A randomised phase II trial of temozolomide with or without cannabinoids in patients with recurrent glioblastoma (ARISTOCRAT): protocol for a multi-centre, double-blind, placebo-controlled trial.

BACKGROUND: Glioblastoma (GBM) is the most common adult malignant brain tumour, with an incidence of 5 per 100,000 per year in England. Patients with tumours showing O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation represent around 40% of newly diagnosed GBM. Relapse/tumour recurrence is inevitable. There is no agreed standard treatment for patients with GBM, therefore, it is aimed at delaying further tumour progression and maintaining health-related quality of life (HRQoL). Limited clinical trial data exist using cannabinoids in combination with temozolomide (TMZ) in this setting, but early phase data demonstrate prolonged overall survival compared to TMZ alone, with few additional side effects. Jazz Pharmaceuticals (previously GW Pharma Ltd.) have developed nabiximols (trade name Sativex®), an oromucosal spray containing a blend of cannabis plant extracts, that we aim to assess for preliminary efficacy in patients with recurrent GBM. METHODS: ARISTOCRAT is a phase II, multi-centre, double-blind, placebo-controlled, randomised trial to assess cannabinoids in patients with recurrent MGMT methylated GBM who are suitable for treatment with TMZ. Patients who have relapsed ≥ 3 months after completion of initial first-line treatment will be randomised 2:1 to receive either nabiximols or placebo in combination with TMZ. The primary outcome is overall survival time defined as the time in whole days from the date of randomisation to the date of death from any cause. Secondary outcomes include overall survival at 12 months, progression-free survival time, HRQoL (using patient reported outcomes from QLQ-C30, QLQ-BN20 and EQ-5D-5L questionnaires), and adverse events. DISCUSSION: Patients with recurrent MGMT promoter methylated GBM represent a relatively good prognosis sub-group of patients with GBM. However, their median survival remains poor and, therefore, more effective treatments are needed. The phase II design of this trial was chosen, rather than phase III, due to the lack of data currently available on cannabinoid efficacy in this setting. A randomised, double-blind, placebo-controlled trial will ensure an unbiased robust evaluation of the treatment and will allow potential expansion of recruitment into a phase III trial should the emerging phase II results warrant this development. TRIAL REGISTRATION: ISRCTN: 11460478. CLINICALTRIALS: Gov: NCT05629702.

Midostaurin added to 10-day decitabine, for patients unfit for intensive chemotherapy with AML and higher risk MDS, irrespective of FLT3 mutational status, does not improve outcome.

The treatment of older patients with acute myeloid leukemia (AML) considered unfit for receiving intensive chemotherapy is challenging. Based on the hypothesis that addition of the broad tyrosine kinase inhibitor (TKI) midostaurin could improve the response to hypomethylating agents, irrespective of FLT3 gene mutational status, we conducted a randomized phase II multicenter study to assess the tolerability and efficacy of the addition of midostaurin to a 10-day schedule of decitabine in unfit (i.e. Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) ≥ 3) AML and higher risk myelodysplasia (MDS) patients (HOVON155 trial). In total, 140 eligible patients were randomly (1:1) assigned to treatment with 10-days of decitabine alone (N = 70) or combined with midostaurin (50 mg bid;starting the day following the last dose of decitabine), (N = 70). Addition of midostaurin was well tolerated and the number of AEs was comparable for both treatment arms. Early death rates (< 30 days) were similar as well (10%). In the decitabine plus midostaurin arm 24% reached CR/CRi, the median OS was 4.8 months and 1-yrs OS was 31% which compared with 34% CR/CRi, median OS of 7.4 months and 1-yrs OS of 37% for the decitabine alone group (NS). Thus, while the addition of midostaurin appears safe, it does not enhance therapeutic efficacy of decitabine in unfit AML patients.

Optimal futility stopping boundaries for binary endpoints.

BACKGROUND: Group sequential designs incorporating the option to stop for futility at the time point of an interim analysis can save time and resources. Thereby, the choice of the futility boundary importantly impacts the design's resulting performance characteristics, including the power and probability to correctly or wrongly stop for futility. Several authors contributed to the topic of selecting good futility boundaries. For binary endpoints, Simon's designs (Control Clin Trials 10:1-10, 1989) are commonly used two-stage designs for single-arm phase II studies incorporating futility stopping. However, Simon's optimal design frequently yields an undesirably high probability of falsely declaring futility after the first stage, and in Simon's minimax design often a high proportion of the planned sample size is already evaluated at the interim analysis leaving only limited benefit in case of an early stop. METHODS: This work focuses on the optimality criteria introduced by Schüler et al. (BMC Med Res Methodol 17:119, 2017) and extends their approach to binary endpoints in single-arm phase II studies. An algorithm for deriving optimized futility boundaries is introduced, and the performance of study designs implementing this concept of optimal futility boundaries is compared to the common Simon's minimax and optimal designs, as well as modified versions of these designs by Kim et al. (Oncotarget 10:4255-61, 2019). RESULTS: The introduced optimized futility boundaries aim to maximize the probability of correctly stopping for futility in case of small or opposite effects while also setting constraints on the time point of the interim analysis, the power loss, and the probability of stopping the study wrongly, i.e. stopping the study even though the treatment effect shows promise. Overall, the operating characteristics, such as maximum sample size and expected sample size, are comparable to those of the classical and modified Simon's designs and sometimes better. Unlike Simon's designs, which have binding stopping rules, the optimized futility boundaries proposed here are not adjusted to exhaust the full targeted nominal significance level and are thus still valid for non-binding applications. CONCLUSIONS: The choice of the futility boundary and the time point of the interim analysis have a major impact on the properties of the study design. Therefore, they should be thoroughly investigated at the planning stage. The introduced method of selecting optimal futility boundaries provides a more flexible alternative to Simon's designs with non-binding stopping rules. The probability of wrongly stopping for futility is minimized and the optimized futility boundaries don't exhibit the unfavorable properties of an undesirably high probability of falsely declaring futility or a high proportion of the planned sample evaluated at the interim time point.

Brightline-2: a phase IIa/IIb trial of brigimadlin (BI 907828) in advanced biliary tract cancer, pancreatic ductal adenocarcinoma or other solid tumors.

Mouse double minute 2 homolog (MDM2) is a key negative regulator of the tumor suppressor p53. Blocking the MDM2-p53 interaction, and restoring p53 function, is therefore a potential therapeutic strategy in MDM2-amplified, TP53 wild-type tumors. MDM2 is amplified in several tumor types, including biliary tract cancer (BTC), pancreatic ductal adenocarcinoma (PDAC), lung adenocarcinoma and bladder cancer, all of which have limited treatment options and poor patient outcomes. Brigimadlin (BI 907828) is a highly potent MDM2-p53 antagonist that has shown promising activity in preclinical and early-phase clinical studies. This manuscript describes the rationale and design of an ongoing phase IIa/IIb Brightline-2 trial evaluating brigimadlin as second-line treatment for patients with advanced/metastatic BTC, PDAC, lung adenocarcinoma, or bladder cancer.

Brightline-2: a phase IIa/IIb trial of brigimadlin (BI 907828) in advanced BTC, PDAC, or other solid tumorsIn some types of cancer, including cancers of the bile duct, pancreas, bladder and lung, the number of copies of a gene called MDM2 is abnormally increased (MDM2 amplification). MDM2 usually regulates p53, a protein that stops cancer cells from growing uncontrollably. When MDM2 is amplified, the cell makes too much of the MDM2 protein, which prevents p53 from stopping cancer growth. Blocking the interaction between MDM2 and p53 may allow p53 to do its job again and stop cancer cells from growing.Brightline-2 is a clinical trial that is currently in progress. This trial is assessing the efficacy and safety of an investigational drug, brigimadlin (or BI 907828), in patients with selected advanced or metastatic cancers. To be included, patients must have advanced biliary tract cancer, pancreatic ductal adenocarcinoma, bladder cancer, or lung adenocarcinoma. The tumor must show amplification of MDM2 when tested by a laboratory. Patients will take a 45 mg tablet of brigimadlin by mouth, once every 3 weeks. In this trial, researchers are investigating the ability of the drug to shrink tumors, the side effects of the drug, and the impact of the drug on a patients' quality of life.The goal of this trial is to assess the potential of brigimadlin as a new treatment option for patients with advanced biliary tract cancer, pancreatic ductal adenocarcinoma, bladder cancer, or lung adenocarcinoma.Clinical Trial Registration: NCT05512377 (ClinicalTrials.gov).

The JAVELIN Bladder Medley trial: avelumab-based combinations as first-line maintenance in advanced urothelial carcinoma.

Results from JAVELIN Bladder 100 established avelumab (anti-PD-L1) first-line maintenance as the standard-of-care treatment for patients with advanced urothelial carcinoma (UC) that has not progressed with first-line platinum-based chemotherapy. We describe the design of JAVELIN Bladder Medley (NCT05327530), an ongoing phase II, multicenter, randomized, open-label, parallel-arm, umbrella trial. Overall, 252 patients with advanced UC who are progression-free following first-line platinum-based chemotherapy will be randomized 1:2:2:2 to receive maintenance therapy with avelumab alone (control group) or combined with sacituzumab govitecan (anti-Trop-2/topoisomerase inhibitor conjugate), M6223 (anti-TIGIT) or NKTR-255 (recombinant human IL-15). Primary end points are progression-free survival per investigator and safety/tolerability of the combination regimens. Secondary end points include overall survival, objective response and duration of response per investigator, and pharmacokinetics.

Urothelial cancer develops in the urinary tract, which contains the parts of the body that move urine from the kidneys to outside of the body. Urothelial cancer is called advanced when it has spread outside of the urinary tract. Chemotherapy is often the first main treatment given to people with advanced urothelial cancer. Avelumab is an immunotherapy drug that can help the body's immune system find and destroy cancer cells. Results from a trial called JAVELIN Bladder 100 looked at avelumab maintenance treatment, which is given after chemotherapy. The trial showed that avelumab maintenance treatment helped people with advanced urothelial cancer live longer than people who were not treated with avelumab. Avelumab also helped people have a longer time without their cancer getting worse. Avelumab is the only approved maintenance treatment available for people with advanced urothelial cancer that has not worsened after chemotherapy. The JAVELIN Bladder Medley trial will assess whether avelumab maintenance treatment given in combination with other anticancer drugs can help people with advanced urothelial cancer live longer and have a longer time without their cancer getting worse compared with avelumab alone. Researchers will also look at the side effects people have when they receive avelumab alone or combined with the other anticancer drugs in this trial. Results will show whether the benefit of avelumab maintenance treatment can be improved by combining avelumab with other anticancer drugs. People started joining this trial in August 2022. Results will be reported in the future. Clinical Trial Registration: NCT05327530 (ClinicalTrials.gov).

Bayesian phase II adaptive randomization by jointly modeling efficacy and toxicity as time-to-event outcomes.

The main goals of Phase II trials are to identify the therapeutic efficacy of new treatments and continue monitoring all the possible adverse effects. In Phase II trials, it is important to develop an adaptive randomization (AR) procedure that takes into account both the efficacy and toxicity. In most existing articles, toxicity is modeled as a binary endpoint through an unobservable random effect (frailty) to link the efficacy and toxicity. However, this approach does not capture toxicity profiles that evolve over time. In this article, we propose a new Bayesian adaptive randomization (BAR) procedure using the covariate-adjusted efficacy-toxicity ratio (ETR) index, where efficacy and toxicity are jointly modelled as time-to-event (TTE) outcomes. Furthermore, we also propose early stopping rules for toxicity and futility such that inferior treatments can be dropped at earlier time of trial. Simulation results show that compared to the BAR procedures based solely on the efficacy and that based on TTE efficacy and binary toxicity outcomes, the proposed BAR procedure can better identify the difference in treatment toxicity such that it can assign more patients to the superior treatment arm under some scenarios.

A phase II study of neoadjuvant atezolizumab and nab-paclitaxel in patients with anthracycline-resistant early-stage triple-negative breast cancer.

PURPOSE: Neoadjuvant anti-PD-(L)1 therapy improves the pathological complete response (pCR) rate in unselected triple-negative breast cancer (TNBC). Given the potential for long-term morbidity from immune-related adverse events (irAEs), optimizing the risk-benefit ratio for these agents in the curative neoadjuvant setting is important. Suboptimal clinical response to initial neoadjuvant therapy (NAT) is associated with low rates of pCR (2-5%) and may define a patient selection strategy for neoadjuvant immune checkpoint blockade. We conducted a single-arm phase II study of atezolizumab and nab-paclitaxel as the second phase of NAT in patients with doxorubicin and cyclophosphamide (AC)-resistant TNBC (NCT02530489). METHODS: Patients with stage I-III, AC-resistant TNBC, defined as disease progression or a < 80% reduction in tumor volume after 4 cycles of AC, were eligible. Patients received atezolizumab (1200 mg IV, Q3weeks × 4) and nab-paclitaxel (100 mg/m2 IV,Q1 week × 12) as the second phase of NAT before undergoing surgery followed by adjuvant atezolizumab (1200 mg IV, Q3 weeks, × 4). A two-stage Gehan-type design was employed to detect an improvement in pCR/residual cancer burden class I (RCB-I) rate from 5 to 20%. RESULTS: From 2/15/2016 through 1/29/2021, 37 patients with AC-resistant TNBC were enrolled. The pCR/RCB-I rate was 46%. No new safety signals were observed. Seven patients (19%) discontinued atezolizumab due to irAEs. CONCLUSION: This study met its primary endpoint, demonstrating a promising signal of activity in this high-risk population (pCR/RCB-I = 46% vs 5% in historical controls), suggesting that a response-adapted approach to the utilization of neoadjuvant immunotherapy should be considered for further evaluation in a randomized clinical trial.

Neoadjuvant chemoradiotherapy plus tislelizumab followed by surgery for esophageal carcinoma (CRISEC study): the protocol of a prospective, single-arm, phase II trial.

BACKGROUND: The failure rate after neoadjuvant chemoradiotherapy followed by surgery is approximately 34.6%-48% for resectable esophageal carcinoma. Pathologic complete response after neoadjuvant chemoradiotherapy is an important factor in predicting lower recurrence and better survival. Whether the sequential addition of immunotherapy to neoadjuvant chemoradiotherapy will be beneficial to improving the pathologic complete response rate is unknown. METHODS: Patients with pathologically confirmed thoracic esophageal squamous cell carcinoma and at clinical T1-2N1-3M0 or T3-4aN0-3M0 (stage II-IVA) according to the eighth edition of American Joint Committee on Cancer staging will be allocated to receive neoadjuvant radiotherapy (41.4 Gy with 23 fractions to planning target volume) with concurrent chemotherapy (albumin-bound paclitaxel, 100 mg/m2, once weekly for five weeks; carboplatin, area under the curve of 2 mg/mL/min, once weekly for five weeks) plus tislelizumab monotherapy sequentially (200 mg every three weeks for three cycles, beginning from the first to the 14th day after the end of radiotherapy). Then, subtotal esophagectomy with two-field lymphadenectomy, including the whole mediastinum and abdomen, will be performed. The primary endpoint for this study is the pathologic complete response rate after neoadjuvant chemoradiotherapy plus tislelizumab. DISCUSSION: The optimal timing of the combination of immunotherapy and neoadjuvant chemoradiotherapy in esophageal carcinoma is not determined. The results of this phase II trial will be helpful to clarify the safety and efficacy of the sequential addition of tislelizumab after neoadjuvant chemoradiotherapy for locally advanced resectable esophageal carcinoma. TRIAL REGISTRATION: This study was approved on January 26, 2021 and retrospectively registered with ClinicalTrials.gov ( NCT04776590 ) on March 1, 2021.

Protocol for the 2ND-STEP study, Japan Clinical Oncology Group study JCOG1802: a randomized phase II trial of second-line treatment for advanced soft tissue sarcoma comparing trabectedin, eribulin and pazopanib.

BACKGROUND: Soft tissue sarcomas (STS) are a rare type of malignancy comprising a variety of histological diagnoses. Chemotherapy constitutes the standard treatment for advanced STS. Doxorubicin-based regimens, which include the administration of doxorubicin alone or in combination with ifosfamide or dacarbazine, are widely accepted as first-line chemotherapy for advanced STS. Trabectedin, eribulin, pazopanib, and gemcitabine plus docetaxel (GD), which is the empirical standard therapy in Japan, are major candidates for second-line chemotherapy for advanced STS, although clear evidence of the superiority of any one regimen is lacking. The Bone and Soft Tissue Tumor Study Group of the Japan Clinical Oncology Group (JCOG) conducts this trial to select the most promising regimen among trabectedin, eribulin, and pazopanib for comparison with GD as the test arm regimen in a future phase III trial of second-line treatment for patients with advanced STS. METHODS: The JCOG1802 study is a multicenter, selection design, randomized phase II trial comparing trabectedin (1.2 mg/m2 intravenously, every 3 weeks), eribulin (1.4 mg/m2 intravenously, days 1 and 8, every 3 weeks), and pazopanib (800 mg orally, every day) in patients with unresectable or metastatic STS refractory to doxorubicin-based first-line chemotherapy. The principal eligibility criteria are patients aged 16 years or above; unresectable and/or metastatic STS; exacerbation within 6 months prior to registration; histopathological diagnosis of STS other than Ewing sarcoma, embryonal/alveolar rhabdomyosarcoma, well-differentiated liposarcoma and myxoid liposarcoma; prior doxorubicin-based chemotherapy for STS, and Eastern Cooperative Oncology Group performance status 0 to 2. The primary endpoint is progression-free survival, and the secondary endpoints include overall survival, disease-control rate, response rate, and adverse events. The total planned sample size to correctly select the most promising regimen with a probability of > 80% is 120. Thirty-seven institutions in Japan will participate at the start of this trial. DISCUSSION: This is the first randomized trial to evaluate trabectedin, eribulin, and pazopanib as second-line therapies for advanced STS. We endeavor to perform a subsequent phase III trial comparing the best regimen selected by this study (JCOG1802) with GD. TRIAL REGISTRATION: This study was registered with the Japan Registry of Clinical Trials ( jRCTs031190152 ) on December 5, 2019.

Preoperative sequential short-course radiation therapy and FOLFOX chemotherapy versus long-course chemoradiotherapy for locally advanced rectal cancer: a multicenter, randomized controlled trial (SOLAR trial).

BACKGROUND: Preoperative (chemo)radiotherapy has been widely used as an effective treatment for locally advanced rectal cancer (LARC), leading to a significant reduction in pelvic recurrence rates. Because early administration of intensive chemotherapy for LARC has more advantages than adjuvant chemotherapy, total neoadjuvant therapy (TNT) has been introduced and evaluated to determine whether it can improve tumor response or treatment outcomes. This study aims to investigate whether short-course radiotherapy (SCRT) followed by intensive chemotherapy improves oncologic outcomes compared with traditional preoperative long-course chemoradiotherapy (CRT). METHODS: A multicenter randomized phase II trial involving 364 patients with LARC (cT3-4, cN+, or presence of extramural vascular invasion) will be conducted. Patients will be randomly assigned to the experimental or control arm at a ratio of 1:1. Participants in the experimental arm will receive SCRT (25 Gy in 5 fractions, daily) followed by four cycles of FOLFOX (oxaliplatin, 5-fluorouracil, and folinic acid) as a neoadjuvant treatment, and those in the control arm will receive conventional radiotherapy (45-50.4 Gy in 25-28 fractions, 5 times a week) concurrently with capecitabine or 5-fluorouracil. As a mandatory surgical procedure, total mesorectal excision will be performed 2-5 weeks from the last cycle of chemotherapy in the experimental arm and 6-8 weeks after the last day of radiotherapy in the control arm. The primary endpoint is 3-year disease-free survival, and the secondary endpoints are tumor response, overall survival, toxicities, quality of life, and cost-effectiveness. DISCUSSION: This is the first Korean randomized controlled study comparing SCRT-based TNT with traditional preoperative LC-CRT for LARC. The involvement of experienced colorectal surgeons ensures high-quality surgical resection. SCRT followed by FOLFOX chemotherapy is expected to improve disease-free survival compared with CRT, with potential advantages in tumor response, quality of life, and cost-effectiveness. TRIAL REGISTRATION: This trial is registered at Clinical Research Information under the identifier Service KCT0004874 on April 02, 2020, and at Clinicaltrial.gov under the identifier NCT05673772 on January 06, 2023.

Estimating the distribution of ratio of paired event times in phase II oncology trials.

With the rapid development of new anti-cancer agents which are cytostatic, new endpoints are needed to better measure treatment efficacy in phase II trials. For this purpose, Von Hoff (1998) proposed the growth modulation index (GMI), that is, the ratio between times to progression or progression-free survival times in two successive treatment lines. An essential task in studies using GMI as an endpoint is to estimate the distribution of GMI. Traditional methods for survival data have been used for estimating the GMI distribution because censoring is common for GMI data. However, we point out that the independent censoring assumption required by traditional survival methods is always violated for GMI, which may lead to severely biased results. In this paper, we construct both nonparametric and parametric estimators for the distribution of GMI, accounting for the dependent censoring of GMI. Extensive simulation studies show that our nonparametric estimators perform well in practical situations and outperform existing estimators, and our parametric estimators perform better than our nonparametric estimators and existing estimators when the parametric model is correctly specified. A phase II clinical trial using GMI as the primary endpoint is provided for illustration.

Intraperitoneal paclitaxel combined with FOLFOX/CAPOX plus bevacizumab for colorectal cancer with peritoneal carcinomatosis (the iPac-02 trial): study protocol of a single arm, multicenter, phase 2 study.

BACKGROUND: The safety of intraperitoneally administrated paclitaxel (op PTX) was demonstrated in the phase I trial of ip PTX combined with conventional systemic chemotherapy for colorectal cancer with peritoneal carcinomatosis. Moreover, the median survival time was 29.3 months, which was longer than that observed in previous studies. Here, we planned the phase II trial of ip PTX: the iPac-02 trial. METHODS: This multicenter, open-label, single assignment interventional clinical study includes patients with colorectal cancer with unresectable peritoneal carcinomatosis. FOLFOX-bevacizumab or CAPOX-bevacizumab is administered concomitantly as systemic chemotherapy. PTX 20 mg/m2 is administered weekly through the peritoneal access port in addition to these conventional systemic chemotherapies. The response rate is the primary endpoint. Progression-free survival, overall survival, peritoneal cancer index improvement rate, rate of negative peritoneal lavage cytology, safety, and response rate to peritoneal metastases are the secondary endpoints. A total of 38 patients are included in the study. In the interim analysis, the study will continue to the second stage if at least 4 of the first 14 patients respond to the study treatment. The study has been registered at the Japan Registry of Clinical Trials (jRCT2031220110). RESULTS: We previously conducted phase I trial of ip PTX combined with conventional systemic chemotherapy for colorectal cancer with peritoneal carcinomatosis [1]. In the study, three patients underwent mFOLFOX, bevacizumab, and weekly ip PTX, and the other three patients underwent CAPOX, bevacizumab, and weekly ip PTX treatment. The dose of PTX was 20 mg/m [2]. The primary endpoint was the safety of the chemotherapy, and secondary endpoints were response rate, peritoneal cancer index improvement rate, rate of negative peritoneal lavage cytology, progression-free survival, and overall survival. Dose limiting toxicity was not observed, and the adverse events of ip PTX combined with oxaliplatin-based systemic chemotherapy were similar to those described in previous studies using systemic chemotherapy alone [3, 4]. The response rate was 25%, peritoneal cancer index improvement rate was 50%, and cytology in peritoneal lavage turned negative in all the cases. The progression-free survival was 8.8 months (range, 6.8-12 months), and median survival time was 29.3 months [5], which was longer than that observed in previous studies. CONCLUSION: Here, we planned the phase II trial of ip paclitaxel combined with conventional chemotherapy for colorectal cancer with peritoneal carcinomatosis: the iPac-02 trial.

Capecitabine maintenance therapy in metastatic colorectal cancer patients with no evidence of disease: CAMCO trial.

Background: In patients with metastatic colorectal cancer (mCRC) exhibiting no evidence of disease (NED), this study assessed the efficacy and safety of capecitabine maintenance therapy. Methods: The single-arm, phase II CAMCO trial enrolled mCRC-NED patients after first-line treatment, administering oral capecitabine maintenance for 1 year. Results: A total of 93 patients were enrolled. The primary end point, 3-year disease-free survival, yielded a rate of 51.6% (95% CI: 41.3-62.0%). Secondary end points included a 3-year overall survival rate of 83.9% (95% CI: 76.3-91.5%). Grade 3 adverse events (AE) were observed in seven patients (7.5%). Predominantly grade 1 and 2, the most common AE was hand-foot syndrome. Conclusion: In mCRC-NED patients, capecitabine maintenance demonstrated a manageable 3-year disease-free survival rate of 51.6%, accompanied by manageable AEs. Clinical Trial Registration: NCT01880658 (ClinicalTrials.gov).

A randomized Bayesian optimal phase II design with binary endpoint.

In this paper, we propose a randomized Bayesian optimal phase II (RBOP2) design with a binary endpoint (e.g., response rate). A beta-binomial distribution is used to model the binary endpoint for a two-arm phase II trial. Posterior probabilities of the endpoint of interest are evaluated at each interim look and used in the decision to stop the trial due to futility. Compared with other Bayesian designs, the proposed RBOP2 design has the following merits: (i) strongly controls the type I error rate at a pre-defined level; (ii) optimizes the stopping boundaries, thus maximizing the power to detect treatment effects and minimizing the expected sample size for futile treatment; (iii) does not limit the number of interim looks, thus enabling frequent trial monitoring; and (iv) allows the stopping boundaries to be pre-defined in the protocol and is easy to implement. We conduct simulation studies to compare the proposed design with a group sequential design and other Bayesian randomized designs and evaluate its operating characteristics under different scenarios.

Efficacy and safety of preoperative chemoradiotherapy with S-1 for advanced rectal cancer: a phase II study.

Background: Preoperative chemoradiotherapy (CRT) for patients with rectal cancer is not yet established in Japan. We aimed to evaluate the efficacy and safety of preoperative CRT with S-1, a fixed-dose combination of tegafur, gimeracil, and oteracil potassium. Materials and methods: We conducted a prospective, interventional, non-randomized single-center study. Radiotherapy was administered at a total dose of 45 Gy (1.8 Gy in 25 fractions) for five weeks. S-1 was administered orally for nine weeks (five weeks during and four weeks after radiotherapy) at a dose of 80 mg/m2/day. The endpoint was the pathological complete response (pCR) rate. Results: Twenty-eight patients were finally enrolled. The following patient characteristics were recorded: clinical Stage (II: n = 12, III: n = 16), median age (66 years, range 40-77 years), male/female ratio (20/8), and lesion site (Ra-Rb:3/Rb:23/Rb-P:2). Preoperative treatment was completed in 27 patients (96%). Treatment abandonment occurred because of diarrhea. Grade 3 or higher adverse events were observed in one (4%) patient with two events. No serious adverse events occurred in the ≥ 70 years group. The response rate was 68% in all patients and 68% among elderly patients. Radical resection was achieved in all patients, including 19 (68%) who underwent sphincter-preserving surgery. The pCR rate was 11% (three patients). The five-year disease-free survival rate was 68%, and the overall survival rate was 82%. Local recurrence occurred in only one patient five years after surgery. Conclusion: Preoperative CRT with S-1 alone may be a safe and acceptable regimen from the perspective of adverse events and oncological outcomes. Trial registration: UMIN Clinical Trial Registry: UMIN000013598. Registered 1 April 2014, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recpt-no=R000015887.

Outcomes from a mechanistic biomarker multi-arm and randomised study of liposomal MTP-PE (Mifamurtide) in metastatic and/or recurrent osteosarcoma (EuroSarc-Memos trial).

The phase III clinical study of adjuvant liposomal muramyl tripeptide (MTP-PE) in resected high-grade osteosarcoma (OS) documented positive results that have been translated into regulatory approval, supporting initial promise for innate immune therapies in OS. There remains, however, no new approved treatment such as MTP-PE for either metastatic or recurrent OS. Whilst the addition of different agents, including liposomal MTP-PE, to surgery for metastatic or recurrent high-grade osteosarcoma has tried to improve response rates, a mechanistic hiatus exists in terms of a detailed understanding the therapeutic strategies required in advanced disease. Here we report a Bayesian designed multi-arm, multi-centre, open-label phase II study with randomisation in patients with metastatic and/or recurrent OS, designed to investigate how patients with OS might respond to liposomal MTP-PE, either given alone or in combination with ifosfamide. Despite the trial closing because of poor recruitment within the allocated funding period, with no objective responses in eight patients, we report the design and feasibility outcomes for patients registered into the trial. We demonstrate the feasibility of the Bayesian design, European collaboration, tissue collection with genomic analysis and serum cytokine characterisation. Further mechanistic investigation of liposomal MTP-PE alone and in combination with other agents remains warranted in metastatic OS.

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.

A phase II trial of the super-enhancer inhibitor Minnelide™ in advanced refractory adenosquamous carcinoma of the pancreas.

Adenosquamous carcinoma of the pancreas (ASCP) is a very rare and highly aggressive variant of pancreatic ductal adenocarcinoma, accounting for 0.5-4% of all pancreatic cancer cases in the USA. Current data indicate that epigenetic changes and MYC overexpression lead to squamous transdifferentiation of pancreatic tumor cells and development of ASCP. Minnelide™, an oral anti-super-enhancer drug that inhibits MYC expression in preclinical models of ASCP, has demonstrated safety in a phase I study. We describe the design for a phase II, open-label, single-arm trial of Minnelide in patients with advanced refractory ASCP.

Adenosquamous carcinoma of the pancreas (ASCP) is a rare and highly aggressive variant of pancreatic cancer, with limited treatment options. Changes in activation of DNA elements called super-enhancers drive the growth of ASCP. Minnelide™ is an oral drug that blocks the super-enhancer network and is safe to give to patients with advanced cancer. This trial is designed to determine whether Minnelide can shrink tumors in patients with ASCP who have already received at least one previous treatment for their cancer.  Clinical Trial Registration: NCT04896073 (ClinicalTrials.gov).

Combi-TED: a new trial testing Tedopi® with docetaxel or nivolumab in metastatic non-small-cell lung cancer progressing after first line.

Despite the positive results obtained by first-line chemoimmunotherapy in patients with metastatic non-small-cell lung cancer (NSCLC), only a few second-line options are available after disease progression. Combi-TED is a phase II international study that will assess the efficacy of Tedopi®, a cancer vaccine, combined with either docetaxel or nivolumab and compared with docetaxel monotherapy in patients with metastatic NSCLC after chemoimmunotherapy. The study, currently in the recruitment phase, will assess 1-year overall survival (primary end point), patient's progression-free survival and overall response rate, as well as the correlation of efficacy with several tumor or blood biomarkers. The results will hopefully provide more information on Tedopi combinational treatment compared with current standard of care in NSCLC patients who fail first-line chemoimmunotherapy. Clinical Trial Registration: NCT04884282 (ClinicalTrials.gov).

Patients with lung cancer that has spread to other parts of the body are usually treated with a combination of chemotherapy and drugs that stimulate the immune system to kill cancer cells, which is referred to as immunotherapy. If after receiving these drugs the cancer still gets worse, patients have only a few treatment options left and are usually treated with chemotherapy only. Researchers will study if a new medicine called Tedopi^®, a vaccine that specifically attacks cancer cells, used together with chemotherapy or immunotherapy, will work better then chemotherapy alone for these patients. The study will monitor how long patients will live after treatment, for how long they will live without their disease getting worse and how many patients will improve after treatment. Moreover, researchers will study if patients present specific features, such as certain molecules in their tumor cells or blood cells, that may indicate that they respond better to certain treatments.

Two-stage screened selection designs for randomized phase II trials with time-to-event endpoints.

Phase II exploratory multiarm studies that randomize among new treatments are found to be broadly useful and appear to be of value both scientifically and logistically, especially in the areas of unmet needs, for example, pediatric cancer. This multiarm design also has a faster recruitment rate because it provides patients with more treatment choices than traditional two-arm randomized controlled trials do. In contrast to direct formal comparisons in multiarm multistage designs, for example, umbrella or platform designs, the screened selection design (SSD) recommends using a promising treatment arm by ranking according to the effect size, which often needs lesser sample sizes than the former. In this paper, the usefulness of the phase II SSD design is exemplified by three real trials. However, the existing SSD methods can only deal with binary endpoints. Motivated by the real trials in the authors' respective institutions, we propose using the two-stage SSD and its variant for randomized phase II trials with the time-to-event endpoint. The proposed methods not only provide a high probability of selecting a superior treatment arm but also control the type I error rate for testing the efficacy of each treatment arm versus a common external control. Sample size calculations have been derived and simulation studies demonstrate desirable operating characteristics. The proposed design has been used for designing three real trials. An R package frequentistSSD has been developed and is freely accessible for practitioners.