A randomized phase I study of the safety and pharmacokinetics of BI 1291583 in healthy Japanese male subjects.

AIMS: Bronchiectasis patients face an unmet need for treatment options that reduce inflammation. Cathepsin C inhibition is expected to achieve this by reducing the activation of neutrophil-derived serine proteases. Here, we present safety and pharmacokinetic (PK) data from a Phase I trial evaluating the novel cathepsin C inhibitor BI 1291583 in healthy Japanese male subjects. METHODS: This randomized, double-blind, placebo-controlled, parallel-group study investigated BI 1291583 in healthy Japanese male subjects (jRCT2071210111) and consisted of a single-rising-dose (SRD) part and a multiple-dose (MD) part. The primary endpoint was the percentage of subjects with drug-related treatment-emergent adverse events (AEs). Secondary PK endpoints (SRD: AUC0-∞ and Cmax; MD: AUCτ,1 and Cmax,1 after first dose and AUCτ,ss and Cmax,ss after last dose), as well as further safety and PK endpoints, were also assessed. RESULTS: Overall, 36 subjects (n = 24 for SRD part; n = 12 for MD part) entered this Phase I trial. BI 1291583 was safe and well tolerated across the doses tested. All AEs were of mild intensity, with no drug-related treatment-emergent AEs, deaths, serious AEs or AEs of special interest reported in either part of the trial. Following both SRD and MD administration, BI 1291583 was readily absorbed, and PK was supraproportional over the doses assessed. CONCLUSION: The results show that BI 1291583 has an appropriate benefit-risk ratio for Japanese patients, with no safety or exposure concerns at the doses studied. Japanese patients with bronchiectasis can be safely integrated into future global clinical trials of BI 1291583, with no dose adjustment required.

Pharmacokinetics and pharmacodynamics of the factor XIa-inhibiting antibody osocimab in healthy male East Asian volunteers: Results from two phase 1 studies.

The pharmacokinetics, pharmacodynamics, immunogenicity, and safety of osocimab single doses in healthy Chinese and Japanese volunteers over 149 days were evaluated. Two phase 1 single-blinded, placebo-controlled studies with 27 Japanese and 50 Chinese participants were conducted. Osocimab was investigated with IV doses of 0.3, 1.25, and 2.5 mg/kg (Chinese study) and 0.3, 1.25, and 5.0 mg/kg (Japanese study), as well as SC doses of 3.0 and 6.0 mg/kg (Chinese study) and 6.0 mg/kg (Japanese study). The maximum plasma concentration was reached 1-3 h and 4-6 days after IV and SC administration, respectively. Osocimab exhibited a deviation from dose-proportional pharmacokinetics for AUC but not Cmax; higher doses had higher apparent clearance and disproportionately lower total exposure. A slightly lower exposure was observed in Japanese compared with Chinese volunteers after IV administration; conversely, relatively higher exposure in Japanese volunteers with SC dosing was identified. Osocimab was associated with a dose-dependent increase in activated partial thromboplastin time (aPTT). Maximal aPTT prolongations were observed 1-4 h and 2-6 days after IV and SC administration, respectively. Anti-drug antibodies of low titer were detected in 1/9 (11.1%) Japanese volunteers administered placebo and 26/40 (65.0%) Chinese volunteers administered osocimab. Adverse events were reported in 8/18 (44.4%) Japanese and 28/40 (70.0%) Chinese volunteers who received osocimab, as well as in 1/9 (11.1%) Japanese and 6/10 (60.0%) Chinese volunteers who received placebo. In conclusion, data did not suggest a clear dose-proportionality for osocimab within the investigated dose range. The effect of osocimab on aPTT was expected per its mechanism of action. Osocimab was generally well tolerated.

iVAC-XS15-CLL01: personalized multi-peptide vaccination in combination with the TLR1/2 ligand XS15 in CLL patients undergoing BTK-inhibitor-based regimens.

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia among adults in Western countries. Despite the introduction of targeted therapies, including first-line Bruton's tyrosine kinase inhibitor (BTKi) treatment, CLL remains largely incurable. Frequent disease relapses occur due to remaining treatment-resistant CLL cells, calling for novel therapies to eliminate minimal residual disease (MRD). Peptide-based vaccination targeting human leucocyte antigen (HLA)-presented CLL-associated antigens represents a promising, low-side-effect therapeutic option to optimize treatment responses and eliminate residual tumor cells by inducing an anti-leukemic immune response. The iVAC-XS15-CLL01 trial is an open-label, first-in-human (FIH) Phase I trial, evaluating the CLL-VAC-XS15 vaccine in CLL patients undergoing BTKi-based therapy. The vaccine was developed from HLA-presented CLL-associated antigen peptides, identified through comparative mass-spectrometry-based immunopeptidome analyses of CLL versus healthy samples in a previous study. To facilitate rapid and cost-effective deployment, vaccine peptides are selected for each patient from a pre-manufactured "peptide warehouse" based on the patient's individual HLA allotype and CLL immunopeptidome. The trial enrolls 20 CLL patients, who receive up to three doses of the vaccine, adjuvanted with the toll-like-receptor (TLR) 1/2 ligand XS15 and emulsified in Montanide ISA 51 VG. The primary objective of the iVAC-XS15-CLL01 trial is to assess the safety and immunogenicity of the CLL-VAC-XS15 vaccine. Secondary objectives are to evaluate the vaccine impact on MRD, progression-free survival, and overall survival, as well as comprehensive immunophenotyping to characterize vaccine-induced T-cell responses. This Phase I trial aims to advance CLL treatment by enhancing immune-mediated disease clearance and guiding the design of subsequent Phase II/III trials to implement a new therapeutic strategy for CLL patients.

Next generation yellow fever vaccine induces an equivalent immune and transcriptomic profile to the current vaccine: observations from a phase I randomised clinical trial.

BACKGROUND: Yellow fever (YF), a mosquito-borne acute viral haemorrhagic illness, is endemic to many tropical and subtropical areas of Africa and Central and South America. Vaccination remains the most effective prevention strategy; however, as repeated outbreaks have exhausted vaccine stockpiles, there is a need for improved YF vaccines to meet global demand. A live-attenuated YF vaccine candidate (referred to as vYF) cloned from a YF-17D vaccine (YF-VAX®) sub-strain, adapted for growth in Vero cells cultured in serum-free media, is in clinical development. We report the innate and adaptive immune responses and the transcriptome profile of selected genes induced by vYF. METHODS: Healthy adults aged 18-60 years were randomised at a 1:1:1:1 ratio to receive one dose of vYF at 4, 5 or 6 Log CCID50 or YF-VAX (reference vaccine), administered subcutaneously in the upper arm (ClinicalTrials.gov identifier: NCT04142086). Blood/serum samples were obtained at scheduled time points through 180 days (D180) post-vaccination. The surrogate endpoints assessed were: serum cytokine/chemokine concentrations, measured by bead-based Multiplex assay; peripheral blood vYF-specific IgG and IgM memory B cell frequencies, measured by FluoroSpot assay; and expression of genes involved in the immune response to YF-17D vaccination by RT-qPCR. FINDINGS: There was no increase in any of the cytokine/chemokine concentrations assessed through D14 following vaccination with vYF or YF-VAX, except for a slight increase in IP-10 (CXCL10) levels. The gene expression profiles and kinetics following vaccination with vYF and YF-VAX were similar, inclusive of innate (antiviral responses [type-1 interferon, IFN signal transduction; interferon-stimulated genes], activated dendritic cells, viral sensing pattern recognition receptors) and adaptive (cell division in stimulated CD4+ T cells, B cell and antibody) immune signatures, which peaked at D7 and D14, respectively. Increases in vYF-specific IgG and IgM memory B cell frequencies at D28 and D180 were similar across the study groups. INTERPRETATION: vYF-induced strong innate and adaptive immune responses comparable to those induced by YF-VAX, with similar transcriptomic and kinetic profiles observed. FUNDING: Sanofi.

Safety and efficacy of itacitinib, a selective JAK1 inhibitor, in advanced hepatocellular cancer: Phase 1b trial (JAKAL).

Overactivation of the JAK/STAT pathway is one of the drivers for the pathophysiology of hepatocellular carcinoma (HCC). We propose a Phase Ib study to evaluate the safety and efficacy of itacitinib, a selective JAK1 inhibitor, as a second-line treatment for patients with advanced or metastatic HCC.Twenty-five patients will receive 400 mg itacitinib orally daily, 28-day cycle. Safety will be reviewed prior to each cycle. Tumor response assessed every 2 months until disease progression, death or withdrawal. Tumor biopsies and blood samples will be taken for presence of JAK1 mutations.Activation of JAK/STAT pathway drives HCC development and is associated with immunotherapy resistance. Itacitinib is hypothesized to be safe and effective in HCC patients that have progressed after first-line therapies.Clinical Trial Registration: EudraCT: 2017-004437-81 NCT04358185 (ClinicalTrials.gov).

[Box: see text].

A Bayesian pharmacokinetics integrated phase I-II design to optimize dose-schedule regimes.

The schedule of administering a drug has profound impact on the toxicity and efficacy profiles of the drug through changing its pharmacokinetics (PK). PK is an innate and indispensable component of the dose-schedule optimization. Motivated by this, we propose a Bayesian PK integrated dose-schedule finding (PKIDS) design to identify the optimal dose-schedule regime by integrating PK, toxicity, and efficacy data. Based on the causal pathway that dose and schedule affect PK, which in turn affects efficacy and toxicity, we jointly model the three endpoints by first specifying a Bayesian hierarchical model for the marginal distribution of the longitudinal dose-concentration process. Conditional on the drug concentration in plasma, we jointly model toxicity and efficacy as a function of the concentration. We quantify the risk-benefit of regimes using utility-continuously updating the estimates of PK, toxicity, and efficacy based on interim data-and make adaptive decisions to assign new patients to appropriate dose-schedule regimes via adaptive randomization. The simulation study shows that the PKIDS design has desirable operating characteristics.

Dose Finding in Oncology Trials Guided by Ordinal Toxicity Grades Using Continuous Dose Levels.

We present a Bayesian adaptive design for dose finding in oncology trials with application to a first-in-human trial. The design is based on the escalation with overdose control principle and uses an intermediate grade 2 toxicity in addition to the traditional binary indicator of dose-limiting toxicity (DLT) to guide the dose escalation and de-escalation. We model the dose-toxicity relationship using the proportional odds model. This assumption satisfies an important ethical concern when a potentially toxic drug is first introduced in the clinic; if a patient experiences grade 2 toxicity at the most, then the amount of dose escalation is lower relative to that wherein if this patient experienced a maximum of grade 1 toxicity. This results in a more careful dose escalation. The performance of the design was assessed by deriving the operating characteristics under several scenarios for the true MTD and expected proportions of grade 2 toxicities. In general, the trial design is safe and achieves acceptable efficiency of the estimated MTD for a planned sample size of twenty patients. At the time of writing this manuscript, twelve patients have been enrolled to the trial.

Dietary protein affects tissue accumulation of mercury and induces hepatic Phase I and Phase II enzyme expression after co-exposure with methylmercury in mice.

Methylmercury (MeHg) is a ubiquitous environmental contaminant, well known for its neurotoxic effects. MeHg can interact with several nutrients in the diet and affect nutrient metabolism, however the interaction between MeHg and dietary proteins has not been thoroughly investigated. Male BALB/c mice were fed diets based on either casein, cod or chicken as protein sources, which were or were not spiked with MeHg (3.5 mg Hg kg-1). Following 13 weeks of dietary exposure to MeHg, the animals accumulated mercury in a varying degree depending on the diet, where the levels of mercury were highest in the mice fed casein and MeHg, lower in mice fed cod and MeHg, and lowest in mice fed chicken and MeHg in all tissues assessed. Assessment of gut microbiota revealed differences in microbiota composition based on the different protein sources. However, the introduction of MeHg eliminated this difference. Proteomic profiling of liver tissue uncovered the influence of the dietary protein sources on a range of enzymes related to Phase I and Phase II detoxification mechanisms, suggesting an impact of the diet on MeHg metabolism and excretion. Also, enzymes linked to pathways including methionine and glycine betaine cycling, which in turn impact the production of glutathione, an important MeHg conjugation molecule, were up-regulated in mice fed chicken as dietary protein. Our findings indicate that dietary proteins can affect expression of hepatic enzymes that potentially influence MeHg metabolism and excretion, highlighting the relevance of considering the dietary composition in risk assessment of MeHg through dietary exposure.

Interstitial lung disease in patients enrolled in early-phase clinical trials: the ILDE study.

BACKGROUND: Interstitial lung disease (ILD) encompasses a heterogeneous group of disorders sharing pathophysiological inflammatory mechanisms, leading to parenchymal distortions. The prevalence of ILD with new cancer drugs is underreported: the identification of potential determinants is priority. MATERIALS AND METHODS: ILDE is a retrospective study aimed at describing the clinical course and potential determinants of ILD in patients receiving experimental treatments. RESULTS: We identified 226 eligible patients, of whom 5.3% (n = 12) had ILD. In five patients, the diagnosis was radiological, while seven patients had initial cough, dyspnea, fatigue or fever. ILD was graded as grade 1 (G1) in four, G2 in five and G3 in three patients. The first occurrence of ILD resolved completely in 50% of patients (n = 6/12). No patient had fatal ILD. Eight patients (66.7%) resumed the treatment after the first episode of ILD, while four patients (33.3%) had to discontinue the therapy. Five out of six patients had resolved the first ILD episode and then resumed treatment, experiencing a second ILD episode (n = 5/6; 83.3%). The second ILD event was G1 in three patients and G2 in two patients, resulting in three patients who eventually discontinued the treatment (n = 3/5; 60%). Correlation analysis showed a higher risk of ILD in older patients (P = 0.051), those who had received previous chest radiation therapy (P = 0.047) or those receiving antibody-drug conjugates (P = 0.006). In a survival analysis adjusted for immortal time bias, ILD was not independently prognostic (hazard ratio 0.50, 95% confidence interval 0.23-1.09, P = 0.082). CONCLUSIONS: In ILDE, patients experiencing ILD had generally good outcomes, and many could resume the cancer treatments. Implementing best practices to prompt diagnosis and management of ILD is critical to treat a potentially severe adverse effect of new drugs, while not affecting patients' outcomes. Research efforts to identify risk factors is warranted, to implement risk-based monitoring schedules and develop ad hoc strategies to improve the cure rates of ILD.

Meta-analyses of phase I dose-finding studies: Application for the development of protein kinase inhibitors in oncology.

This study aimed to assess the feasibility of applying two recent phase I meta-analyses methods to protein kinase inhibitors (PKIs) developed in oncology and to identify situations where these methods could be both feasible and useful. This ancillary study used data from a systematic review conducted to identify dose-finding studies for PKIs. PKIs selected for meta-analyses were required to have at least five completed dose-finding studies involving cancer patients, with available results, and dose escalation guided by toxicity assessment. To account for heterogeneity caused by various administration schedules, some studies were divided into study parts, considered as separate entities in the meta-analyses. For each PKI, two Bayesian random-effects meta-analysis methods were applied to model the toxicity probability distribution of the recommended dose and to estimate the maximum tolerated dose (MTD). Meta-analyses were performed for 20 PKIs including 96 studies corresponding to 115 study parts. The median posterior probability of toxicity probability was below the toxicity thresholds of 0.20 for 70% of the PKIs, even if the resulting credible intervals were very wide. All approved doses were below the MTD estimated for the minimum toxicity threshold, except for one, for which the approved dose was above the MTD estimated for the maximal threshold. The application of phase I meta-analysis methods has been feasible for the majority of PKI; nevertheless, their implementation requires multiple conditions. However, meta-analyses resulted in estimates with large uncertainty, probably due to limited patient numbers and/or between-study variability. This calls into question the reliability of the recommended doses.

A phase I safety and efficacy clinical trial of plocabulin and gemcitabine in patients with advanced solid tumors.

Plocabulin (Plo) induces depolymerization of tubulin fibers with disorganization and fragmentation of the microtubule network leading to mitosis. Plo combined with gemcitabine (Gem) showed synergistic anti-tumor activity in preclinical studies. This phase I trial evaluated the safety, pharmacokinetics (PK) and efficacy of Plo 10-min infusion plus Gem on Day 1 and 8 every 3-week in patients with advanced solid tumors. Fifty-seven patients were enrolled into 8 dose levels (DLs); 74%: females; 74%: ECOG performance status 1; median age: 62 years; median number of prior lines of therapy:3. Dose-limiting toxicities (DLT) in Cycle 1 were grade (G) 3 intestinal obstruction at the maximum tolerated dose (MTD), G3 peripheral sensory neuropathy (PSN), G3 abdominal pain, and G4 thrombocytopenia (1 patient each). The highest DL (DL8: Plo 10.5 mg/m2/Gem 1000 mg/m2) was the MTD. Accrual into DL7 (Plo 10.0 mg/m2/Gem 1000 mg/m2) was stopped before it was formally defined as the recommended dose (RD). Most common treatment-related adverse events (AEs) were fatigue (56%), nausea (55%), diarrhea (31%); G3/4 hematologic toxicities comprised anemia (35%), neutropenia (27%) and thrombocytopenia (17%). No treatment-related deaths occurred. PK parameters for Gem or dFdU at all DLs were in line with reference values from the literature. Six of 46 evaluable pts were responders (overall response rate:13%). Of note, 2 partial responses (PR) and 2 stable disease (SD) ≥ 4 months occurred among 13 pts with ovarian cancer. The combination of Plo and Gem is well tolerated. The MTD was Plo 10.5 mg/m2/Gem 1000 mg/m2. No PK drug-drug interaction was found. The most encouraging outcome occurred in ovarian cancer patients.

A Personalized Dose-Finding Algorithm Based on Adaptive Gaussian Process Regression.

Dose-finding studies play a crucial role in drug development by identifying the optimal dose(s) for later studies while considering tolerability. This not only saves time and effort in proceeding with Phase III trials but also improves efficacy. In an era of precision medicine, it is not ideal to assume patient homogeneity in dose-finding studies as patients may respond differently to the drug. To address this, we propose a personalized dose-finding algorithm that assigns patients to individualized optimal biological doses. Our design follows a two-stage approach. Initially, patients are enrolled under broad eligibility criteria. Based on the Stage 1 data, we fit a regression model of toxicity and efficacy outcomes on dose and biomarkers to characterize treatment-sensitive patients. In the second stage, we restrict the trial population to sensitive patients, apply a personalized dose allocation algorithm, and choose the recommended dose at the end of the trial. Simulation study shows that the proposed design reliably enriches the trial population, minimizes the number of failures, and yields superior operating characteristics compared to several existing dose-finding designs in terms of both the percentage of correct selection and the number of patients treated at target dose(s).

Safety and Pharmacokinetics of a Combined Antioxidant Therapy against Myocardial Reperfusion Injury: A Phase 1 Randomized Clinical Trial in Healthy Humans.

Myocardial reperfusion injury (MRI) accounts for up to 50% of the final size in acute myocardial infarction and other conditions associated with ischemia-reperfusion. Currently, there is still no therapy to prevent MRI, but it is well known that oxidative stress has a key role in its mechanism. We previously reduced MRI in rats through a combined antioxidant therapy (CAT) of ascorbic acid, N-acetylcysteine, and deferoxamine. This study determines the safety and pharmacokinetics of CAT in a Phase I clinical trial. Healthy subjects (n = 18) were randomized 2:1 to CAT or placebo (NaCl 0.9% i.v.). Two different doses/infusion rates of CATs were tested in a single 90-minute intravenous infusion. Blood samples were collected at specific times for 180 minutes to measure plasma drug concentrations (ascorbic acid, N-acetylcysteine, and deferoxamine) and oxidative stress biomarkers. Adverse events were registered during infusion and followed for 30 days. Both CAT1 and CAT2 significantly increased the CAT drug concentrations compared to placebo (P < .05). Most of the pharmacokinetic parameters were similar between CAT1 and CAT2. In total, 6 adverse events were reported, all nonserious and observed in CAT1. The ferric-reducing ability of plasma (an antioxidant biomarker) increased in both CAT groups compared to placebo (P < .001). The CAT is safe in humans and a potential treatment for patients with acute myocardial infarction undergoing reperfusion therapy.

Exploratory comparative transcriptomic analysis reveals potential gene targets associated with Cry1A.105 and Cry2Ab2 resistance in fall armyworm (Spodoptera frugiperda).

Genetically modified (GM) crops, expressing Bacillus thuringiensis (Bt) insecticidal toxins, have substantially transformed agriculture. Despite rapid adoption, their environmental and economic benefits face scrutiny due to unsustainable agricultural practices and the emergence of resistant pests like Spodoptera frugiperda, known as the fall armyworm (FAW). FAW's adaptation to Bt technology in corn and cotton compromises the long-term efficacy of Bt crops. To advance the understanding of the genetic foundations of resistance mechanisms, we conducted an exploratory comparative transcriptomic analysis of two divergent FAW populations. One population exhibited practical resistance to the Bt insecticidal proteins Cry1A.105 and Cry2Ab2, expressed in the genetically engineered MON-89Ø34 - 3 maize, while the other population remained susceptible to these proteins. Differential expression analysis supported that Cry1A.105 and Cry2Ab2 significantly affect the FAW physiology. A total of 247 and 254 differentially expressed genes were identified in the Cry-resistant and susceptible populations, respectively. By integrating our findings with established literature and databases, we underscored 53 gene targets potentially involved in FAW's resistance to Cry1A.105 and Cry2Ab2. In particular, we considered and discussed the potential roles of the differentially expressed genes encoding ABC transporters, G protein-coupled receptors, the P450 enzymatic system, and other Bt-related detoxification genes. Based on these findings, we emphasize the importance of exploratory transcriptomic analyses to uncover potential gene targets involved with Bt insecticidal proteins resistance, and to support the advantages of GM crops in the face of emerging challenges.

Pharmacokinetics and Safety of Oliceridine Fumarate Injection in Chinese Patients with Chronic Non-Cancer Pain: A Phase I, Single-Ascending-Dose, Open-Label Clinical Trial.

Background: Oliceridine is a novel G protein-biased ligand µ-opioid receptor agonist. This study aimed to assess the pharmacokinetics and safety profile of single-ascending doses of oliceridine fumarate injection in Chinese patients with chronic non-cancer pain. Methods: Conducted as a single-center, open-label trial, this study administered single doses of 0.75, 1.5, and 3.0 mg to 32 adult participants. The trial was conducted in two parts. First, we conducted a preliminary test comprising the administration of a single dose of 0.75mg to 2 participants. Then, we conducted the main trial involving intravenous administration of escalating doses of oliceridine fumarate (0.75 to 3 mg) to 30 participants. Pharmacokinetic (PK) parameters were derived using non-compartmental analysis. Additionally, the safety evaluation encompassed the monitoring of adverse events (AEs). Results: 32 participants were included in the PK and safety analyses. Following a 2-min intravenous infusion of oliceridine fumarate injection (0.75, 1.5, or 3 mg), Cmax and Tmax ranged from 51.293 to 81.914 ng/mL and 0.034 to 0.083 h, respectively. AUC0-t and half-life (t1/2) increased more than proportionally with dosage (1.85-2.084 h). Treatment emergent adverse events (TEAEs) were found to be consistent with the commonly reported adverse effects of opioids, both post-administration and as documented in the original trials conducted in the United States. Critically, no serious adverse events were observed. Conclusion: Oliceridine demonstrated comparable PK parameters and a consistent PK profile in the Chinese population, in line with the PK results observed in the original trials conducted in the United States. Oliceridine was safe and well tolerated in Chinese patients with chronic non-cancer pain at doses ranging from 0.75 mg to 3.0 mg. Trial Registration: The trial is registered at chictr.org.cn (ChiCTR2100047180).

Neoadjuvant radiotherapy combined with fluorouracil-cisplatin plus cetuximab in operable, locally advanced esophageal carcinoma: Results of a phase I-II trial (FFCD-0505/PRODIGE-3).

Background: Radiotherapy combined with fluorouracil (5FU) and cisplatin for locally advanced esophageal cancer is associated with a 20-25% pathologic complete response (pCR) rate. Cetuximab increases the efficacy of radiotherapy in patients with head and neck carcinomas. The aim of this phase I/II trial was to determine the optimal doses and the pCR rate with chemoradiotherapy (C-RT) plus cetuximab. Methods: A 45-Gy radiotherapy regimen was delivered over 5 weeks. The phase I study determined the dose-limiting toxicity and the maximum tolerated dose of 5FU-cisplatin plus cetuximab. The phase II trial aimed to exhibit a pCR rate > 20 % (25 % expected), requiring 33 patients (6 from phase I part plus 27 in phase II part). pCR was defined as ypT0Nx. Results: The phase I study established the following recommended doses: weekly cetuximab (400 mg/m2 one week before, and 250 mg/m2 during radiotherapy); 5FU (500 mg/m2/day, d1-d4) plus cisplatin (40 mg/m2, d1) during week 1 and 5. In the phase II part, 32 patients received C-RT before surgery, 31 patients underwent surgery, and resection was achieved in 27 patients. A pCR was achieved in five patients (18.5 %) out of 27. After a median follow-up of 19 months, the median progression-free survival was 13.7 months, and the median overall survival was not reached. Conclusions: Adding cetuximab to preoperative C-RT was toxic and did not achieve a pCR > 20 % as required. The recommended doses, determined during the phase I part, could explain these disappointing results due to a reduction in chemotherapy dose-intensity. Trial registration: This trial was registered with EudraCT number 2006-004770-27.

STRILL: Phase I Trial Evaluating Stereotactic Body Radiotherapy (SBRT) Dose Escalation for Re-Irradiation of Inoperable Peripheral Lung Lesions.

Few data are available on the role of SBRT re-irradiation for isolated recurrences. We designed a prospective phase I study to evaluate the maximum tolerated dose (MTD) of SBRT for thoracic re-irradiation, for peripheral lung lesions. RT was delivered with a dose escalation design from 30 Gy in five fractions up to 50 Gy in five fractions. The primary end point was the definition of the maximum tolerated dose (MTD) of SBRT for thoracic re-irradiation. The dose-limiting toxicity was pneumonia ≥G3. Fifteen patients were enrolled. No cases of pneumonia ≥G3 occurred in any of our cohorts. Only one patient developed pneumonia G1 during treatment. Three patients developed acute toxicities that included dyspnea G1, cardiac failure G3, and chest wall pain. One patient developed G3 late toxicity with acute coronary syndrome. After a median follow-up of 21 months (range 3.6-29.1 months), six patients (40%) had a local relapse. Distant relapse occurred in five patients (33.3%). At the last follow-up, six patients died, all but two due to progressive disease. SBRT dose escalation for thoracic re-irradiation is an effective and well-tolerated option for patients with inoperable lung lesions after a first thoracic RT with acceptable acute and late toxicities.

U-PRO-CRM: designing patient-centred dose-finding trials with patient-reported outcomes.

BACKGROUND: Determining the maximum tolerated dose (MTD) remains the primary objective for the majority of dose-finding oncology trials. Whilst MTD determination often relies upon clinicians to identify dose-limiting toxicities (DLTs) experienced by patients during the trial, research suggests that clinicians may underreport patient's adverse events. Therefore, contemporary practice may be exposed to recommending intolerable doses to patients for further investigation in subsequent trials. There is increasing interest in patients self-assessing their own symptoms using patient-reported outcomes (PROs) in dose-finding trials. DESIGN: We present Utility-PRO-Continual Reassessment Method (U-PRO-CRM), a novel trial design which simultaneously uses clinician-rated and patient-rated DLTs (Clinician-DLTs and Patient-DLTs, respectively) to make dose (de-)escalation decisions and to recommend an MTD. U-PRO-CRM contains the published PRO-CRM as a special case and provides greater flexibility to trade-off the rate of Patient-DLTs and Clinician-DLTs to find an optimal dose. We present simulation results for U-PRO-CRM. RESULTS: For specified trade-offs between Clinician-DLT and Patient-DLT rate, U-PRO-CRM outperforms the PRO-CRM design by identifying the true MTD more often. In the special case where U-PRO-CRM generalises to PRO-CRM, U-PRO-CRM performs as well as its published counterpart. U-PRO-CRM minimises the number of patients overdosed whilst maintaining a similar proportion of patients allocated to the true MTD. CONCLUSIONS: By using a utility-based dose selection approach, U-PRO-CRM offers the flexibility to define a trade-off between the risk of patient-rated and clinician-rated DLTs for an optimal dose. Patient-centric dose-finding strategies, which integrate PROs, are poised to assume an ever more pivotal role in significantly advancing our understanding of treatment tolerability. This bears significant implications in shaping the future landscape of early-phase trials.