Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Urinary Bladder Neoplasms

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Urinary Bladder Diseases

Urologic Diseases

Male Urogenital Diseases

Antineoplastic Agents

All Drugs and Chemicals

Nivolumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Nivolumab at a dose of 480 mg will be administered as an IV infusion over 60 minutes every 4 weeks until disease recurrence or discontinuation due to unacceptable toxicity for a maximum of 12 treatments over an expected duration of 1 year.

This is a phase 2, single arm, open label trial to evaluate the rate of failure free survival at 2 years after start of chemoradiation with adjuvant nivolumab in adult subjects who undergo chemoradiation for localized bladder cancer.

This is a phase 2, single arm, open label trial

Adjuvant Nivolumab Following Chemo-Radiation in Localized Muscle-Invasive Bladder Cancer

A Phase II Open Label Single Arm Study of Adjuvant Nivolumab Following Chemo-Radiation in Localized Muscle-Invasive Bladder Cancer (NEXT)

The definition of failure will include loco-regional recurrence, and distant recurrence. The primary endpoint of the FFS will be determined based on disease recurrence date defined as the time between the start date of chemoradiation and the date of first recurrence or non-cancer related death.

This will be measured only in subjects who do not have local recurrence requiring radical cystectomy. The endpoint of FFSIB will be determined based on disease recurrence date defined as the time between the start date of chemoradiation and the date of first recurrence or non-cancer related death.

The endpoint of the FFS on nivolumab will be determined based on disease recurrence date defined as the time between the start date of nivolumab and the date of first recurrence or non-cancer related death.

Evaluate cystoscopic local control at 6 months, 1 year and 2 years post start of chemoradiation after censoring for distant recurrence. The endpoint will be measurement of local recurrence at 6 months, 1 year and 2 years as determined by cystoscopy.

Evaluate the rate of salvage cystectomy. This will be measured by the endpoint of radical cystectomy for local recurrence during study treatment.

Evaluate the rate of distant failure free survival at two years in subjects with intact bladder and those who discontinue study to undergo salvage cystectomy. This will be measured in subjects who do and do not have local recurrence requiring radical cystectomy during study treatment. The endpoint FFS will be determined based on disease recurrence date defined as the time between the start date of chemoradiation and the date of first distant recurrence or non-cancer related death.

Evaluate overall survival up to 5 years. This will be measured using Kaplan-Meier methodology for up to 5 years from start of chemoradiation

Bristol-Myers Squibb

University of Utah

Pembrolizumab

Antibodies

Immunoglobulins

Radiotherapy: 24Gy in 6f Pembrolizumab: 100mg

Radiotherapy: 24Gy in 6f Pembrolizumab: 200mg

Radiotherapy: 24Gy in 4f Pembrolizumab: 100mg

Radiotherapy: 24Gy in 4f Pembrolizumab: 200mg

Radiotherapy: 30Gy in 5f Pembrolizumab: 200mg

Radiotherapy

Sijy Pillai

Professor Robert Huddart

PLUMMB is an phase I trial to investigate the safety, tolerability and effectiveness of an immunotherapy drug called Pembrolizumab used in combination with radiotherapy. The study will also investigate two different doses of pembrolizumab, starting at 100mg (through an intravenous drip) and increasing to 200mg for the next cohort of patients, if the first dose is well tolerated. The patients suitable for this study will be: Group A those with locally advanced bladder cancer or Group B patients whose cancer has spread from the bladder (metastatic bladder cancer).

Treatment in the PLUMMB trial will start with a pembrolizumab 2 weeks prior to starting a course of 4 - 6 weeks radiotherapy. Treatment with pembrolizumab will then be given every three weeks. Patients in Group A will then continue to take pembrolizumab for up to a year unless they have disease progression or unacceptable side effects in the meantime. Patients in Group B will continue taking pembrolizumab for as long as needed until they have disease progression or unacceptable side effects.

Patients will be seen every 3 weeks during treatment and every 3-6 months thereafter. CT scans will be done every 3 months during treatment and as per usual care (usually 6 monthly) after the treatment has finished. Patients in Group A will also have a cystoscopy (camera test) to look into the bladder 3 months after they finish radiotherapy. This is standard care and would be the same for patients not on a research study.

1. Risk and burden for patients

   Patients in this study have cancer that often proves hard to control with standard care. The early phase nature of this study means that the intervention may not have any benefit for patients who take part in the study. However, they will still receive the standard treatment of radiotherapy. Throughout the study, any patients who have significant side effects from the trial drug will be withdrawn from the trial and will still be eligible to receive standard care. The study itself carries a number of potential burdens:
   * Experimental nature of the study drug. The drug stimulates the immune system to produce more proteins that will attack the tumour cells. It is thought that this will be selective for tumour cells; however it is possible that effects on normal tissues may cause side effects. These risks will be managed as much as possible by regular (3 weekly) clinical assessments as a hospital outpatient, by experienced clinicians while having the study treatment. Comprehensive assessments for safety will be carried out including more intensive monitoring with blood tests.
   * Burden of frequent hospital visits and tests. Participants in this study must attend hospital frequently for safety reasons to check for any toxicity of the study treatment. Blood tests (more than usual), clinical examination and urine tests are part of the safety assessment.
   * Additional investigations may be carried out as part of the study, for research purposes for which consent will be sought form the patient, such as additional blood samples and additional scans (CT thorax, abdomen and pelvis).
2. Phase 1 trial of Pembrolizumab: Patients will be carefully monitored for toxicity throughout the trial. A phase I trial has already been conducted to determine the maximum tolerated dose (MTD) of pembrolizumab in bladder cancer. To date no MTD has been defined and the maximum dose tested showed acceptable toxicity and positive effects on reducing tumour size. This study will assess two dose levels of pembrolizumab: 100mg and 200mg and differing radiotherapy doses (24-30Gy in 4-6f). Dose escalation will only occur if the current cohort have shown no signs of unacceptable toxicity at 6 weeks after completing radiotherapy.
3. Recruitment

   Participants will be offered information about this study by their clinical teams if they are considered to meet the entry criteria and express interest in taking part in an experimental study. It will be made clear that the study is experimental in nature and that there will not necessarily be a therapeutic benefit from taking part in the study. It will also be made clear that, should patients decide not to take part their future care will not be affected. Patients will be given sufficient time and information to make an informed decision about entering the trial, and not less than 24 hours; all patients entering the trial will give written informed consent. Inclusion and exclusion criteria for this study are standard for a phase 1 trial of a new oncology drug.
4. Confidentiality

   Patients will be linked to a unique identifier the code for which will be held on a password protected database held only by the study team. Blood samples, tumour sample processing and other data analysis will take place at the laboratories of Royal Marsden and Institute of Cancer Research in London or Sutton. Sample processing will take place using the study number only. No other patient identifiable information will be available on study samples. Investigators will have access to patient identifiable information on password protected NHS hospital notes and databases only.
5. Conflict of Interest

   Patients may be recruited to the study by those involved in their prior clinical care. The investigators do not expect conflict of interest between research and healthcare duties for a number of reasons: patients must give their full informed consent before entering the study, specifically regarding the unknown efficacy of the study drug and the intensive nature of the study. Those patients who do not continue in the study will maintain a relationship with the clinical team if required for symptom control. At the end of the study, patients will be able to access the results if they wish, through the Royal Marsden Website or contact the study team directly.
6. Use of tissue samples in future research

If participants give their consent, any leftover blood or tissue samples which are not required for this study will be stored for future unspecified research in line with the human tissue act regulations. Access and use of samples for research purposes will require appropriate ethical approval. Future researchers will not be able to identify individual patients from their biobank data, demographic and clinical information will be available.

Pembrolizumab in Muscle Invasive/Metastatic Bladder Cancer

Phase I Study of Hypofractionated Radiotherapy and Anti-PD1 Antibody (Pembrolizumab) in the Treatment of Advanced Bladder Cancer

Measurement of progression-free survival in patients with no PD-1/PDL-1 expression vs high levels of PD-1/PDL-1 in their tumour

Adverse events will be graded and assessed by CTCAEv4.

Report the proportion of patients with complete or partial response in non-irradiated metastases measured via RECIST.

Establishing the maximum tolerated dose (MTD) that can be safely combined with hypofractionated radiotherapy to the bladder in the absence of dose limiting toxicity (DLT) by assessing adverse events in the patient population.

Late grade 2+ and 3+ adverse events will be assessed by CTCAEv4.

Determining the proportion of patients treated with the combination of Pembrolizumab and radiotherapy with local control of their bladder cancer (based on cystoscopy and/or diffusion weighted MRI) via RECIST.

Measurement of progression free and overall survival rate

Merck Sharp & Dohme LLC

Institute of Cancer Research, United Kingdom

National Institute for Health Research, United Kingdom

Royal Marsden NHS Foundation Trust

Immune System Diseases

Rare Diseases

Carcinoma

Carcinoma, Transitional Cell

Hypersensitivity

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Transitional Cell Carcinoma

Bladder cancer (BC) is a heterogeneous malignancy with dismal outcome.Despite treatment, the 5-year overall survival rates for MIBC are \<50%, with many patients unresponsive or inapt, necessitating biomarkers to select those most likely to respond or fit for treatment

In this study was assessed the associations among most frequently mutated genes and with clinicopathological features, as well as the prognostic significance of the presence of mutations in the top mutated and DNA Damage response (DDR) mutated genes in terms of Overall Survival (OS). Moreover, overall tumor-infiltrating lymphocytes (TILs) density was measured, analyzed immunohistochemically the expression of PD-L1, the four MMR proteins (MLH1, MSH2, MSH6 and PMS2) and tumor or stromal CD8+ cytotoxic T lymphocyte infiltrates and assessed their association with each other, top mutated genes and available clinicopathological parameters together with their role in prognosis.

Prognostic Biomarkers in Patients With Urothelial Carcinoma

Investigation of Prognostic Biomarkers in Patients With Urothelial Carcinoma Treated With Platinum Regimens

Hellenic Cooperative Oncology Group

Standard dose Adaptive tumour focused radiotherapy (SART)

Dose escalated Adaptive tumour boost radiotherapy (DART)

One RT plan with whole bladder treated to standard dose.

WBRT

Three plans (small, medium \& large) generated with the standard dose of RT focused on the tumour, sparing the normal bladder from full dose radiation. Pretreatment cone beam CTs will be used to select the best fitting of the three plans prior to treatment.

SART

Three plans (small, medium \& large) generated with a higher dose than standard focused on the tumour and the remainder of the bladder treated to the same dose as in the SART group. Pretreatment cone beam CTs will be used to select the best fitting of the three plans prior to treatment.

DART

Robert Huddart

Bladder cancer is the seventh most common cancer in the UK, with 10,399 new cases diagnosed in 2011. In a quarter of these cases the cancer has infiltrated the muscular wall of the bladder (muscle invasive) and is life threatening. This type of bladder cancer is usually treated either with surgical removal of the bladder, or daily radiotherapy treatment (high strength xrays which kill cells), given every day for 4 or 7 weeks. RAIDER will investigate methods which have the potential to improve how well this radiotherapy works.

RAIDER is based on a study of novel radiotherapy techniques which was conducted at a single UK NHS Trust. Bladder radiotherapy is normally delivered using a single plan throughout treatment and treats the whole bladder with the same radiotherapy dose. In adaptive radiotherapy the delivery plan is chosen from 3 possible plans. In cancer (tumour) focused radiotherapy, the highest dose of the radiotherapy is aimed at the tumour within the bladder.

In RAIDER, at least 240 participants with muscle invasive bladder cancer will be in one of 3 treatment groups:

1. standard whole bladder radiotherapy
2. standard dose tumour focused adaptive radiotherapy
3. dose escalated tumour boost adaptive radiotherapy

Participants will visit the hospital 4 weeks, 3, 6, 9, 12, 18 and 24 months after radiotherapy and annually thereafter to check whether the cancer has returned and to receive treatment for any symptoms they may be experiencing.

RAIDER aims to confirm in a multicentre setting that novel techniques allow a higher radiotherapy dose than standard to be reliably targeted at the tumour within the bladder and to check that the long term side effects of the treatment are acceptable. If this is the case, results of RAIDER will be used to develop a study to establish whether dose escalated radiotherapy is better at treating bladder cancer than standard dose.

RAIDER has a two stage design. Stage 1 will establish the feasibility of delivering DART in a multi-centre setting, and stage 2 will establish the toxicity of DART. 72 patients will be recruited in stage 1, with at least an additional 168 patients in stage 2 (sufficient to recruit 57 evaluable participants to the DART group in each fractionation cohort).

Both fractionation regimens in standard use in UK are included - 32f and 20f. Participants will be permitted to receive concomitant chemotherapy. Primary endpoints will be assessed in each fractionation cohort separately with the flexibility to drop either a fractionation cohort or an experimental treatment group (on advice of Independent Data Monitoring Committee) following completion of stage 1.

Study of Tumour Focused Radiotherapy for Bladder Cancer

A Randomised Phase II Trial of Adaptive Image Guided Standard or Dose Escalated Tumour Boost Radiotherapy in the Treatment of Transitional Cell Carcinoma of the Bladder

Primary outcome of stage 1 of study, predefined radiotherapy dose constraints for bladder, bowel and rectum met for medium plan in DART group.

Primary outcome of stage 2 of study, late CTC toxicity grade 3 or higher.

Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE) questionnaire

excerpt of the EORTC QLQ-BLM30 questionnaire

Assessment of Late Effects of RadioTherapy - Bowel (ALERT-B) questionnaire

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Adjuvant Nivolumab Following Chemo-Radiation in Localized Muscle-Invasive Bladder Cancer	NCT03171025	Bladder Cancer	Nivolumab	18 Years -	University of Utah
Pembrolizumab in Muscle Invasive/Metastatic Bladder Cancer	NCT02560636	Invasive Bladde...	Pembrolizumab Radiotherapy	18 Years -	Royal Marsden NHS Foundation Trust
Prognostic Biomarkers in Patients With Urothelial Carcinoma	NCT04872036	Bladder Cancer		18 Years -	Hellenic Cooperative Oncology Group
Study of Tumour Focused Radiotherapy for Bladder Cancer	NCT02447549	Bladder Cancer	WBRT SART DART	16 Years -	Institute of Cancer Research, United Kingdom
Adjuvant Nivolumab Following Chemo-Radiation in Localized Muscle-Invasive Bladder Cancer	NCT03171025	Bladder Cancer	Nivolumab	18 Years -	University of Utah
Pembrolizumab in Muscle Invasive/Metastatic Bladder Cancer	NCT02560636	Invasive Bladde...	Pembrolizumab Radiotherapy	18 Years -	Royal Marsden NHS Foundation Trust
Study of Tumour Focused Radiotherapy for Bladder Cancer	NCT02447549	Bladder Cancer	WBRT SART DART	16 Years -	Institute of Cancer Research, United Kingdom
Prognostic Biomarkers in Patients With Urothelial Carcinoma	NCT04872036	Bladder Cancer		18 Years -	Hellenic Cooperative Oncology Group

Spots Global Cancer Trial Database for muscle invasive