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We present an adaptive Bayesian method for dose‐finding in phase I/II clinical trials based on trade‐offs between the probabilities of treatment efficacy and toxicity. The method accommodates either trinary or bivariate binary outcomes, as well as efficacy probabilities that possibly are nonmonotone in dose. Doses are selected for successive patient cohorts based on a set of efficacy–toxicity trade‐off contours that partition the two‐dimensional outcome probability domain. Priors are established by solving for hyperparameters that optimize the fit of the model to elicited mean outcome probabilities. For trinary outcomes, the new algorithm is compared to the method of Thall and Russell (1998, Biometrics54, 251–264) by application to a trial of rapid treatment for ischemic stroke. The bivariate binary outcome case is illustrated by a trial of graft‐versus‐host disease treatment in allogeneic bone marrow transplantation. Computer simulations show that, under a wide rage of dose‐outcome scenarios, the new method has high probabilities of making correct decisions and treats most patients at doses with desirable efficacy–toxicity trade‐offs.

Background Patients with locally advanced head and neck squamous cell carcinoma are receiving adjuvant radio(chemo)therapy as standard of care, according to national guidelines. However, patients with human papilloma virus (HPV) driven oropharyngeal squamous cell carcinoma (OPSCC), are shown to have superior locoregional control (LRC) rates, suggesting that they are likely being overtreated. To date it is unknown, if and to which extent adjuvant radiotherapy can be safely reduced. Methods and design The interventional multicentric DELPHI trial is investigating step-wise radiation dose reduction in patients with both p16-overexpressing and HPV16 DNA positive OPSCC. Depending on international clinical and histopathological risk factors, patients are being enrolled in the high-risk or intermediate-risk arm. Patients of the high-risk arm are receiving standard simultaneous chemotherapy with cisplatin. Patients with smoking history of at least 30 packyears are being treated in the observational arm. Primary endpoint of the DELPHI trial is LRC after 24 months. Secondary endpoints are acute and late toxicity, quality of life during and up to 24 months after the end of therapy as well as LRC and overall survival after 60 months. Discussion Primary aim of the DELPHI trial is to show that radiation dose reduction is safe and therefore feasible in patients with HPV-positive OPSCC. Secondary objective is to show that radiation-dose reduction leads to less late toxicity compared with standard treatment and thus improves quality of life. Trial registration The DELPHI trial is registered at clinicaltrials.gov under the identifier NCT03396718.

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.

ObjectivesIf patients are to reap the benefits of continued drug development, an understanding of why healthy participants take part in phase I clinical trials is imperative. The current study aimed to explore the nature of these underlying motivations which may, in turn, improve the overall participant experience and assist in the development of more effective recruitment and retention strategies.DesignThis study used a qualitative design based on the theory of planned behaviour. Specifically, it explored healthy participants’ underlying behavioural, control and normative beliefs which influence their participation in phase I clinical trials.SettingThis study took place at a company that specialises in conducting phase I and phase II clinical trials in the Australian state of Queensland.ParticipantsParticipants (n=31) were either currently undergoing a phase I clinical trial or had previously taken part in a phase I clinical trial.ResultsResults showed that the motivations were varied and not solely centred on financial gains. Reported advantages of participation included altruism, while inconvenience was most often reported as a disadvantage. Friends were reported as those most likely to approve, while one’s mother was reported as most likely to disapprove. Having a suitable time frame/flexible scheduling and feeling comfortable taking part in the trial were both the most commonly reported facilitators, while inflexible scheduling/time commitment was the most commonly reported barrier.ConclusionsPractical implications included the need for organisations involved in clinical trials to be mindful of inflexible scheduling and exploring the possibility of making educational materials available to family members who may be concerned about the risks associated with participation. Overall, it is anticipated that the results of this study will improve the understanding of factors that influence phase I clinical trial participation which may, ultimately, help develop new therapeutics to improve patient health.

Purpose Depletion of cellular nicotinamide adenine dinucleotide (NAD) by inhibition of its synthesis is a new pharmacological principle for cancer treatment currently in early phases of clinical development. We present new and previously published data on the safety and efficacy of these drugs based on early clinical trials. Methods A phase I clinical trial of CHS 828 in patients with advanced solid tumours was performed. Published clinical trials on NAD depleting drugs for cancer treatment were summarised for safety and efficacy. Results Seven patients with previously treated solid tumours received oral administration of CHS 828 in the dose range 20-80 mg once weekly for 3 weeks in 4 weeks cycles. Toxicity was dominated by gastrointestinal symptoms including nausea, vomiting, diarrhoea, constipation, subileus and gastric ulcer. One patient had thrombocytopenia grade 2. There were two cases each of grade 3-4 hyperuricemia and hypokalemia. Safety and efficacy of the NAD depleting drugs CHS 828 and FK866 have been reported from four phase I clinical trials, including a total of 97 patients with previously treated solid tumours. Outstanding toxicity reported was thrombocytopenia and various gastrointestinal symptoms. No objective tumour remission has been observed in the total of 104 patients treated in the above early trials. Conclusions Critical toxicity from NAD depleting cancer drugs to consider in future trials seems to be thrombocytopenia and various gastrointestinal symptoms. Efficacy of NAD depleting drugs when used alone is expected to be low.

Background Appropriate exploratory efficacy data from Phase I trials are vital for subsequent phases. Owing to the uniqueness of brain tumors (BTs), use of different strategies to evaluate efficacy is warranted. We studied exploratory efficacy evaluation in Phase I trials involving BTs. Methods Using Clarivate’s Cortellis ™ , 42 Phase I trials of BT interventions conducted from 2020 to 2022 were analyzed for efficacy endpoints, which were set as primary endpoints (PEs) or secondary endpoints (SEs). Additionally, these metrics were compared in two subgroups: trials including only BTs (Group-A) and those including BTs among mixed solid tumors (Group-B). Results Selected studies included a median of 1.5 PEs (range, 1–6) and 5 SEs (range, 0–19). Efficacy endpoints were included as PEs and SEs in 2 (5%) and 31 (78%) trials, respectively. Among the latter 31 trials that included 94 efficacy endpoints, 24, 22, 20, 9, and 8 reflected overall response rate (ORR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and disease control rate (DCR), respectively. ORR for BT was determined using various methods; however, the Response Evaluation Criteria in Solid Tumors (RECIST) was used less frequently in Group-A than in Group-B ( p  = 0.0039). Conclusions Recent Phase I trials included efficacy endpoints as SEs, with ORR, PFS, or OS included in ~ 50% trials and DOR or DCR in ~ 25%. No established criteria exist for imaging evaluation of BTs. Phase I trials involving mixed solid tumor cohorts revealed challenges in designing methods to assess the exploratory efficacy of BTs.

Background The combined use of a FGFR1 blocker and aromatase inhibitors is appealing for treating breast cancer patients with FGFR1 amplification. However, no pharmacodynamic studies have addressed the effects of this combined target modulation. We conducted a phase 0/I clinical trial in an adjuvant setting, with the goal of obtaining pharmacodynamic proof of the effects of combined aromatase and FGFR1 inhibition and to establish the RP2D for nintedanib combined with letrozole. Patients and methods Women with early-stage luminal breast cancer were eligible for enrollment in the study. Dose level 1 was nintedanib (150 mg/bid) plus letrozole (2.5 mg/day) administered for a single 28-day cycle (DLT assessment period), followed by a classic 3 + 3 schedule. FGF23 and 17-B-estradiol levels were determined on days 0 and 15; pharmacokinetic parameters were assessed on days 1 and 28. Patients were allowed to continue treatment for 6 cycles. The primary study endpoint was a demonstration of FGFR1 modulation (defined as a 25% increase in the plasma FGF23 level). Results A total of 19 patients were enrolled in the study (10 in the expansion cohort following dose escalation). At the RP2D (nintedanib 200 mg/bid plus letrozole 2.5 mg/day), we observed a 55% mean increase in the plasma FGF23 level, and 81.2% of the patients had no detectable level of 17-B-estradiol in their plasma (87.5% of the patients treated with letrozole alone). Nintedanib and letrozole displayed a pharmacokinetic interaction that led to three- and twofold increases in their respective plasma concentrations. Most G3 toxic events (5 out of 6: 2 diarrhea and 3 hypertransaminasemia) occurred subsequent to the DLT assessment period. Conclusion Combined treatment with nintedanib (200 mg/bid) plus letrozole (2.5 mg/day) effectively suppressed FGFR1 and aromatase activity, and these respective doses can be used as starting doses in any subsequent trials. However, drug-drug interactions may produce tolerability issues when these drugs are co-administered for an extended time period (e.g., 6 months). Patients enrolled in future trials with these drugs should be carefully monitored for their FGF23 levels and signs of toxicity, and those findings should guide individualized treatment decisions. Trial registration This trial was registered at www.clinicaltrials.gov under reg. # NCT02619162, on December 2, 2015.

Introduction The prognosis of patients with advanced or metastatic sarcoma is very poor, and a new strategy for patients who fail systemic treatment is urgently required. Apatinib is a small molecule tyrosine kinase inhibitor of VEGFR‐2, which can exert an antitumor effect by blocking downstream PI3K/AKT and VEGFR2/STAT3 signaling pathways of sarcoma. Dysregulation of the cyclin D (CCND)‐cyclin‐dependent kinase 4/6 (CDK4/6)‐retinoblastoma 1 (Rb) pathway is highly prevalent in sarcoma. Thus, blocking VEGFR2 and CDK4/6 may exert a synergistic effect. We hypothesize that a combination of apatinib and dalpiciclib, an oral, highly effective, and selective small molecule CDK4/6 inhibitor, may result in higher antitumor efficacy in patients with refractory sarcoma. Methods In this open‐label, single‐arm, single‐center phase I trial, participants diagnosed with sarcoma who failed standard systemic treatment will be enrolled. Dose escalation will be conducted into three groups according to traditional 3 + 3 principle: dose 1, dalpiciclib 100 mg once daily oral d1‐21+ apatinib 250 mg once daily oral d1‐28, every 28 days as one cycle; dose 2, dalpiciclib 100 mg d1‐21+ apatinib 500 mg d1–28; dose 3, dalpiciclib 150 mg d–21+ apatinib 500 mg d1–28. The primary endpoint is the safety and tolerability of combined treatment. The secondary endpoint is to evaluate the initial efficacy, including objective response rate (ORR), disease control rate (DCR), duration of response (DoR), and progression‐free survival (PFS). Discussion This trial will provide evidence of the tolerability, safety, and efficacy of dalpiciclib in combination with apatinib in metastatic sarcoma patients who have failed first‐line systemic treatment. In sarcomas, Apatinib and dalpiciclib may exert cell cycle control and antitumor synergistic effects by inhibiting the downstream PI3K/AKT pathway and blocking the CDKN2A ‐CCND‐CDK4/6‐RB pathway, respectively.

It can be assumed that patients' participation in a phase I study will have an important impact on their partners' life. However, evaluation of partners' experiences while patients are undergoing experimental treatment and of their well-being after the patient's death is lacking. We aimed to explore partners' experience of patients' participation in phase I studies and to investigate their well-being after a patient's death. This was an observational study conducted after the patient's death. Partners of deceased patients who had participated in a phase I study completed a questionnaire designed by us for experience evaluation and the Beck Depression Inventory for Primary Care, the Hospital Anxiety and Depression Scale, the Inventory of Traumatic Grief, and the RAND-36 Health Survey. The median age of the 58 participating partners was 58 years (range: 51-65), and 67% was female. Partners reported negative effects on patients' quality of life, but only 5% of partners regretted patients' participation. Approximately two years after the patients' death, 19% of partners scored for depression, 36% for psychological distress, and 46% for complicated grief, and partners generally scored significantly lower on social and mental functioning compared to normative comparators. Although partners reported negative consequences on patients' quality of life, most did not regret patients' participation in the phase I studies. Prevalence of depression, psychological distress, and complicated grief seemed important problems after a patient's death, and these must be considered when shaping further support for partners of patients participating in phase I trials.

Background Ixazomib is the first oral, proteasome inhibitor to reach phase III trials. Here, we present an integrated nonclinical and clinical assessment of ixazomib’s effect on QTc intervals. Methods Nonclinical studies assessed (1) the in vitro binding of ixazomib to the hERG channel and (2) its effect on QT/QTc in dogs ( N  = 4) via telemetry. Pharmacokinetic-matched triplicate electrocardiograms were collected in four clinical phase I studies of intravenous (0.125–3.11 mg/m 2 , N  = 125, solid tumors/lymphoma) or oral (0.24–3.95 mg/m 2 , N  = 120, multiple myeloma) ixazomib. The relationship between ixazomib plasma concentration and heart rate (HR)-corrected QT using Fridericia (QTcF) or population (QTcP) methods was analyzed using linear mixed-effects models with fixed effects for day and time. Results In vitro binding potency for ixazomib to the hERG channel was weak ( K i 24.9 μM; IC 50 59.6 μM), and nonclinical telemetry studies showed no QT/QTc prolongation at doses up to 4.2 mg/m 2 . In cancer patients, ixazomib, when evaluated at doses yielding various plasma concentrations (with 26 % of data greater than mean C max for the 4 mg phase 3 dose), had no meaningful effect on QTc based on model-predicted mean change in QTcF/QTcP from baseline. There was no relationship between ixazomib concentration and RR, suggesting no effect on HR. Conclusions Ixazomib has no clinically meaningful effects on QTc or HR. Integrating preclinical data and concentration–QTc modeling of phase 1 data may obviate the need for a dedicated QTc study in oncology. A framework for QT assessment in oncology drug development is proposed.