Jessica Kendall

Background: High‐risk non‐muscle‐invasive bladder cancer (HRNMIBC) has a variable prognosis, managed predominantly by local surgical resection and intravesical Bacillus Calmette–Guérin (BCG), or radical cystectomy (RC). Current treatments are poorly tolerated, have supply limitations and often fail to control the disease. Treatments overcoming these limitations are needed to improve HRNMIBC outcomes. Many novel agents have been approved in recent years (including systemic pembrolizumab, nogapendekin alfa inbakicept‐pmln, N‐803), but long‐term efficacy is unknown. Given advanced bladder cancer findings, we believe direct intravesical administration of atezolizumab may aid with managing HRNMIBC or muscle‐invasive bladder cancer in patients who are ineligible for cisplatin‐based neoadjuvant chemotherapy. Study design: The INtraVESical immunoTherapy (INVEST) trial is a UK‐based, open‐label, non‐randomised, single‐centre, Phase Ib dose escalation, window of opportunity study exploring atezolizumab administration via intravesical routes (passive instillation and direct injection [sub‐urothelial]) in patients with bladder cancer with all stages undergoing RC. For both routes, an initial dose confirmation stage will determine toxicity and recommended atezolizumab dosage, followed by a dose expansion stage to further evaluate safety and toxicity at the recommended dose. Endpoints: We aim to investigate safety (primary) and preliminary activity (secondary) of intravesical atezolizumab delivered by passive instillation and direct injection into the tumour/bladder wall in patients with bladder urothelial cell carcinoma prior to RC. Primary endpoints include dose limiting toxicities and adverse events. Secondary endpoints include progression‐free survival, pathological complete response rate and treatment compliance. Exploratory endpoints include pharmacokinetic profile (assessed by serum and urine concentrations at prespecified timepoints), spatial analysis of atezolizumab distribution within RC tissue by imaging mass spectrometry and overall survival. Patients and Methods: Atezolizumab will be administered intravesically by either passive instillation or direct injection into the tumour/bladder wall. Cohorts will receive either 600 mg or 1200 mg doses administered as a single dose or as multiple doses (weekly for 3–6 weeks). Trial Registration: International Standard Randomised Controlled Trial Number: ISRCTN15842444 , registered 2 December 2022.

Introduction: Multiple myeloma is a malignancy of plasma cells with around 6000 new cases per year in the UK. Cyclophosphamide plus prednisolone is considered a standard of care for disease and symptom control in the advanced relapsed or refractory myeloma setting within the UK NHS. The selective nuclear export inhibitor, selinexor, has been relatively well tolerated in previous clinical trials and offers promise when used in combination with a wide range of other anti-cancer treatments. Here, we investigate if the addition of selinexor can improve responses to cyclophosphamide plus prednisolone without adding prohibitive toxicity. Methods and analysis: MUKtwelve is a UK-based, randomised, controlled, open, parallel group, multicentre phase II trial designed to evaluate clinical efficacy of selinexor in combination with cyclophosphamide and prednisolone (SCP) in patients with relapsed or refractory multiple myeloma. A calibration arm will receive cyclophosphamide and prednisolone alone (CP). Participants who experience disease progression on the CP arm may, if eligible, receive SCP. The MUK twelve trial results will be the first to assess clinical efficacy of selinexor with low-dose CP in relapsed/refractory multiple myeloma. It is widely accepted that the relapsing-remitting nature of the disease is accompanied by cellular changes that often result in the requirement for novel agents and drug combinations to regain disease control. Patients also often experience cumulative toxicities throughout their treatments, limiting the treatment intensity that can be given at relapse. Thus, there is a need for novel effective combination therapies with acceptable toxicity profiles. Ethics and dissemination: Ethics approval is obtained. Results will be submitted for publication in a peer-reviewed journal. Trial registration number: ISRCTN15028850 .

Background: A substantial proportion of breast cancer patients develop metastatic disease, with over 450,000 deaths globally per year. Bone is the most common first site of metastatic disease accounting for 40% of all first recurrence and 70% of patients with advanced disease develop skeletal involvement. Treatment of bone metastases currently focusses on symptom relief and prevention and treatment of skeletal complications. However, there remains a need for further treatment options for patients with bone metastases. Combining systemic therapy with a bone-targeted agent, such as radium-223, may provide an effective treatment with minimal additional side effects. Methods/design: CARBON is a UK-based, open-label, multi-centre study which comprises an initial safety phase to establish the feasibility and safety of combining radium-223 given on a 6-weekly schedule in combination with orally administered capecitabine followed by a randomised extension phase to further characterise the safety profile and provide preliminary estimation of efficacy. Discussion: The CARBON study is important as the results will be the first to assess radium-223 with chemotherapy in advanced breast cancer. If the results find acceptable rates of toxicity with a decrease in bone turnover markers, further work will be necessary in a phase II/III setting to assess the efficacy and clinical benefit. Trial registration: ISRCTN, ISRCTN92755158, Registered on 17 February 2016.