Muscle-Invasive Bladder CarcinomaPhase 2NCT04506554
A Study of Risk Enabled Therapy After Neoadjuvant Immunochemotherapy for Bladder Cancer
A Phase 2 study testing AMVAC + Nivolumab in people with Muscle-Invasive Bladder Carcinoma, run by Fox Chase Cancer Center at 4 sites in United States.
Trial summary
Neoadjuvant accelerated methotrexate/vinblastine/adriamycin/cisplatin (AMVAC) in combination with nivolumab is under evaluation for the treatment of muscle invasive bladder cancer (MIBC). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Muscle-Invasive Bladder Carcinoma
- What is being tested?
- AMVAC + Nivolumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 81 participants
- Where
- 4 sitesUnited States
- Study dates
- 1 Dec 2020to Nov 2028
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
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
- Male or female patients ≥18 years
- Primary urothelial or predominantly urothelial carcinoma of the bladder confirmed from pathology report. Patients with some component of variant histology mixed with predominant urothelial carcinoma will be allowed. Upper tract urothelial carcinoma patients are not allowed.
- Urothelial carcinoma of the prostatic urethra in men is allowed
- Histologic evidence of muscularis propria invasion.
- AJCC23 clinical stage T2-T3 N0M0.
- No radiographic evidence of lymph node positive disease as per RECIST 1.1 (≥15 mm short axis diameter). Lymph node positive disease is defined as clinical lymphadenopathy on staging CT or MRI greater than 1.4 cm in the short axis. If a lymph node is greater than 1.4 cm, it has to be biopsy proven negative for the patient to be eligible.
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- No metastatic disease (M0).
- ECOG performance status 0, or 1.
- Left ventricular ejection fraction ≥ 50% by MUGA or ECHO within 6 months of study entry.
- Negative pregnancy test in women of child bearing potential within 24 hours of study registration. If the pregnancy test is positive, the patient must not receive protocol treatment and must not be enrolled in the study.
- Normal organ and bone marrow function (Leukocytes ≥ 3,000/mcL, Absolute neutrophil count ≥ 1,500/mcL, Platelets ≥ 100,000/mcL, Total bilirubin ≤ institutional upper limit of normal (ULN) unless patient has known Gilbert's disease, in which case an elevated bilirubin is allowed, AST(SGOT)/ALT(SGPT) ≤ 2.5 X institutional ULN, Creatinine Clearance ≥ 50 mL/min calculated using the Cockroft-Gault formula or measured with 24 hour urine collection)
Who cannot join
- Any component of small cell histology.
- Prior systemic chemotherapy or radiation therapy for urothelial carcinoma or cytotoxic chemotherapy for another malignancy within 1 year of study entry are ineligible. Patients who received immunotherapy for non-muscle invasive bladder cancer will be excluded
- Has a known additional malignancy that has had progression or has required active treatments in the last three years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. A history of prostate cancer that was treated with surgery is acceptable, provided that the following criteria are met: Stage T2N0M0 or lower; PSA undetectable for 1 year while off androgen deprivation therapy. Patients on active surveillance for low grade prostate cancer are allowed to participate.
- Patients who have received experimental agents within 4 weeks of study entry.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to Methotrexate, Vinblastine, Doxorubicin or Cisplatin or other agents used in the study
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (defined by current oral or intravenous antibiotic therapy), symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
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- Pregnant women are excluded from this study due to the potential for teratogenic or abortifacient effects of cytotoxic chemotherapy.
- Known HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with cytotoxic chemotherapy. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy.
- Patients with hydronephrosis that has not been addressed with a documented assessment (i.e. normal GFR, no intervention necessary) or an intervention such as placement of a stent or nephrostomy tube.
- Any condition requiring systemic treatment with corticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days prior to first dose of study drug. Inhaled or topical steroids and adrenal replacement steroid doses > 10 mg daily prednisone or equivalent are permitted in the absence of active autoimmune disease. Use of steroids as pre-medication for contrast allergy prior to CT scans is permitted. It is acceptable to use steroids as pre-medication for AMVAC.
- 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 antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.
- Prior treatment with CD137 agonists, anti-programmed death-1 (PD-1), or anti-PD-L1 therapeutic antibody or pathway-targeting agents.
- Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin [IL]-2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to enrolment.
Trial locations and contacts
4 sites in 1 country.
United States4 sites
UNC Lineberger Comprehensive Cancer Center
Chapel Hill, North Carolina, 27599
UT Southwestern Medical Center
Dallas, Texas, 75390
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania, 19107
Fox Chase Cancer Center - Philadelphia
Philadelphia, Pennsylvania, 19111-2497
About this study
Official title: A Phase II Trial of Risk Enabled Therapy After Neoadjuvant Immunochemotherapy for Bladder Cancer
Neoadjuvant accelerated methotrexate/vinblastine/adriamycin/cisplatin (AMVAC) in combination with nivolumab is under evaluation for the treatment of muscle invasive bladder cancer (MIBC). Patients with pre-specified tumor mutations and complete clinical response with neoadjuvant therapy will preserve their bladders and go on active surveillance.
Read the detailed description
Muscle invasive bladder cancer (MIBC) constitutes 20-25% of all cases with 5 year survival estimated at 45% regardless of treatment.1-4 Although neoadjuvant cisplatin-based chemotherapy (NAC) followed by a radical cystectomy or cystoprostatectomy with a lymph node dissection is the preferred treatment choice for MIBC in the United States, there are several drawbacks and challenges with this approach. Patients must be fit to undergo a surgical intervention. Grade 2 through 5 complications have been documented in 53% of patients undergoing cystectomy at a tertiary care center, and the surgical mortality rate is 1.5%.5, 6 Furthermore, urinary diversion commonly requires an ileal conduit and an external appliance, impacting patient's quality of life.
By incorporating neoadjuvant nivolumab with AMVAC, our goal in RETAIN-2 is to increase the number of patients who would be eligible for bladder preservation while maintaining the long-term oncologic outcomes. Nivolumab, an anti-PD1 therapy, is FDA approved for treatment of metastatic urothelial carcinoma post platinum-based chemotherapy.20 Recently, neoadjuvant pembrolizumab (anti-PD1) and atezolizumab (anti-PDL1) was tested in MIBC in the PURE-01 and ABACUS studies, and a pT0 rate of 38.6% and 29%, respectively, was achieved.21, 22 Additionally, recent work by Kim et al. presented at AACR 2019 demonstrated that AMVAC induces gene signatures in luminal tumors and may have a synergistic response with immunotherapy. Given the impressive activity of both AMVAC and nivolumab in the neoadjuvant setting, in this study the investigators hypothesize that using the combination of neoadjuvant nivolumab and AMVAC will lead to higher cT0 rate and metastasis-free survival at 2 years. At the same time by using the risk adapted strategy, a select group of patients will be able to preserve their bladders and significantly improve their quality-of-life.
- Conditions
- Muscle-Invasive Bladder Carcinoma
- Being tested
- AMVAC + Nivolumab
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AMVAC + NivolumabDrug
Nivolumab 240mg will be administered intravenously for 3 doses - on days 1, 15 and 29. AMVAC will be dosed intravenously every 2 weeks for 3 doses on days 1, 15 and 29 with Neulasta or equivalent. Standard AMVAC dose is as follows: methotrexate 30mg/m2, vinblastine 3mg/m2, doxorubicin 30mg/m2, and cisplatin 70mg/m2.
| Study group | Role | What they receive |
|---|---|---|
| AMVAC + nivolumab | Experimental | This will be a single-arm, open-label, multicenter phase 2 study of neoadjuvant nivolumab with AMVAC. Approximately 70 evaluable patients will be enrolled into this study. Eligible patients will be those with diagnosis of muscle invasive urothelial carcinoma of the bladder who are cT2 or cT3 but not clinical N1 at diagnosis. Clinical stage is confirmed by transurethral resection of bladder tumor (TURBT#1). Receives: Drug: AMVAC + Nivolumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Incidence of Metastasis-free survival (MFS)
MFS is defined as a recurrence of urothelial carcinoma that is >cN1 (more than one clinically suspicious pelvic lymph node) or surgically unresectable local recurrence (e.g., >cT4a) or M1 disease.
Measured: 2 years
Secondary outcomes (3)
Number of days of Overall survival
Overall Survival (OS) will be defined as the number of days from study entry to death. Individuals who are alive at last contact will be censored on the date of last contact.
Measured: up to 5 years
Number of days of Progression free survival
Progression Free Survival (PFS) for this study will be defined as the number of days from study entry to date of first evidence of tumor progression (presence of muscle invasive disease, nodal or distant recurrence) or until death from any cause, whichever comes first. Individuals that are alive and remain free of muscle invasive disease, nodal recurrence and distant disease recurrence will be censored on the date of last clinical visit.
Measured: up to 5 years
Number of patients erporting Toxicity of neoadjuvant nivolumab and AMVAC therapy
Toxicity, AEs, SAEs for all patients that are associated with nivolumab or AMVAC will be collected/reported at each cycle and until 100 days after lastnivolumab/AMVAC.
Toxicity, AEs, SAEs for the CRT arm specifically will be collected/reported as follows. Grade 1-5 toxicity at C1 (start of nivolumab/AMVAC), C2 (second cycle ofnivolumab/AMVAC), C3 (third cycle of nivolumab/AMVAC), start of chemoradiation, 1/2 completion chemoradiation, completion of chemoradiation, and up to 30 days after completion of chemoradiation.
Measured: until 100 days after the last nivolumab/AMVAC
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Aug 2020
- Study start1 Dec 2020
- Primary completionMay 2027 (estimated)
- Study completionNov 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Muscle-Invasive Bladder CarcinomaStudies of the same condition, open and under way.
- 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
- Masking
- None (open label)
- Enrolment
- 81 participants (actual)
Sponsor and investigators
- Lead sponsor
- Fox Chase Cancer Center
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Pooja Ghatalia, MD, Principal investigator, Fox Chase Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04506554
- Sponsor's protocol ID
- GU-176
- Other IDs
- 20-1047
- Status last verified
- Sep 2026
- First submitted
- 30 Jul 2020
- Last updated
- 21 Sep 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 21 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase II Trial of Risk Enabled Therapy After Neoadjuvant Immunochemotherapy for Bladder Cancer
- ClinicalTrials.gov ID
- NCT04506554
- Acronym / sponsor ID
- GU-176
- Conditions
- Muscle-Invasive Bladder Carcinoma
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 81 participants (actual)
- Lead sponsor
- Fox Chase Cancer CenterUniversity, hospital or other
- Study start
- 1 Dec 2020 (actual)
- Primary completion
- May 2027 (estimated)
- Study completion
- Nov 2028 (estimated)
- First posted
- 10 Aug 2020 (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.
Neoadjuvant accelerated methotrexate/vinblastine/adriamycin/cisplatin (AMVAC) in combination with nivolumab is under evaluation for the treatment of muscle invasive bladder cancer (MIBC). Patients with pre-specified tumor mutations and complete clinical response with neoadjuvant therapy will preserve their bladders and go on active surveillance.
Detailed description
Muscle invasive bladder cancer (MIBC) constitutes 20-25% of all cases with 5 year survival estimated at 45% regardless of treatment.1-4 Although neoadjuvant cisplatin-based chemotherapy (NAC) followed by a radical cystectomy or cystoprostatectomy with a lymph node dissection is the preferred treatment choice for MIBC in the United States, there are several drawbacks and challenges with this approach. Patients must be fit to undergo a surgical intervention. Grade 2 through 5 complications have been documented in 53% of patients undergoing cystectomy at a tertiary care center, and the surgical mortality rate is 1.5%.5, 6 Furthermore, urinary diversion commonly requires an ileal conduit and an external appliance, impacting patient's quality of life.
By incorporating neoadjuvant nivolumab with AMVAC, our goal in RETAIN-2 is to increase the number of patients who would be eligible for bladder preservation while maintaining the long-term oncologic outcomes. Nivolumab, an anti-PD1 therapy, is FDA approved for treatment of metastatic urothelial carcinoma post platinum-based chemotherapy.20 Recently, neoadjuvant pembrolizumab (anti-PD1) and atezolizumab (anti-PDL1) was tested in MIBC in the PURE-01 and ABACUS studies, and a pT0 rate of 38.6% and 29%, respectively, was achieved.21, 22 Additionally, recent work by Kim et al. presented at AACR 2019 demonstrated that AMVAC induces gene signatures in luminal tumors and may have a synergistic response with immunotherapy. Given the impressive activity of both AMVAC and nivolumab in the neoadjuvant setting, in this study the investigators hypothesize that using the combination of neoadjuvant nivolumab and AMVAC will lead to higher cT0 rate and metastasis-free survival at 2 years. At the same time by using the risk adapted strategy, a select group of patients will be able to preserve their bladders and significantly improve their quality-of-life.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| AMVAC + nivolumab | Experimental | Drug: AMVAC + NivolumabThis will be a single-arm, open-label, multicenter phase 2 study of neoadjuvant nivolumab with AMVAC. Approximately 70 evaluable patients will be enrolled into this study. Eligible patients will be those with diagnosis of muscle invasive urothelial carcinoma of the bladder who are cT2 or cT3 but not clinical N1 at diagnosis. Clinical stage is confirmed by transurethral resection of bladder tumor (TURBT#1). |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- Male or female patients ≥18 years
- Primary urothelial or predominantly urothelial carcinoma of the bladder confirmed from pathology report. Patients with some component of variant histology mixed with predominant urothelial carcinoma will be allowed. Upper tract urothelial carcinoma patients are not allowed.
- Urothelial carcinoma of the prostatic urethra in men is allowed
- Histologic evidence of muscularis propria invasion.
- AJCC23 clinical stage T2-T3 N0M0.
Key exclusion criteria (13 listed)
- Any component of small cell histology.
- Prior systemic chemotherapy or radiation therapy for urothelial carcinoma or cytotoxic chemotherapy for another malignancy within 1 year of study entry are ineligible. Patients who received immunotherapy for non-muscle invasive bladder cancer will be excluded
- Has a known additional malignancy that has had progression or has required active treatments in the last three years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. A history of prostate cancer that was treated with surgery is acceptable, provided that the following criteria are met: Stage T2N0M0 or lower; PSA undetectable for 1 year while off androgen deprivation therapy. Patients on active surveillance for low grade prostate cancer are allowed to participate.
- Patients who have received experimental agents within 4 weeks of study entry.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to Methotrexate, Vinblastine, Doxorubicin or Cisplatin or other agents used in the study
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 |
|---|---|---|
| AMVAC + NivolumabNivolumab 240mg will be administered intravenously for 3 doses - on days 1, 15 and 29. AMVAC will be dosed intravenously every 2 weeks for 3 doses on days 1, 15 and 29 with Neulasta or equivalent. Standard AMVAC dose is as follows: methotrexate 30mg/m2, vinblastine 3mg/m2, doxorubicin 30mg/m2, and cisplatin 70mg/m2. | Drug | AMVAC + nivolumab |
Primary outcome
Incidence of Metastasis-free survival (MFS)
Time frame: 2 years
MFS is defined as a recurrence of urothelial carcinoma that is >cN1 (more than one clinically suspicious pelvic lymph node) or surgically unresectable local recurrence (e.g., >cT4a) or M1 disease.
3 secondary outcomes
Number of days of Overall survival
Time frame: up to 5 years
Number of days of Progression free survival
Time frame: up to 5 years
Number of patients erporting Toxicity of neoadjuvant nivolumab and AMVAC therapy
Time frame: until 100 days after the last nivolumab/AMVAC
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Sep 2026.
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Trial of Nadofaragene Firadenovec vs. Observation in Participants With Intermediate Risk Non-Muscle Invasive Bladder Cancer
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Combining Immunotherapy and Radiation Therapy to Help Patients Avoid Bladder Removal After Treatment Shrinks Muscle Invasive Bladder Cancer, BRIGHT Trial
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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.
Pooja Ghatalia, MD principal investigator
Fox Chase Cancer Center
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing AMVAC + Nivolumab in people with Muscle-Invasive Bladder Carcinoma, run by Fox Chase Cancer Center at 4 sites in United States.
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 11 inclusion and 13 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: under way, not looking for participants, as of the sponsor's last update on 21 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in United States. 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?
This study is still under way. Results are not available in the source record yet.
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?
Incidence of Metastasis-free survival (MFS) (time frame: 2 years). 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 21 Sep 2026.