomarkers.

A clinical phase I dose-finding design with adaptive shrinking boundaries for drug combination trials.

BACKGROUND: Combinations of drugs are becoming increasingly common in oncology treatment. In some cases, patients can benefit from the interaction between two drugs, although there is usually a higher risk of developing toxicity. Due to drug-drug interactions, multidrug combinations often exhibit different toxicity profiles than those of single drugs, leading to a complex trial scenario. Numerous methods have been proposed for the design of phase I drug combination trials. For example, the two-dimensional Bayesian optimal interval design for combination drug (BOINcomb) is simple to implement and has desirable performance. However, in scenarios where the lowest and starting dose is close to being toxic, the BOINcomb design may tend to allocate more patients to overly toxic doses, and select an overly toxic dose combination as the maximum tolerated dose combination. METHOD: To improve the performance of BOINcomb in the above extreme scenarios, we widen the range of variation of the boundaries by setting the self-shrinking dose escalation and de-escalation boundaries. We refer to the new design as adaptive shrinking Bayesian optimal interval design for combination drug (asBOINcomb). We conduct a simulation study to evaluate the performance of the proposed design using a real clinical trial example. RESULTS: Our simulation results show that asBOINcomb is more accurate and stable than BOINcomb, especially in some extreme scenarios. Specifically, in all ten scenarios, the percentage of correct selection is higher than the BOINcomb design within 30 to 60 patients. CONCLUSION: The proposed asBOINcomb design is transparent and simple to implement and can reduce the trial sample size while maintaining accuracy compared with the BOINcomb design.

A new era of the Asian clinical research network: a report from the ATLAS international symposium.

This report summarizes the presentations and discussions in the first Asian Clinical Trials Network for Cancers (ATLAS) international symposium that was held on 24 April 2022, in Bangkok, Thailand, and hosted by the National Cancer Center Hospital (NCCH), co-hosted by the Pharmaceuticals and Medical Devices Agency (PMDA), Clinical Research Malaysia (CRM) and the Thai Society of Clinical Oncology (TSCO), and supported by Embassy of Japan in Thailand. Since 2020, the NCCH has conducted the ATLAS project to enhance research environments and infrastructures to facilitate international clinical research and cancer genomic medicine in the Asian region. The purpose of the symposium was to discuss what we can achieve under the ATLAS project, to share the latest topics and common issues in cancer research and to facilitate mutual understanding. Invitees included stakeholders from academic institutions, mainly at ATLAS collaborative sites, as well as Asian regulatory authorities. The invited speakers discussed ongoing collaborative research, regulatory perspectives to improve new drug access in Asia, the status of phase I trials in Asia, the introduction of research activities at the National Cancer Center (NCC) and the implementation of genomic medicine. As the next steps after this symposium, the ATLAS project will foster increased cooperation between investigators, regulatory authorities and other stakeholders relevant to cancer research, and establish a sustainable pan-Asian cancer research group to increase the number of clinical trials and deliver novel drugs to patients with cancer in Asia.

A phase I study of the safety and efficacy of talimogene laherparepvec in Japanese patients with advanced melanoma.

Talimogene laherparepvec (T-VEC) is approved for the treatment of unresectable melanoma in the USA, Europe, and Australia. This phase I, multicenter, open-label, dose de-escalation study evaluated the safety and efficacy of T-VEC in Japanese patients with unresectable stage IIIB-IV melanoma. Eligible adult patients had histologically confirmed stage IIIB-IVM1c cutaneous melanoma, may have received prior systemic anticancer therapy, must have had ≥1 injectable lesion, serum lactate dehydrogenase ≤1.5x upper limit of normal, ECOG performance status of 0 or 1, and adequate hematologic, hepatic, and renal function. T-VEC was injected intralesionally (first dose, ≤4.0 ml of 106  PFU/ml; after 3 weeks and then every 2 weeks thereafter, ≤4.0 ml of 108  PFU/ml). Primary endpoints were dose-limiting toxicities (DLTs) and durable response rate (DRR). Of 18 enrolled patients (72.2% female), 16 had received ≥1 prior line of therapy. Ten patients discontinued T-VEC due to disease progression. Median (range) follow-up was 20.0 (4-37) months. No DLTs were observed; 17 (94.4%) patients had treatment-emergent adverse events (AEs). Fourteen (77.8%) patients had treatment-related AEs; the most frequent were pyrexia (44.4%), malaise (16.7%), chills, decreased appetite, pruritus, and skin ulcer (11.1% each). The primary efficacy endpoint was met: 2 (11.1%) patients had a durable partial response ≥6 months. The DRR was consistent with that observed in a phase III trial of T-VEC in non-Asian patients. The safety profile was consistent with the patients' underlying disease and the known safety profile of T-VEC.

Clinical development of anticancer drugs can be enhanced using efficacy data of small population clinical trials.

WHAT IS KNOWN AND OBJECTIVE: Although there are accelerated approval pathways based on data of small populations and surrogate endpoints, the concern that these pathways authorize the use of inefficacious drugs based on limited data from earlier phase clinical trials remains. We retrospectively investigated the efficacy of anticancer drugs, which were approved or whose development was terminated in small and large clinical trials, and verified whether small clinical trials could reflect the results for efficacy in large clinical trials. METHODS: All anticancer drugs approved in Japan or whose development was terminated from 2015 to 2019 were searched. The median overall survival (OS), median progression-free survival (PFS), and overall response rates (ORR) between small clinical trials (sample size ≤100) and large clinical trials (sample size >100) with identical target populations and treatment settings were compared. Simple linear regression analysis, Spearman's correlation analysis, and paired sample t-test were performed. RESULTS AND DISCUSSION: A total of 61 comparable small and large clinical trials were identified. For all endpoints, statistically significant linear trends and correlation were detected (p < 0.001). There were no statistically significant differences in the median PFS and ORR between small and large clinical trials. The mean differences of both clinical trials were -0.102 months and -1.531%, respectively. WHAT IS NEW AND CONCLUSION: Even when the sample size of the clinical trial was increased, the efficacy data of anticancer drugs could not be changed significantly. These results supported the accelerated approval pathway based on the promising efficacy data of small populations in anticancer drug development.

Metabolic Effect of Blocking Sodium-Taurocholate Co-Transporting Polypeptide in Hypercholesterolemic Humans with a Twelve-Week Course of Bulevirtide-An Exploratory Phase I Clinical Trial.

Bile acids (BA) play an important role in cholesterol metabolism and possess further beneficial metabolic effects as signalling molecules. Blocking the hepatocellular uptake of BA via sodium-taurocholate co-transporting polypeptide (NTCP) with the first-in-class drug bulevirtide, we expected to observe a decrease in plasma LDL cholesterol. In this exploratory phase I clinical trial, volunteers with LDL cholesterol > 130 mg/dL but without overt atherosclerotic disease were included. Thirteen participants received bulevirtide 5 mg/d subcutaneously for 12 weeks. The primary aim was to estimate the change in LDL cholesterol after 12 weeks. Secondary endpoints included changes in total cholesterol, HDL cholesterol, lipoprotein(a), inflammatory biomarkers, and glucose after 12 weeks. In addition, cardiac magnetic resonance imaging (CMR) was performed at four time points. BA were measured as biomarkers of the inhibition of hepatocellular uptake. After 12 weeks, LDL cholesterol decreased not statistically significantly by 19.6 mg/dL [−41.8; 2.85] (Hodges−Lehmann estimator with 95% confidence interval). HDL cholesterol showed a significant increase by 5.5 mg/dL [1.00; 10.50]. Lipoprotein(a) decreased by 1.87 mg/dL [−7.65; 0]. Inflammatory biomarkers, glucose, and cardiac function were unchanged. Pre-dose total BA increased nearly five-fold (from 2026 nmol/L ± 2158 (mean ± SD) at baseline to 9922 nmol/L ± 7357 after 12 weeks of treatment). Bulevirtide was generally well tolerated, with most adverse events being administration site reactions. The exploratory nature of the trial with a limited number of participants allows the estimation of potential effects, which are crucial for future pharmacological research on bile acid metabolism in humans.

Safety and pharmacokinetics of milademetan, a MDM2 inhibitor, in Japanese patients with solid tumors: A phase I study.

Milademetan (DS-3032, RAIN-32) is an orally available mouse double minute 2 (MDM2) antagonist with potential antineoplastic activity owing to increase in p53 activity through interruption of the MDM2-p53 interaction. This phase I, dose-escalating study assessed the safety, tolerability, efficacy, and pharmacokinetics of milademetan in 18 Japanese patients with solid tumors who relapsed after or were refractory to standard therapy. Patients aged ≥ 20 years received oral milademetan once daily (60 mg, n = 3; 90 mg, n = 11; or 120 mg, n = 4) on days 1 to 21 in a 28-day cycle. Dose-limiting toxicities, safety, tolerability, maximum tolerated dose, pharmacokinetics, and recommended dose for phase II were determined. The most frequent treatment-emergent adverse events included nausea (72.2%), decreased appetite (61.1%), platelet count decreased (61.1%), white blood cell count decreased (50.0%), fatigue (50.0%), and anemia (50.0%). Dose-limiting toxicities (three events of platelet count decreased and one nausea) were observed in the 120-mg cohort. The plasma concentrations of milademetan increased in a dose-dependent manner. Stable disease was observed in seven out of 16 patients (43.8%). Milademetan was well tolerated and showed modest antitumor activity in Japanese patients with solid tumors. The recommended dose for phase II was considered to be 90 mg in the once-daily 21/28-day schedule. Future studies would be needed to further evaluate the potential safety, tolerability, and clinical activity of milademetan in patients with solid tumors and lymphomas. The trial was registered with Clinicaltrials.jp: JapicCTI-142693.

Activity of preclinical and phase I clinical trial of a novel androgen receptor antagonist GT0918 in metastatic breast cancer.

PURPOSE: To evaluate GT0918, a 2nd-generation AR antagonist, for its AR down-regulation activity among breast cancer patients. METHODS: The effect of GT0918 on AR protein expression was evaluated in AR expression breast cancer cells and in breast cancer xenograft model. A 3 + 3 phase I dose-escalation study was launched in Peking University Cancer Hospital. The endpoints included dose finding, safety, pharmacokinetics, and antitumor activity. RESULTS: GT0918 was demonstrated to effectively suppress the expression of AR protein and the growth of AR-positive breast cancer tumors in mouse xenograft tumor models. All patients treated with GT0918 were at a QD dose-escalation of five dose levels from 100 to 500 mg. The most common treatment-related AEs of any grade were asthenia, anemia, decreased appetite, increased blood cholesterol, increased blood triglycerides, decreased white blood cell count, and increased low-density lipoprotein. Grade 3 AEs were fatigue (2 of 18, 11.1%), aspartate aminotransferase increase (1 of 18, 5.6%), alanine aminotransferase increase (1 of 18, 5.6%), and neutrophil count decrease (1 of 18, 5.6%). Clinical benefit rate (CBR) in 16 weeks was 23.1% (3/13). Among 7 AR-positive patients, 6 can evaluate efficacy, and 2 completed 23.5- and 25-cycle treatment, respectively (as of 2020/1/20). PK parameters showed a fast absorption profile of GT0918 in the single-dose study. GT0918 and its major metabolite reached steady-state serum concentration levels at day 21 after multiple dosing. CONCLUSION: GT0918 can effectively inhibit AR-positive breast cancer tumor growth. GT0918 was demonstrated well tolerated with a favorable PK profile. The suitable dose of GT0918 was 500 mg QD and may provide clinical benefits for AR-positive mBC.

Phase I study of liposomal irinotecan in patients with metastatic breast cancer: findings from the expansion phase.

PURPOSE: Metastatic breast cancer (mBC) remains incurable and is associated with low survival rates. This study assessed the efficacy and safety of liposomal irinotecan in heavily pretreated patients with mBC, with or without active brain metastases (BM). METHODS: Following the dose escalation phase and determination of recommended phase 2 dose, the expansion phase of this phase I, open-label, non-randomized study, assigned adult women to cohorts based on mBC subtype: cohort 1, hormone receptor +/human epidermal growth factor receptor 2-; cohort 2, triple-negative breast cancer; or cohort 3, any mBC subtype with active BM. Patients received liposomal irinotecan 50 or 70 mg/m2 free base every 2 weeks. Here, we report secondary outcomes including best overall response (BOR), objective response rate (ORR), and treatment-emergent adverse events (TEAEs). RESULTS: For non-central nervous system (non-CNS) disease across all cohorts (intent-to-treat population, N = 29), the ORR was 34.5% (95% confidence interval: 17.94-54.33), with a BOR of partial response in 10 patients (34.5%), stable disease in five (17.2%), progressive disease in 10 (34.5%); four patients were unevaluable (13.8%). The ORR for the CNS cohort was 30.0% (95% confidence interval: 6.67-65.25) using modified Response Evaluation Criteria in Solid Tumors. Common grade 3 or higher TEAEs were diarrhea (27.6%), nausea (17.2%), fatigue (13.8%), asthenia (10.3%), and hypokalemia (10.3%). Serious treatment-related TEAEs were reported in six patients (20.7%). No treatment-related TEAEs resulted in death. CONCLUSIONS: Liposomal irinotecan monotherapy demonstrated antitumor activity in heavily pretreated patients with mBC, with or without BM. The observed safety profile was consistent with that in previous studies. CLINICAL TRIAL REGISTRATION: Trial registration ID NCT01770353.

Quantitative Multiplex Immunofluorescence Evaluation of the Tumor Microenvironment in Pretreatment Tumors of Patients with Metastatic Breast Cancer and Serous Ovarian Carcinoma Treated with Liposomal Eribulin.

Eribulin inhibits microtubule polymerization and suppresses epithelial-mesenchymal transition. Conventional pathology approaches have not identified a precise predictive biomarker for Eribulin. We performed qmIF on pre-treatment tissue from 11 patients (6 TNBC, 5 HGSOC) treated with Eribulin-LF. T-lymphocytes were the dominant immune-subset in TME, with higher levels detected in stroma vs tumor (9% vs 2%). Greater density of CD3+ (p = 0.01) and CD3 + CD8+ (p = 0.03) cells and closer proximity between CD3 + CD8+ and tumor cells was observed in the patients with disease control (PR + SD) vs. progressive disease. QmIF identified an association between TIL infiltration and Eribulin-LF sensitivity, which should be evaluated further in prospective studies.

Nonclinical & clinical interface - extrapolation of nonclinical data to support Phase I clinical studies.

A review of the Investigator's Brochure and Clinical Study Reports for 58 non-oncology small molecule and biopharmaceutical drug candidates tested in a healthy volunteer subject population was conducted. Key findings were (1) a vital role for nonclinical pharmacology and toxicology testing was confirmed to allow setting of clinical starting dose and supporting use of highest dose based on No Observed Adverse Effect Levels (NOAELs), Pharmacologically Active Doses (PADs) and other approaches, (2) for clinical starting dose calculation, reference to the NOAEL was key, whether in calculation of a Maximum Recommended Starting Dose (MRSD), or by supporting PAD approaches (small molecules); or, through pharmacokinetic/pharmacodynamic (PK/PD) data modelling (biopharmaceuticals), (3) starting dose for small molecules was very conservative with human exposure >100- to 100-fold (46%) lower or between 10- and 100-fold (41%) lower than that seen at the NOAEL; high margins over exposure seen at NOAELs were also seen for biopharmaceuticals, (4) at the highest doses used, about 25% of studies for small molecules and 12% of studies for biopharmaceuticals showed exposure greater than that seen at the NOAEL and (5) adverse event evaluation showed that our current paradigm of moving from nonclinical testing into SAD/MAD Phase I testing is remarkably safe.

Adaptive Bayesian phase I clinical trial designs for estimating the maximum tolerated doses for two drugs while fully utilizing all toxicity information.

The combined treatments with multiple drugs are very common in the contemporary medicine, especially for medical oncology. Therefore, we developed a Bayesian adaptive Phase I clinical trial design entitled escalation with overdoing control using normalized equivalent toxicity score for estimating maximum tolerated dose (MTD) contour of two drug combination (EWOC-NETS-COM) used for oncology trials. The normalized equivalent toxicity score (NETS) as the primary endpoint of clinical trial is assumed to follow quasi-Bernoulli distribution and treated as quasi-continuous random variable in the logistic linear regression model which is used to describe the relationship between the doses of the two agents and the toxicity response. Four parameters in the dose-toxicity model were re-parameterized to parameters with explicit clinical meanings to describe the association between NETS and doses of two agents. Noninformative priors were used and Markov chain Monte Carlo was employed to update the posteriors of the four parameters in dose-toxicity model. Extensive simulations were conducted to evaluate the safety, trial efficiency, and MTD estimation accuracy of EWOC-NETS-COM under different scenarios, using the EWOC as reference. The results demonstrated that EWOC-NETS-COM not only efficiently estimates MTD contour of multiple drugs but also provides better trial efficiency by fully utilizing all toxicity information.

First-in-human phase I study of E7090, a novel selective fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors.

Fibroblast growth factor receptors (FGFR) are a family of transmembrane receptor tyrosine kinases involved in regulating cellular processes. FGFR mutations are implicated in oncogenesis, representing therapeutic potential in the form of FGFR inhibitors. This phase I, first-in-human study in Japan evaluated safety and tolerability of E7090, a potent selective FGFR1-3 inhibitor, in patients with advanced solid tumors. Dose escalation (daily oral dose of 1-180 mg) was carried out to assess dose-limiting toxicity (DLT), maximum tolerated dose, and pharmacokinetics. Pharmacodynamic markers (serum phosphate, fibroblast growth factor 23, and 1,25-(OH)2 -vitamin D) were also evaluated. A total of 24 patients refractory to standard therapy or for whom no appropriate treatment was available were enrolled. No DLT were observed up to the 140-mg dose; one patient in the 180-mg cohort experienced a DLT (increased aspartate aminotransferase/alanine aminotransferase, grade 3). The maximum tolerated dose was not reached. Dose-dependent increases in the maximum concentration and area under the curve from time 0 to the last measurable concentration were observed up to 180 mg. Dose-dependent increases were observed in all pharmacodynamic markers and plateaued at 100-140 mg, indicating sufficient FGFR pathway inhibition at doses ≥100 mg. In conclusion, E7090 showed a manageable safety profile with no DLT at doses ≤140 mg. Maximum tolerated dose was not determined. The recommended dose for the follow-up expansion part, restricted to patients with tumors harboring FGFR alterations, was determined as 140 mg, once daily.

A phase I study of an oral selective gamma secretase (GS) inhibitor RO4929097 in combination with neoadjuvant paclitaxel and carboplatin in triple negative breast cancer.

Upregulation of Notch pathway is associated with poor prognosis in breast cancer. We present the results of a phase I study of an oral selective gamma secretase (GS) inhibitor (critical to Notch signaling), RO4929097 in combination with neoadjuvant chemotherapy for operable triple negative breast cancer. The primary objective was to determine the maximum tolerated dose (MTD) of RO4929097. Secondary objectives were to determine real-time pharmacokinetics of RO4929097 and paclitaxel, safety and pathologic (pCR) complete response to study treatment. Eligible patients, initiated carboplatin at AUC 6 administered intravenously (IV) on day 1, weekly paclitaxel at 80 mg/m2 IV and RO4929097 10 mg daily given orally (PO) on days 1-3, 8-10 and 15-17 for six 21-day cycles. RO4929097 was escalated in 10 mg increments using the 3 + 3 dose escalation design. Two DLTs were observed in 14 patients - Grade (G) 4 thrombocytopenia in dose level 1 (10 mg) and G3 hypertension in dose level 2 (20 mg). Protocol-defined MTD was not determined due to discontinuation of RO4929097 development. However, 4 of 5 patients enrolled to 20 mg dose of RO4929097 required dose reduction to 10 mg due to toxicities (including neutropenia, thrombocytopenia and hypertension) occurring during and beyond the DLT observation period. Thus, 10 mg would have been the likely dose level for further development. G3 or higher hematologic toxicities included neutropenia (N = 8, 57%) and thrombocytopenia (N = 5, 36%) patients. Six (43%) patients had G2-3 neuropathy requiring paclitaxel dose reduction. No signs of drug-drug interaction between paclitaxel and RO4929097 were evident. Five patients (36%) had pCR.

Improving safety of the continual reassessment method via a modified allocation rule.

This article proposes a novel criterion for the allocation of patients in phase I dose-escalation clinical trials, aiming to find the maximum tolerated dose (MTD). Conventionally, using a model-based approach, the next patient is allocated to the dose with the toxicity estimate closest (in terms of the absolute or squared distance) to the maximum acceptable toxicity. This approach, however, ignores the uncertainty in point estimates and ethical concerns of assigning a lot of patients to overly toxic doses. In fact, balancing the trade-off between how accurately the MTD can be estimated and how many patients would experience adverse events is one of the primary challenges in phase I studies. Motivated by recent discussions in the theory of estimation in restricted parameter spaces, we propose a criterion that allows to balance these explicitly. The criterion requires a specification of one additional parameter only that has a simple and intuitive interpretation. We incorporate the proposed criterion into the one-parameter Bayesian continual reassessment method and show, using simulations, that it can result in similar accuracy on average as the original design, but with fewer toxic responses on average. A comparison with other model-based dose-escalation designs, such as escalation with overdose control and its modifications, demonstrates that the proposed design can result in either the same mean accuracy as alternatives but fewer toxic responses or in a higher mean accuracy but the same number of toxic responses. Therefore, the proposed design can provide a better trade-off between the accuracy and the number of patients experiencing adverse events, making the design a more ethical alternative over some of the existing methods for phase I trials.

Pharmacokinetics, pharmacodynamics and safety of the inverse retinoic acid-related orphan receptor γ agonist AZD0284.

AIMS: Retinoic acid-related orphan receptor γ (RORγ), a master regulator of T-helper 17 (Th17) cell function and differentiation, is an attractive target for treatment of Th17-driven diseases. This first-in-human study aimed to investigate the pharmacokinetics, pharmacodynamics, safety and tolerability of the inverse RORγ agonist AZD0284. METHODS: We conducted a phase I, randomized, single-blind, placebo-controlled, two-part, first-in-human study with healthy subjects receiving single (4-238 mg) or multiple (12-100 mg) oral doses of AZD0284 or placebo after overnight fasting. Subjects in the one single dose cohort additionally received a single dose of AZD0284 after a high-calorie meal. AZD0284 plasma concentrations, as well as inhibition of ex vivo-stimulated interleukin (IL)-17A release in whole blood, were frequently measured after both single and multiple dosing. RESULTS: Eighty-three men participated in the study. AZD0284 was absorbed rapidly into plasma after oral dosing and exhibited a terminal half-life of 13-16 hours. Both the area under the concentration-time curve (AUC) and maximum concentration (Cmax ) increased subproportionally with increasing dose (95% confidence intervals of slope parameter were 0.71-0.84 and 0.72-0.88 for AUC and Cmax , respectively). Food intake delayed the absorption of AZD0284 but did not affect the overall exposure or half-life. AZD0284 showed dose-dependent reduction of ex vivo-stimulated IL-17A release after both single and multiple doses. No significant safety concerns were identified in the study. CONCLUSIONS: AZD0284 was well tolerated, rapidly and dose-dependently absorbed, and reduced stimulated IL-17A release after single and multiple dosing. The results of this study support further clinical development of AZD0284.

Designing and evaluating dose-escalation studies made easy: The MoDEsT web app.

BACKGROUND/AIMS: Dose-escalation studies are essential in the early stages of developing novel treatments, when the aim is to find a safe dose for administration in humans. Despite their great importance, many dose-escalation studies use study designs based on heuristic algorithms with well-documented drawbacks. Bayesian decision procedures provide a design alternative that is conceptually simple and methodologically sound, but very rarely used in practice, at least in part due to their perceived statistical complexity. There are currently very few easily accessible software implementations that would facilitate their application. METHODS: We have created MoDEsT, a free and easy-to-use web application for designing and conducting single-agent dose-escalation studies with a binary toxicity endpoint, where the objective is to estimate the maximum tolerated dose. MoDEsT uses a well-established Bayesian decision procedure based on logistic regression. The software has a user-friendly point-and-click interface, makes changes visible in real time, and automatically generates a range of graphs, tables, and reports. It is aimed at clinicians as well as statisticians with limited expertise in model-based dose-escalation designs, and does not require any statistical programming skills to evaluate the operating characteristics of, or implement, the Bayesian dose-escalation design. RESULTS: MoDEsT comes in two parts: a 'Design' module to explore design options and simulate their operating characteristics, and a 'Conduct' module to guide the dose-finding process throughout the study. We illustrate the practical use of both modules with data from a real phase I study in terminal cancer. CONCLUSION: Enabling both methodologists and clinicians to understand and apply model-based study designs with ease is a key factor towards their routine use in early-phase studies. We hope that MoDEsT will enable incorporation of Bayesian decision procedures for dose escalation at the earliest stage of clinical trial design, thus increasing their use in early-phase trials.