Durvalumab Plus Tremelimumab With Concurrent Radiotherapy for Localized Muscle Invasive Bladder Cancer Treated With a Selective Bladder Preservation Approach

Study Overview
=================
Brief Summary
-----------------
Combined-modality treatment of localized muscle invasive bladder cancer including transurethral resection (TUR), radiotherapy and dual checkpoint inhibition immunotherapy could achieve pathological complete response in some patients. These patients could avoid to undergone radical surgery with radical cystectomy and preserve their bladder, without the side-effects associated with chemotherapy and surgery. This study has been design to determine the efficacy of durvalumab plus tremelimumab with concurrent radiotherapy in terms of pathological response rate in patients with localized muscle invasive bladder cancer treated with bladder preservation intent.

Detailed Description
-----------------
The treatment consisted of initial TUR of the tumor, with multiple random biopsies of normal-appearing bladder urothelium, followed by durvalumab 1500 mg i.v. plus tremelimumab 75 mg i.v., every 4 weeks for a total of 3 doses. Two weeks after the initiation of immunotherapy, normofractionated external-beam radiotherapy with high-energy photons will be started. Radiotherapy will be administered concurrently with immunotherapy at doses of 46 Gy to the minor pelvis and 64-66 Gy to the bladder. Six weeks after the end of radiotherapy, ALL patients will undergo a new cystoscopy with biopsies of the tumor bed and all residual present lesions as an efficacy determination. In patients with persistent prominent inflammatory reaction at this moment, the cystoscopy can be performed 1-2 weeks later (6 to 8 weeks after the end of radiotherapy). Response is defined as an absence of invasive cancer at post immunotherapy biopsy (≤cT1). Patients with response to immunotherapy will be candidates to bladder preservation, whereas in those with residual muscle invasive tumor the possibility of salvage radical cystectomy must be evaluated. Patients developing an isolated bladder invasive relapse during follow-up will be also possible candidates to salvage cystectomy, whereas those developing a superficial relapse in the preserved bladder will be managed with TUR and intravesical BCG. Patients will be followed up every 3 months the first year, every 4 months the second year and every 6 months thereafter with abdomen and pelvis CT scan, Rx thorax, urine cytology. Additionally, the mandatory efficacy cystoscopy and bladder biopsy (6w post RT), other cystoscopy and bladder biopsy will be performed in case of detection abnormalities in the cytology or imaging studies. The study will be closed 2 years after the last patient inclusion.

Official Title
-----------------
Phase II Trial of Durvalumab (Medi4736) Plus Tremelimumab With Concurrent Radiotherapy in Patients With Localized Muscle Invasive Bladder Cancer Treated With a Selective Bladder Preservation Approach

Conditions
-----------------
Invasive Bladder Cancer

Intervention / Treatment
-----------------
* Drug: Durvalumab
* Drug: Tremelimumab
* Radiation: Radiotherapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must have signed the informed consent prior to undergoing any study procedure. Patients must be 18 years of age or older. Patients must have Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1. A paraffin-embedded tumor sample must be available for the associate molecular study. Body weight >30 Kg. Adequate normal organ and marrow function. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre- menopausal patients. Patient is willing and able to comply with the protocol for the duration of the study. Exclusion Criteria: Involvement in the planning and/or conduct of the study (applies to both Sponsor staff and/or staff at the study site). Participation in another clinical study with an investigational product during the last 30 days. Concurrent enrolment in another clinical study unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study. Previous treatment with radiotherapy to the bladder, systemic chemotherapy or immune checkpoint inhibitors. Prior intravesical Bacillus Calmette-Guérin (BCG) treatment for non-muscle invasive bladder cancer is allowed, 28 days prior to study. Presence of regional lymph node or metastatic extension of the disease. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart) <<for durvalumab monotherapy and durvalumab + tremelimumab combination studies this criterion can be removed. For durvalumab ±tremelimumab in combination with an agent with pro-arrhythmic potential or where effect of the combination on QT is not known if this criterion should be retained. Patient safety and the cardiac ECG should be consulted as needed>>. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the Study Physician. Any concurrent chemotherapy, investigational product (IP) other than studied in this protocol, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable. History of allogenic organ transplantation. Active or prior documented autoimmune or inflammatory disorders. Uncontrolled intercurrent illness. History of another primary malignancy. History of active primary immunodeficiency. Active infection. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. Receipt of live attenuated vaccine within 30 days prior to the first dose of the investigationa medical products (IMP). Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients. Prior randomisation or treatment in a previous durvalumab and/or tremelimumab clinical study. Judgment by the investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements. Known allergy or hypersensitivity to IP or any excipient.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: The study will be conducted using a two-stage sequential design. Using the assumption that the treatment would be considered ineffective if it had a response proportion similar to radiotherapy alone (P0: 0.5) but would be of considerable interest if it had a response proportion of 70% of more (P1: 0.7), the sample size requirement is 12 patients for the first stage and 20 additional patients for the second stage. Six or more responses in the first stage were required for continuation to second stage accrual. The study was planned to have a type I error of 0.10 and a power of 80% in a one sided test.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Durvalumab + Tremelimumab<br>The treatment consisted of initial TUR of the tumor, with multiple random biopsies of normal-appearing bladder urothelium, followed by durvalumab 1500 mg i.v. plus tremelimumab 75 mg i.v., every 4 weeks for a total of 3 doses. Two weeks after the initiation of immunotherapy, normofractionated external-beam radiotherapy with high-energy photons will be started. Radiotherapy will be administered concurrently with immunotherapy at doses of 46 Gy to the minor pelvis and 64-66 Gy to the bladder. | Drug: Durvalumab<br>* All patients will receive durvalumab (MEDI4736) (1500mg Q4W) in combination with tremelimumab (75 mg IV Q4W) for up to 3 doses/cycles each, unless there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met. If a patient's weight falls to 30kg or below the patient should receive weight-based dosing equivalent to 20 mg/kg of durvalumab Q4W and 1mg/kg tremelimumab Q4W until the weight improves to >30 kg, at which point the patient should start receiving the fixed dosing of durvalumab 1500mg plus tremelimumab 75 mg Q4W.<br>* Other names: MEDI4736;Drug: Tremelimumab<br>* All patients will receive durvalumab (MEDI4736) (1500mg Q4W) in combination with tremelimumab (75 mg IV Q4W) for up to 3 doses/cycles each, unless there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met. If a patient's weight falls to 30kg or below the patient should receive weight-based dosing equivalent to 20 mg/kg of durvalumab Q4W and 1mg/kg tremelimumab Q4W until the weight improves to >30 kg, at which point the patient should start receiving the fixed dosing of durvalumab 1500mg plus tremelimumab 75 mg Q4W.<br>Radiation: Radiotherapy<br>* Radiotherapy at doses of 46 Gy to the minor pelvis and 64-66 Gy to the bladder.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with pathological response | Pathological response is defined as the absence of muscle- invasive bladder cancer at post-treatment biopsy (≤cT1). Cystoscopy and bladder biopsy six weeks since the end of radiotherapy. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of patients with bladder preserved | Number of patients whom bladder has been preserved after cytoscopic evaluation. | 24 months | 
| Rate of immediate salvage cystectomies | Number of patients with indication of salvage cystectomies after first trial-related cystoscopic evaluation. | 24 months | 
| Rate of late salvage cystectomies | Number of patients with indication of salvage cystectomies based on follow-up cystoscopic evaluation. | 24 months | 
| Survival with bladder preserved free of tumor | Time from the start of immunotherapy to either the date of cystectomy or the date of recurrence of muscle- invasive bladder carcinoma or metastasis. | 24 months | 
| Disease-free survival | Time from the start of therapy to the date of recurrence of muscle invasive bladder carcinoma or metastases. | 24 months | 
| Overall survival | Time from the start of immunotherapy to the date of death due to any cause. | 24 months | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | Frequency, nature and number of patients developing adverse events throughout follow up | 24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
tremelimumab, localized muscle invasive bladder cancer, bladder preservation, durvalumab, radiotherapy