Muscle-invasive Bladder CancerPhase 2NITIMIBNCT03234153
Neoadjuvant Immunotherapy With Durvalumab and Tremelimumab for Bladder Cancer Patients Ineligible for Cisplatin
A Phase 2 study testing Durvalumab (Imfinzi) and Tremelimumab in people with Muscle-invasive Bladder Cancer, run by Insel Gruppe AG, University Hospital Bern at 1 site in Switzerland.
Trial summary
The trial assess the safety and antitumor activity of the anti-PD-L1 antibody Durvalumab in combination with the anti-CTLA4 antibody Tremelimumab. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Muscle-invasive Bladder Cancer
- What is being tested?
- Durvalumab (Imfinzi) and Tremelimumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 6 participants
- Where
- 1 siteSwitzerland
- Study dates
- 15 Jul 2018to 18 May 2020
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age ≥ 18 years
- Signed Informed Consent Form
- ECOG performance status of 0 or 1
- Histologically confirmed muscle-invasive urothelial carcinoma of the bladder (T2-T4 and/or N+). Patients with mixed histologies are required to have a dominant transitional cell pattern.
- Measurable disease according to RECIST v1.1 criteria
- Representative fresh tumor specimen; TURB (transurethral resection of bladder ) specimens must contain a muscle invasive component (at least T2)
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- Ineligible to receive cisplatin-based neoadjuvant chemotherapy based on at least one of the following criteria:
- Creatinin clearance less than 60ml/min (24h urine)
- CTCAE Gr ≥ 2 hearing loss
- CTCAE Gr ≥ 2 neuropathy
- Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
- Body weight >30 kg
- Adequate hematologic and end-organ function, defined by the following laboratory results obtained within 14 days prior the first study treatment:
- Absolute neutrophil count (ANC) ≥ 1500 cells/µl
- WBC counts > 2500/µl
- Platelet count ≥ 100,000/µl
- Hemoglobin ≥ 9.0 g/dL
- AST, ALT and alkaline phosphatase ≤ 2.5 times the upper limit of normal (ULN)
- Serum bilirubin ≤ 1.5 x ULN
- INR and aPTT ≤ 1.5 x ULN
- Serum creatinine clearance (CrCl) ≥ 40 mL/min using the Cockcroft-Gault equation
- Evidence of post-menopausal status or negative urinary or serum pregnancy test for premenopausal female. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause.
Who cannot join
- Known metastatic disease
- Intravesical chemo- or biological/immune (BCG) therapy within 6 weeks of first treatment dose
- Prio treatment with immune checkpoint blockade therapies like anti-CTLA-4, anti-PD1 and anti-PD-L1 therapeutic antibodies, including durvalumab and tremelimumab
- History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid syndrome, Wegner's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis or glomerulonephritis Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone are eligible for this study. Patients with controlled Type I diabetes mellitus on a stable dose of insulin regimen are eligible for this study
- Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of investigational drug.
- Female patients who are pregnant or breast feeding as well as male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 180 days after the last dose of durvalumab + tremelimumab combination therapy.
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- Known allergy or hypersensitivity to any of the investigational study drugs or any of the study excipients.
- Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment.
- Uncontrolled intercurrent illness, including but limited to, ongoing infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirements, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
- Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within the previous 3 months, unstable arrhythmias, or unstable angina.
- Patients with prior allogeneic stem cell or solid organ transplantation
- History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest CT scan
- Positive test for HIV
- Patients with active hepatitis B (defined as having a positive hepatitis B surface antigen test at screening) or hepatitis C.
- Active tuberculosis
- Administration of a living, attenuated vaccine within 4 weeks prior to treatment start
- Severe infection within 4 weeks prior to cycle 1, day 1
- Treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior treatment start or anticipated requirement for systemic immunosuppressive medications during the trial. The use of inhaled corticosteroids, physiologic replacement doses of glucocorticoids, and mineralocorticoids is allowed
- Known allergy or hypersensitivity to any of the study drugs or any of the study excipients.
Trial locations and contacts
1 site in 1 country.
Switzerland1 site
Departement of Medical Oncology, University Hospital Berne
Bern, 3010
About this study
Official title: Neoadjuvant Immunotherapy With Durvalumab in Combination With Tremelimumab in Patients With Muscle-invasive Bladder Cancer Ineligible for Cisplatin-based Chemotherapy.
The trial assess the safety and antitumor activity of the anti-PD-L1 antibody Durvalumab in combination with the anti-CTLA4 antibody Tremelimumab.
Read the detailed description
Background and Rationale:
The outcome for patients with muscle-invasive bladder cancer treated with surgery alone remains dismal with a 5 year survival rate between 25% to 80% depending on the tumor stage and lymph node status. Cisplatin-based chemotherapy regimens (Methotrexate, Vinblastine, Doxorubicin, Cisplatin ; Cisplatin, Methotrexate, Vinblastine; Gemcitabine/Cisplatin) have demonstrated a modest but absolute benefit in overall survival of 5-8% when administered in the neoadjuvant setting. Therefore, neoadjuvant Cisplatin-based regimens are regarded as a standard of care in treating patients with muscle-invasive bladder cancer. However, bladder cancer is a disease of the elderly and due to age-associated factors (e.g. hearing impaired ≥ grade 2), peripheral neuropathy (≥ grade 2), disease associated impairment of renal function (Glomerular filtration rate < 60 mL/min) and performance status (ECOG ≥ 2) 30 to 50% are ineligible for cisplatin-based chemotherapy regimens. Several combinations with Carboplatin have been tested in single arm, phase II trials in patients ineligible for Cisplatin but no standard regimen has been established for this patient population thus far. The Guidelines of the European association of Urology (EAU) do not recommend any neoadjuvant treatment for Cisplatin-ineligible patients.
The advent of immune checkpoint inhibitors like Durvalumab or Azetolizumab, both antibodies blocking the PD1/PD-L1 interaction, have shown promising results as single agents in terms of response (15-46%) and tolerability in the metastatic setting of bladder cancer.
A trial evaluating the safety, tolerability and antitumor activity of the combination of the immune-checkpoint inhibitors Durvarlumab and the anti-CTLA4 antibody Tremelimumab in various solid tumors, including urothelial carcinoma of the bladder is ongoing (protocol D4190C0010). Blocking the PD1/PD-L1 pathway in combination with an anti-CTLA4 antibody has shown greater antitumor activity than each antibody alone in malignant melanoma trials and showed a promising antitumor activity (17% overall response rate, irrespective of the PD-L1 expression status on tumor cells) in a phase Ib study of metastatic non-small-cell lung cancer. The safety profile was acceptable (42% grade 3-4 treatment related adverse events across all dosing cohorts, most common were diarrhea, colitis and increase lipase), however, the rate of adverse events (e.g. autoimmune phenomena) and treatment interruptions was higher as compared to single agent use.
Objective:
The Primary objective of the trial is to assess the safety and antitumor activity of the anti-PD-L1 antibody Durvalumab in combination with the anti-CTLA4 antibody Tremelimumab.
Study Duration:
Trial study duration encompassed the time from when the participant signs the informed consent until the last protocol-specific procedure has been completed (Cystectomy between week 17 to 23). All patients will be followed up for up to 78 weeks after end of treatment.
This study will be conducted in compliance with the protocol, the current version of the Declaration of Helsinki, the ICH-GCP as well as all national legal and regulatory requirements.
- Conditions
- Muscle-invasive Bladder Cancer
- Being tested
- Durvalumab (Imfinzi), Tremelimumab
- Keywords
- Muscle-invasive Bladder Cancer, Ineligible for Cisplatin-based Chemotherapy, Durvalumab, Tremelimumab
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Durvalumab (Imfinzi)Drug
Also called Neoadjuvant Immunotherapy
Durvalumab 1500 mg i.v. every 4 weeks in combination with Tremelimumab 75 mg i.v. every 4 weeks for a total of 4 cycles before surgery.
TremelimumabDrug
Also called Neoadjuvant Immunotherapy
Tremelimumab 75 mg i.v. in combination with Durvalumab 1500 mg i.v. every 4 weeks every 4 weeks for a total of 4 cycles before surgery.
| Study group | Role | What they receive |
|---|---|---|
| Durvalumab and Tremelimumab | Experimental | Durvalumab 1500 mg i.v. every 4 weeks in combination with Tremelimumab 75 mg i.v. every 4 weeks for a total of 4 cycles before surgery. Receives: Drug: Durvalumab (Imfinzi); Drug: Tremelimumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Objective Response Rate
Response rate (computer tomography or magnet resonance imaging) as measured per standard RECIST v1.1 after four cycles of combined treatment with Durvalumab (MEDI4736) and tremelimumab.
Measured: 16 weeks
Secondary outcomes (3)
Adverse Events
Number of Patients experiencing Toxicity/Adverse Events (AE)
Measured: 26 weeks
Recurrence-free Survival
Number of Patients with Recurrence-free Survival at 78 weeks
Measured: 78 weeks
Overall Survival
Number of Patients alive at 78 weeks
Measured: 78 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted31 Jul 2017
- Study start15 Jul 2018
- Primary completion8 Nov 2019
- Study completion18 May 2020
Why it stopped: low accrual
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Muscle-invasive Bladder CancerStudies of the same condition, open and under way.
- More trials run by Insel Gruppe AG, University Hospital BernThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Single Arm open-Label prospective Phase II
- Masking
- None (open label)
- Enrolment
- 6 participants (actual)
Sponsor and investigators
- Lead sponsor
- Insel Gruppe AG, University Hospital Bern
- Sponsor type
- University, hospital or other
- Collaborators
- AstraZeneca
- Responsible party
- Sponsor
- Investigators
- Julian Schardt, MD, Study chair, Departement of Medical Oncology, University Hospital Berne
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03234153
- Sponsor's protocol ID
- NITIMIB-Trial
- Acronym
- NITIMIB
- Status last verified
- Jun 2020
- First submitted
- 26 Jul 2017
- Last updated
- 17 Jun 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 17 Jun 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Neoadjuvant Immunotherapy With Durvalumab in Combination With Tremelimumab in Patients With Muscle-invasive Bladder Cancer Ineligible for Cisplatin-based Chemotherapy.
- ClinicalTrials.gov ID
- NCT03234153
- Acronym / sponsor ID
- NITIMIB / NITIMIB-Trial
- Conditions
- Muscle-invasive Bladder Cancer
- Keywords
- Muscle-invasive Bladder Cancer, Ineligible for Cisplatin-based Chemotherapy, Durvalumab, Tremelimumab
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: low accrual
- Enrolment
- 6 participants (actual)
- Lead sponsor
- Insel Gruppe AG, University Hospital BernUniversity, hospital or other
- Collaborators
- AstraZeneca
- Study start
- 15 Jul 2018 (actual)
- Primary completion
- 8 Nov 2019 (actual)
- Study completion
- 18 May 2020 (actual)
- First posted
- 31 Jul 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The trial assess the safety and antitumor activity of the anti-PD-L1 antibody Durvalumab in combination with the anti-CTLA4 antibody Tremelimumab.
Detailed description
Background and Rationale:
The outcome for patients with muscle-invasive bladder cancer treated with surgery alone remains dismal with a 5 year survival rate between 25% to 80% depending on the tumor stage and lymph node status. Cisplatin-based chemotherapy regimens (Methotrexate, Vinblastine, Doxorubicin, Cisplatin ; Cisplatin, Methotrexate, Vinblastine; Gemcitabine/Cisplatin) have demonstrated a modest but absolute benefit in overall survival of 5-8% when administered in the neoadjuvant setting. Therefore, neoadjuvant Cisplatin-based regimens are regarded as a standard of care in treating patients with muscle-invasive bladder cancer. However, bladder cancer is a disease of the elderly and due to age-associated factors (e.g. hearing impaired ≥ grade 2), peripheral neuropathy (≥ grade 2), disease associated impairment of renal function (Glomerular filtration rate < 60 mL/min) and performance status (ECOG ≥ 2) 30 to 50% are ineligible for cisplatin-based chemotherapy regimens. Several combinations with Carboplatin have been tested in single arm, phase II trials in patients ineligible for Cisplatin but no standard regimen has been established for this patient population thus far. The Guidelines of the European association of Urology (EAU) do not recommend any neoadjuvant treatment for Cisplatin-ineligible patients.
The advent of immune checkpoint inhibitors like Durvalumab or Azetolizumab, both antibodies blocking the PD1/PD-L1 interaction, have shown promising results as single agents in terms of response (15-46%) and tolerability in the metastatic setting of bladder cancer.
A trial evaluating the safety, tolerability and antitumor activity of the combination of the immune-checkpoint inhibitors Durvarlumab and the anti-CTLA4 antibody Tremelimumab in various solid tumors, including urothelial carcinoma of the bladder is ongoing (protocol D4190C0010). Blocking the PD1/PD-L1 pathway in combination with an anti-CTLA4 antibody has shown greater antitumor activity than each antibody alone in malignant melanoma trials and showed a promising antitumor activity (17% overall response rate, irrespective of the PD-L1 expression status on tumor cells) in a phase Ib study of metastatic non-small-cell lung cancer. The safety profile was acceptable (42% grade 3-4 treatment related adverse events across all dosing cohorts, most common were diarrhea, colitis and increase lipase), however, the rate of adverse events (e.g. autoimmune phenomena) and treatment interruptions was higher as compared to single agent use.
Objective:
The Primary objective of the trial is to assess the safety and antitumor activity of the anti-PD-L1 antibody Durvalumab in combination with the anti-CTLA4 antibody Tremelimumab.
Study Duration:
Trial study duration encompassed the time from when the participant signs the informed consent until the last protocol-specific procedure has been completed (Cystectomy between week 17 to 23). All patients will be followed up for up to 78 weeks after end of treatment.
This study will be conducted in compliance with the protocol, the current version of the Declaration of Helsinki, the ICH-GCP as well as all national legal and regulatory requirements.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Single Arm open-Label prospective Phase II
| Arm | Type | Receives |
|---|---|---|
| Durvalumab and Tremelimumab | Experimental | Drug: Durvalumab (Imfinzi), Drug: TremelimumabDurvalumab 1500 mg i.v. every 4 weeks in combination with Tremelimumab 75 mg i.v. every 4 weeks for a total of 4 cycles before surgery. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (22 listed)
- Age ≥ 18 years
- Signed Informed Consent Form
- ECOG performance status of 0 or 1
- Histologically confirmed muscle-invasive urothelial carcinoma of the bladder (T2-T4 and/or N+). Patients with mixed histologies are required to have a dominant transitional cell pattern.
- Measurable disease according to RECIST v1.1 criteria
Key exclusion criteria (19 listed)
- Known metastatic disease
- Intravesical chemo- or biological/immune (BCG) therapy within 6 weeks of first treatment dose
- Prio treatment with immune checkpoint blockade therapies like anti-CTLA-4, anti-PD1 and anti-PD-L1 therapeutic antibodies, including durvalumab and tremelimumab
- History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid syndrome, Wegner's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis or glomerulonephritis Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone are eligible for this study. Patients with controlled Type I diabetes mellitus on a stable dose of insulin regimen are eligible for this study
- Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of investigational drug.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Durvalumab (Imfinzi)Also: Neoadjuvant ImmunotherapyDurvalumab 1500 mg i.v. every 4 weeks in combination with Tremelimumab 75 mg i.v. every 4 weeks for a total of 4 cycles before surgery. | Drug | Durvalumab and Tremelimumab |
| TremelimumabAlso: Neoadjuvant ImmunotherapyTremelimumab 75 mg i.v. in combination with Durvalumab 1500 mg i.v. every 4 weeks every 4 weeks for a total of 4 cycles before surgery. | Drug | Durvalumab and Tremelimumab |
Primary outcome
Objective Response Rate
Time frame: 16 weeks
Response rate (computer tomography or magnet resonance imaging) as measured per standard RECIST v1.1 after four cycles of combined treatment with Durvalumab (MEDI4736) and tremelimumab.
3 secondary outcomes
Adverse Events
Time frame: 26 weeks
Recurrence-free Survival
Time frame: 78 weeks
Overall Survival
Time frame: 78 weeks
Results and safety
The study was stopped early (reason given: low accrual). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Jun 2020.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Julian Schardt, MD study chair
Departement of Medical Oncology, University Hospital Berne
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Durvalumab (Imfinzi) and Tremelimumab in people with Muscle-invasive Bladder Cancer, run by Insel Gruppe AG, University Hospital Bern at 1 site in Switzerland.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 22 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 17 Jun 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: low accrual). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Objective Response Rate (time frame: 16 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Jun 2020.