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BRIEF TITLE: Risk Enabled Therapy After Neoadjuvant Immunochemotherapy for Bladder Cancer

A Phase II Trial of Risk Enabled Therapy After Neoadjuvant Immunochemotherapy for Bladder Cancer

  • Org Study ID: GU-176
  • Secondary ID: 20-1047
  • NCT ID: NCT04506554
  • NCT Alias:
  • Sponsor: Fox Chase Cancer Center - Other
  • Source: Fox Chase Cancer Center

Brief Summary

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.

Overal Status Start Date Phase Study Type
Recruiting December 1, 2020 Phase 2 Interventional

Primary Outcomes:

Primary Outcome 1 - Measure: Incidence of Metastasis-free survival (MFS)

Primary Outcome 1 - Time Frame: 2 years


  • Muscle-Invasive Bladder Carcinoma


Inclusion Criteria:

- 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

- No metastatic disease (M0).

- ECOG performance status 0, or 1.

- Left ventricular ejection fraction ≥ 50% by MUGA or ECHO within 6 months of study

- 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)

Exclusion Criteria:

- 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

- 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.

- 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

- 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.
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Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

Official Information

Name: Pooja Ghatalia, MD

Role: Principal Investigator

Affiliation: Fox Chase Cancer Center

Overall Contact

Name: Pooja Ghatalia, MD

Phone: 215-728-3889



Facility Status Contact
Fox Chase Cancer Center - Philadelphia
Philadelphia, Pennsylvania 19111-2497
United States
Recruiting Pooja Ghatalia, MD