First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure.

Diminished hepatocyte regeneration is a key feature of acute and chronic liver diseases and after extended liver resections, resulting in the inability to maintain or restore a sufficient functional liver mass. Therapies to restore hepatocyte regeneration are lacking, making liver transplantation the only curative option for end-stage liver disease. Here, we report on the structure-based development and characterization (nuclear magnetic resonance [NMR] spectroscopy) of first-in-class small molecule inhibitors of the dual-specificity kinase MKK4 (MKK4i). MKK4i increased liver regeneration upon hepatectomy in murine and porcine models, allowed for survival of pigs in a lethal 85% hepatectomy model, and showed antisteatotic and antifibrotic effects in liver disease mouse models. A first-in-human phase I trial (European Union Drug Regulating Authorities Clinical Trials [EudraCT] 2021-000193-28) with the clinical candidate HRX215 was conducted and revealed excellent safety and pharmacokinetics. Clinical trials to probe HRX215 for prevention/treatment of liver failure after extensive oncological liver resections or after transplantation of small grafts are warranted.

Determining the maximum tolerated dose of paclitaxel combined with fixed dose of cisplatin for hyperthermic intraperitoneal chemotherapy in ovarian cancer: A multicenter phase I trial.

OBJECTIVE: To determine the maximum tolerated dose (MTD) of paclitaxel combined with a fixed dose of cisplatin (75 mg/m2) delivered via hyperthermic intraperitoneal chemotherapy (HIPEC) to patients with ovarian cancer. METHODS: This multicenter Phase I trial employed a Bayesian Optimal Interval (BOIN) design. The MTD was determined to have a target dose-limiting toxicity (DLT) rate of 25%. The starting dose was 175 mg/m2. The Data and Safety Monitoring Board made decisions regarding dose escalation or de-escalation in increments of 25 mg/m2 for subsequent patient cohorts, up to a maximum sample size of 30 or 12 patients treated at a given dose. RESULTS: Twenty-one patients participated in this study. Among the three evaluable patients who received 150 mg/m2 paclitaxel, no DLTs were observed. Among the 12 evaluable patients who received 175 mg/m2 paclitaxel, two reported DLTs: one had grade 4 neutropenia and one had grade 4 anemia, neutropenia, and leukopenia. Four of the six evaluable patients who received 200 mg/m2 paclitaxel reported DLTs: one patient had grade 4 diarrhea, one had grade 3 kidney injury, and two had grade 4 anemia. The isotonic estimate of the DLT rate in the 175 mg/m2 dose group was 0.17 (95% confidence interval, 0.02-0.42), and this dose was selected as the MTD. CONCLUSION: Paclitaxel, when combined with a fixed dose of cisplatin (75 mg/m2), can be safely administered intraperitoneally at a dose of 175 mg/m2 in patients with ovarian cancer who received HIPEC (43 °C, 90 min) following cytoreductive surgery.

Fractional accumulative calibration-free odds (f-aCFO) design for delayed toxicity in phase I clinical trials.

The calibration-free odds (CFO) design has been demonstrated to be robust, model-free, and practically useful but faces challenges when dealing with late-onset toxicity. The emergence of the time-to-event (TITE) method and fractional method leads to the development of TITE-CFO and fractional CFO (fCFO) designs to accumulate delayed toxicity. Nevertheless, existing CFO-type designs have untapped potential because they primarily consider dose information from the current position and its two neighboring positions. To incorporate information from all doses, we propose the accumulative CFO (aCFO) design by utilizing data at all dose levels similar to a tug-of-war game where players distant from the center also contribute their strength. This approach enhances full information utilization while still preserving the model-free and calibration-free characteristics. Extensive simulation studies demonstrate performance improvement over the original CFO design, emphasizing the advantages of incorporating information from a broader range of dose levels. Furthermore, we propose to incorporate late-onset outcomes into the TITE-aCFO and f-aCFO designs, with f-aCFO displaying superior performance over existing methods in both fixed and random simulation scenarios. In conclusion, the aCFO and f-aCFO designs can be considered robust, efficient, and user-friendly approaches for conducting phase I trials without or with late-onsite toxicity.

Implementing the time-to-event continual reassessment method in the presence of partial orders in a phase I head and neck cancer trial.

BACKGROUND: In this article we describe the methodology of the time-to-event continual reassessment method in the presence of partial orders (PO-TITE-CRM) and the process of implementing this trial design into a phase I trial in head and neck cancer called ADePT-DDR. The ADePT-DDR trial aims to find the maximum tolerated dose of an ATR inhibitor given in conjunction with radiotherapy in patients with head and neck squamous cell carcinoma. METHODS: The PO-TITE-CRM is a phase I trial design that builds upon the time-to-event continual reassessment method (TITE-CRM) to allow for the presence of partial ordering of doses. Partial orders occur in the case where the monotonicity assumption does not hold and the ordering of doses in terms of toxicity is not fully known. RESULTS: We arrived at a parameterisation of the design which performed well over a range of scenarios. Results from simulations were used iteratively to determine the best parameterisation of the design and we present the final set of simulations. We provide details on the methodology as well as insight into how it is applied to the trial. CONCLUSIONS: Whilst being a very efficient design we highlight some of the difficulties and challenges that come with implementing such a design. As the issue of partial ordering may become more frequent due to the increasing investigations of combination therapies we believe this account will be beneficial to those wishing to implement a design with partial orders. TRIAL REGISTRATION: ADePT-DDR was added to the European Clinical Trials Database (EudraCT number: 2020-001034-35) on 2020-08-07.

On the relative conservativeness of Bayesian logistic regression method in oncology dose-finding studies.

The Bayesian logistic regression method (BLRM) is a widely adopted and flexible design for finding the maximum tolerated dose in oncology phase I studies. However, the BLRM design has been criticized in the literature for being overly conservative due to the use of the overdose control rule. Recently, a discussion paper titled "Improving the performance of Bayesian logistic regression model with overall control in oncology dose-finding studies" in Statistics in Medicine has proposed an overall control rule to address the "excessive conservativeness" of the standard BLRM design. In this short communication, we discuss the relative conservativeness of the standard BLRM design and also suggest a dose-switching rule to further enhance its performance.

Carbon ion radiotherapy with pencil beam scanning for hepatocellular carcinoma: Long-term outcomes from a phase I trial.

This study evaluates the feasibility of the pencil beam scanning technique of carbon ion radiotherapy (CIRT) in the setting of hepatocellular carcinoma (HCC) and establishes the maximum tolerated dose (MTD) calculated by the Local Effect Model version I (LEM-I) with a dose escalation plan. The escalated relative biological effectiveness-weighted dose levels included 55, 60, 65, and 70 Gy in 10 fractions. Active motion management techniques were employed, and several measures were applied to mitigate the interplay effect induced by a moving target. CIRT was planned with the LEM-I-based treatment planning system and delivered by raster scanning. Offline PET/CT imaging was used to verify the beam range. Offline adaptive replanning was performed whenever required. Twenty-three patients with a median tumor size of 4.3 cm (range, 1.7-8.5 cm) were enrolled in the present study. The median follow-up time was 56.1 months (range, 5.7-74.4 months). No dose limiting toxicity was observed until 70 Gy, and MTD had not been reached. No patients experienced radiation-induced liver disease within 6 months after the completion of CIRT. The overall survival rates at 1, 3, and 5 years were 91.3%, 81.9%, and 67.1% after CIRT, respectively. The local progression-free survival and progression-free survival rates at 1, 3 and 5 years were 100%, 94.4%, and 94.4% and 73.6%, 59.2%, and 37.0%, respectively. The raster scanning technique could be used to treat HCC. However, caution should be exercised to mitigate the interplay effect. CIRT up to 70 Gy in 10 fractions over 2 weeks was safe and effective for HCC.

Phase I study of opaganib, an oral sphingosine kinase 2-specific inhibitor, in relapsed and/or refractory multiple myeloma.

Multiple myeloma (MM) remains an incurable disease and there is an unmet medical need for novel therapeutic drugs that do not share similar mechanisms of action with currently available agents. Sphingosine kinase 2 (SK2) is an innovative molecular target for anticancer therapy. We previously reported that treatment with SK2 inhibitor opaganib inhibited myeloma tumor growth in vitro and in vivo in a mouse xenograft model. In the current study, we performed a phase I study of opaganib in patients with relapsed/refractory multiple myeloma (RRMM). Thirteen patients with RRMM previously treated with immunomodulatory agents and proteasome inhibitors were enrolled and treated with single-agent opaganib at three oral dosing regimens (250 mg BID, 500 mg BID, or 750 mg BID, 28 days as a cycle). Safety and maximal tolerated dose (MTD) were determined. Pharmacokinetics, pharmacodynamics, and correlative studies were also performed. Opaganib was well tolerated up to a dose of 750 mg BID. The most common possibly related adverse event (AE) was decreased neutrophil counts. There were no serious AEs considered to be related to opaganib. MTD was determined as at least 750 mg BID. On an intent-to-treat basis, one patient (7.7%) in the 500 mg BID dose cohort showed a very good partial response, and one other patient (7.7%) achieved stable disease for 3 months. SK2 is an innovative molecular target for antimyeloma therapy. The first-in-class SK2 inhibitor opaganib is generally safe for administration to RRMM patients, and has potential therapeutic activity in these patients. Clinicaltrials.gov: NCT02757326.

Incorporating patient-reported outcomes in dose-finding clinical trials with continuous patient enrollment.

Dose-finding clinical trials in oncology estimate the maximum tolerated dose (MTD), based on toxicity obtained from the clinician's perspective. While the collection of patient-reported outcomes (PROs) has been advocated to better inform treatment tolerability, there is a lack of guidance and methods on how to use PROs for dose assignments and recommendations. The PRO continual reassessment method (PRO-CRM) has been proposed to formally incorporate PROs into dose-finding trials. In this paper, we propose two extensions of the PRO-CRM, which allow continuous enrollment of patients and longer toxicity observation windows to capture late-onset or cumulative toxicities by using a weighted likelihood to include the partial toxicity follow-up information. The TITE-PRO-CRM uses both the PRO and the clinician's information during the trial for dose assignment decisions and at the end of the trial to estimate the MTD. The TITE-CRM + PRO uses clinician's information solely to inform dose assignments during the trial and incorporates PRO at the end of the trial for the estimation of the MTD. Simulation studies show that the TITE-PRO-CRM performs similarly to the PRO-CRM in terms of dose recommendation and assignments during the trial while almost halving trial duration in case of an accrual of two patients per observation window. The TITE-CRM + PRO slightly underperforms compared to the TITE-PRO-CRM, but similar performance can be attained by requiring larger sample sizes. We also show that the performance of the proposed methods is robust to higher accrual rates, different toxicity hazards, and correlated time-to-clinician toxicity and time-to-patient toxicity data.

Time-to-event calibration-free odds design: A robust efficient design for phase I trials with late-onset outcomes.

Compared with most of the existing phase I designs, the recently proposed calibration-free odds (CFO) design has been demonstrated to be robust, model-free, and easy to use in practice. However, the original CFO design cannot handle late-onset toxicities, which have been commonly encountered in phase I oncology dose-finding trials with targeted agents or immunotherapies. To account for late-onset outcomes, we extend the CFO design to its time-to-event (TITE) version, which inherits the calibration-free and model-free properties. One salient feature of CFO-type designs is to adopt game theory by competing three doses at a time, including the current dose and the two neighboring doses, while interval-based designs only use the data at the current dose and is thus less efficient. We conduct comprehensive numerical studies for the TITE-CFO design under both fixed and randomly generated scenarios. TITE-CFO shows robust and efficient performances compared with interval-based and model-based counterparts. As a conclusion, the TITE-CFO design provides robust, efficient, and easy-to-use alternatives for phase I trials when the toxicity outcome is late-onset.

A Phase Ib Study of Lucitanib (AL3810) in a Cohort of Patients with Recurrent and Metastatic Nasopharyngeal Carcinoma.

BACKGROUND: Lucitanib is a novel multi-target inhibitor of FGFR1-3, VEGFR 1-3, and PDGFR α/ß. Here, we evaluated the safety, tolerability, and preliminary efficacy of lucitanib in recurrent and metastatic nasopharyngeal carcinoma (RM-NPC). METHODS: Patients with pretreated RM-NPC were randomly divided into two treatment arms: continuous or intermittent treatment. The primary endpoint was safety and tolerability. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). RESULTS: One hundred percent of patients in the continuous arm and 90% of patients in the intermittent arm had at least one treatment-related AE (TRAE). Grade ≥3 related TRAEs occurred in 5 patients in the continuous arm (5/10, 50%). No TRAEs grade >3 occurred in the intermittent arm. The ORR and DCR of the continuous arm was 20% and 90%, and the intermittent arm was 10% and 60%, respectively. All responses were observed by the first evaluation. The duration of response was more than 1 year, with two patients still on treatment with sustained response at more than 3 years. CONCLUSION: Lucitanib has promising clinical activity and tolerable safety profile in heavily pretreated patients with NPC. Patients who responded to lucitanib treatment generally achieved a long DoR. Lucitanib is now being evaluated in phase II/III studies. CLINICALTRIALS.GOV IDENTIFIER: NCT03260179.

Flexible use of copula-type model for dose-finding in drug combination clinical trials.

Identification of the maximum tolerated dose combination (MTDC) of cancer drugs is an important objective in phase I oncology trials. Numerous dose-finding designs for drug combination have been proposed over the years. Copula-type models exhibit distinctive advantages in this task over other models used in existing competitive designs. For example, their application enables the consideration of dose-limiting toxicities attributable to one of two agents. However, if a particular combination therapy demonstrates extremely synergistic toxicity, copula-type models are liable to induce biases in toxicity probability estimators due to the associated Fréchet-Hoeffding bounds. Consequently, the dose-finding performance may be worse than those of other competitive designs. The objective of this study is to improve the performance of dose-finding designs based on copula-type models while maintaining their advantageous properties. We propose an extension of the parameter space of the interaction term in copula-type models. This releases the Fréchet-Hoeffding bounds, making the estimation of toxicity probabilities more flexible. Numerical examples in various scenarios demonstrate that the performance (e.g., the percentage of correct MTDC selection) of the proposed method is better than those exhibited by existing copula-type models and comparable with those of other competitive designs, irrespective of the existence of extreme synergistic toxicity. The results obtained in this study could motivate the real-world application of the proposed method in cases requiring the utilization of the properties of copula-type models.

Access to early-phase clinical trials for children with relapsed and refractory neuroblastoma: A multicentre international study.

OBJECTIVES: Neuroblastoma is the most common extracranial tumour in children, and prognosis for refractory and relapsed disease is still poor. Early-phase clinical trials play a pivotal role in the development of novel drugs. Ensuring adequate recruitment is crucial. The primary aim was to determine the rate of participation trials for children with refractory/relapsed neuroblastoma in two of the largest drug development European institutions. METHODS: Data from patients diagnosed with refractory/relapsed neuroblastoma between January 2012 and December 2018 at the two institutions were collected and analysed. RESULTS: Overall, 48 patients were included. A total of 31 (65%) refractory/relapsed cases were enrolled in early-phase trials. The main reasons for not participating in clinical trials included not fulfilling eligibility criteria prior to consent (12/17, 70%) and screening failure (2/17, 12%). Median time on trial was 4.3 months (range 0.6-13.4). Most common cause for trial discontinuation was disease progression (67.7%). Median overall survival was longer in refractory (28 months, 95% CI: 20.9-40.2) than in relapsed patients (14 months, 95% CI: 8.1-20.1) (p = .034). CONCLUSIONS: Although two thirds of children with refractory/relapsed neuroblastoma were enrolled in early-phase trials, recruitment rates can still be improved. The main cause for not participating on trials was not fulfilling eligibility criteria prior to consent, mainly due to performance status and short life expectancy. This study highlights the hurdles to access to innovative therapies for children with relapsed/refractory neuroblastomas, and identifies key areas of development to improve recruitment to early-phase trials.

Phase I trial of concurrent chemoradiotherapy with docetaxel, cisplatin and 5-fluorouracil (TPF-CRT) for locally advanced squamous cell carcinoma of the external auditory canal.

PURPOSE: Chemoradiotherapy with docetaxel (DOC), cisplatin (CDDP), and 5-FU (TPF-CRT) for locally advanced external auditory canal cancer (EACC) has favorable oncological and functional outcomes. To establish TPF-CRT as a standard of care for advanced EACC, we conducted this study to determine the maximum tolerated (MTD) and recommended dose (RD) of DOC in TPF-CRT for locally advanced EACC. METHODS: To determine the recommended (RD) and maximum tolerated dose (MTD) of DOC in TPF-CRT for EACC, a phase I trial was conducted using the standard "3 + 3" design for maximum dose finding. DOC was administered twice every 4 weeks, CDDP at 70 mg/m2 and 5-FU at 700 mg/m2; patients were also receiving radiotherapy (66 Gy). Eight patients with T3 or T4 EACC were prospectively enrolled. RESULTS: Two patients treated with DOC, 50 mg/m2, and one out of six patients treated with DOC, 40 mg/m2, had dose-limiting toxicities. Prolonged febrile neutropenia was observed in three patients. Grade 3 non-hematological toxicities were observed in only three patients. At study completion, six patients survived, five of whom were disease free. CONCLUSION: The RD and MTD of DOC in TPF-CRT for locally advanced EACC are 40 mg/m2 when doses of CDDP and 5-FU are 70 mg/m2 and 700 mg/m2, respectively.

A semi-mechanistic dose-finding design in oncology using pharmacokinetic/pharmacodynamic modeling.

While a number of phase I dose-finding designs in oncology exist, the commonly used ones are either algorithmic or empirical model-based. We propose a new framework for modeling the dose-response relationship, by systematically incorporating the pharmacokinetic (PK) data collected in the trial and the hypothesized mechanisms of the drug effects, via dynamic PK/PD modeling, as well as modeling of the relationship between a latent cumulative pharmacologic effect and a binary toxicity outcome. This modeling framework naturally incorporates the information on the impact of dose, schedule and method of administration (e.g., drug formulation and route of administration) on toxicity. The resulting design is an extension of existing designs that make use of pre-specified summary PK information (such as the area under the concentration-time curve [AUC] or maximum serum concentration [Cmax ]). Our simulation studies show, with moderate departure from the hypothesized mechanisms of the drug action, that the performance of the proposed design on average improves upon those of the common designs, including the continual reassessment method (CRM), Bayesian optimal interval (BOIN) design, modified toxicity probability interval (mTPI) method, and a design called PKLOGIT that models the effect of the AUC on toxicity. In case of considerable departure from the underlying drug effect mechanism, the performance of the design is shown to be comparable with that of the other designs. We illustrate the proposed design by applying it to the setting of a phase I trial of a γ-secretase inhibitor in metastatic or locally advanced solid tumors. We also provide R code to implement the proposed design.

Prospective surveillance model in the home for breast cancer-related lymphoedema: a feasibility study.

PURPOSE: The aim of this study was to assess the feasibility of delivering a prospective surveillance model in the home over 6 months for women at high risk of developing lymphoedema. METHODS: A single-group, intervention study recruited 20 women who had surgical and medical treatment for confirmed node-positive invasive breast cancer and therefore at high risk of developing arm lymphoedema. Participants received a package including Bioimpedance Spectroscopy (BIS) monitoring, lymphoedema education and support to promote self-management and physical activity. RESULTS: Participants adhered to BIS monitoring 74% of the time, and felt extremely confident in using the device. By 6 months, mean BIS L-Dex scores had increased from 3.5 (SD 5.6) to 8.4 (SD 11.1); five women (25%) who experienced > + 6.5 increase in L-Dex score were fitted with a compression garment. Self-reported symptoms and distress decreased by 0.4 out of 10 (95% CI 0.1 to 0.7); number of self-management strategies used increased by 0.6 (95% CI 0.1 to 1.2); and planned exercise increased by 2.8 h/week (95% CI 0.4 to 5.2). CONCLUSIONS: These findings indicate a prospective surveillance model of care in the home with BIS is feasible and associated with increased self-management. A Phase II randomised trial is warranted as well as research exploring the costs associated with implementing this model of care for high-risk individuals.

Phase I dose-escalation study of the safety, tolerability, and pharmacokinetics of aflibercept in combination with S-1 in Japanese patients with advanced solid malignancies.

Background Aflibercept, a recombinant fusion protein binding VEGF-A, VEGF-B and placental growth factor, inhibits tumor growth by blocking angiogenesis. The aim of this phase I dose-escalation study was to determine the recommended phase II dose (RP2D) of aflibercept in combination with S-1 in Japanese patients with solid tumors. Patients and methods Sequential cohorts of 3-6 patients with metastatic or unresectable solid tumors, who had failed at least one prior line of standard treatment or who were not suitable for such treatment, were to receive escalating doses of aflibercept every 2 weeks, starting at 2 mg/kg, combined with S-1 at 40 mg/m2 twice daily (80 mg/m2/day; 4 weeks on/2 weeks off). Dose-escalation was to be based on the incidence of dose-limiting toxicity (DLT). Blood samples were collected for pharmacokinetic analysis. Results At the first dose level (aflibercept 2 mg/kg plus S-1) 1 of 6 patients experienced a DLT (grade 4 proteinuria). The aflibercept dose was consequently escalated to 4 mg/kg; 1 of 3 patients treated at this dose level had a DLT (grade 2 pleural effusion), and another patient experienced grade 3 reversible posterior leukoencephalopathy syndrome after the DLT assessment period. Additional patients were therefore enrolled into the first dose level to explore safety and tolerability. The study was subsequently terminated prematurely. The maximum tolerated dose was not reached and the RP2D was not determined in Japanese patients. Conclusions The tolerability and safety of aflibercept 2 mg/kg in combination with S-1 was confirmed in Japanese patients with advanced solid tumors.

Incorporating patient-reported outcomes in dose-finding clinical trials.

Oncology dose-finding clinical trials determine the maximum tolerated dose (MTD) based on toxicity outcomes captured by clinicians. With the availability of more rigorous instruments for measuring toxicity directly from patients, there is a growing interest to incorporate patient-reported outcomes (PRO) in clinical trials to inform patient tolerability. This is particularly important for dose-finding trials to ensure the identification of a well-tolerated dose. In this paper, we propose three extensions of the continual reassessment method (CRM), termed PRO-CRMs, that incorporate both clinician and patient outcomes. The first method is a marginal modeling approach whereby clinician and patient toxicity outcomes are modeled separately. The other two methods impose a constraint using a joint outcome defined based on both clinician and patient toxicities and model them either jointly or marginally. Simulation studies show that while all three PRO-CRMs select well-tolerated doses based on clinician's and patient's perspectives, the methods using a joint outcome perform better and have similar performance. We also show that the proposed PRO-CRMs are consistent under robust model assumptions.

A simulation-free approach to assessing the performance of the continual reassessment method.

The continual reassessment method (CRM) is an adaptive design for Phase I trials whose operating characteristics, including appropriate sample size, probability of correctly identifying the maximum tolerated dose, and the expected proportion of participants assigned to each dose, can only be determined via simulation. The actual time to determine a final "best" design can take several hours or days, depending on the number of scenarios that are examined. The computational cost increases as the kernel of the one-parameter CRM design is expanded to other settings, including additional parameters, monitoring of both toxicity and efficacy, and studies of combinations of two agents. For a given vector of true DLT probabilities, we have developed an approach that replaces a simulation study of thousands of hypothetical trials with a single simulation. Our approach, which is founded on the consistency of the CRM, very accurately reflects the results produced by the simulation study, but does so in a fraction of time required by the simulation study. Relative to traditional simulations, we extensively examine how our method is able to assess the operating characteristics of a CRM design for a hypothetical trial whose characteristics are based upon a previously published Phase I trial. We also provide a metric of nonconsistency and demonstrate that although nonconsistency can impact the operating characteristics of our method, the degree of over- or under-estimation is unpredictable. As a solution, we provide an algorithm for maintaining the consistency of a chosen CRM design so that our method is applicable for any trial.

Characteristics of parental decision-making for children with advanced cancer who are offered enrollment in early-phase clinical trials: A systematic review.

Limited research is available on parental decision-making regarding their children's participation in pediatric phase I oncology trials compared with the adult population. The objectives of this review were to describe: (1) the process of parental decision-making in this situation; (2) the optimal communication features physicians need when proposing inclusion in such trials; and (3) the place of the child/adolescent in the assent process. Thirty relevant studies meeting inclusion criteria were identified by searching five computerized databases (PubMed, Web of Science, Cairn, Psychinfo, EM Premium). Parental decision-making is a complex process based on hopeful expectations, multiple family considerations and the child's previous cancer experience. It is highly impacted by the quality of physicians' communication. A therapeutic alliance along with an empathetic attitude and a timely delivery of accurate information is essential. Due weight should be given to the voice of children or adolescents and their optimal level of involvement may be discussed depending on their age and maturity. They should be given age-adapted information in order to empower them to be rightfully and meaningfully involved in early-phase research. This review highlights the main gaps and necessary remedial actions to support an optimal patient care management in this situation. Physicians' training in communication, structured interdisciplinary teamwork and early integration of palliative care are three key challenges which need to be implemented to actively engage in optimization strategies which would improve patient care and family support when offering enrollment in a phase I trial.

Phase I clinical trial of the combination of eribulin and everolimus in patients with metastatic triple-negative breast cancer.

BACKGROUND: Alteration of the PI3K/AKT/mTOR pathway is a common genomic abnormality detected in triple-negative breast cancer (TNBC). Everolimus acts synergistically with eribulin in TNBC cell lines and xenograft models. This phase I trial was designed to test the safety and tolerability of combining eribulin and everolimus in patients with metastatic TNBC. METHODS: The primary objective of this study was to evaluate the safety and toxicities of the combination. Patients with metastatic TNBC who had up to four lines of prior chemotherapies were enrolled. The combination of eribulin and everolimus was tested using three dosing levels: A1 (everolimus 5 mg daily; eribulin 1.4 mg/m2 days 1 and 8 every 3 weeks), A2 (everolimus 7.5 mg daily; eribulin 1.4 mg/m2, days 1 and 8 every 3 weeks), and B1 (everolimus 5 mg daily; eribulin 1.1 mg/m2 days 1 and 8 every 3 weeks). RESULTS: Twenty-seven patients with median age 55 years were enrolled. Among 8 evaluable patients who received dose level A1, 4 had dose-limiting toxicities (DLTs). Among 3 evaluable patients treated with dose level A2, 2 had DLTs. Among 12 evaluable patients who received dose level B1, 4 had DLTs. The DLTs were neutropenia, stomatitis, and hyperglycemia. Over the study period, 59% had a ≥ grade 3 toxicity, 44% had ≥ grade 3 hematologic toxicities, and 22% had grade 4 hematologic toxicities. The most common hematological toxicities were neutropenia, leukopenia, and lymphopenia. Thirty-three percent had grade 3 non-hematologic toxicities. The most common non-hematological toxicities were stomatitis, hyperglycemia, and fatigue. The median number of cycles completed was 4 (range 0-8). Among 25 eligible patients, 9 patients (36%) achieved the best response as partial response, 9 (36%) had stable disease, and 7 (28%) had progression. The median time to progression was 2.6 months (95% CI [2.1, 4.0]), and median overall survival (OS) was 8.3 months (95% CI [5.5, undefined]). CONCLUSION: Eribulin 1.1 mg/m2 days 1 and 8 every 3 weeks with everolimus 5 mg daily was defined as the highest dose with acceptable toxicity (RP2D). The combination is safe, and efficacy is modest. A post hoc analysis showed that participants that used dexamethasone mouthwash stayed on treatment for one additional cycle. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02120469. Registered 18 April 2014.