Primary Objective:
• To estimate the difference in pathologic complete response rate as defined as no evidence of disease (ypT0N0) or carcinoma in situ within the bladder only (ypTcisN0) in patients after administration of the combination of dose-dense MVAC and durvalumab versus dose-dense MVAC alone.
Secondary Objectives:
* To estimate the difference in the rate of patients eligible for surgical consolidation within 90 days of completion of pre-surgical treatment.
* To estimate the difference in the proportion of patients with relapse free survival at 12 and 36 months following surgery in each treatment arm.
* To estimate the difference in overall survival for both arms on study.
* To measure lymph node response with those with measurable disease via RECIST v1.1 criteria at baseline, week 6, and week 12 on study.
* To evaluate the toxicity of the combination of dose-dense MVAC chemotherapy and durvalumab.
Correlative Objectives:
• Exploratory biomarkers to study the correlation between immunological and molecular changes in tumor tissues and peripheral blood with pathologic complete response, time until relapse and rate of adverse events, with a specific emphasis upon comparison of tissue samples in patients exposed to combination dose-dense MVAC and durvalumab versus dose-dense MVAC alone
Inclusion Criteria:
- Patients must have histological diagnosis of urothelial carcinoma of the bladder and
must meet criteria for stage cTanyN1-3M0 disease via AJCC 8th edition staging
criteria30
- Patients must provide tissue by agreeing to transurethethral biopsy of the bladder and
the lymph node prior to initiating treatment. If patient is unable or unwilling to
undergo biopsy at screening and tissue is available, patient may be eligibile per PI
discretion.
- Patients must be ≥18 years of age.
- Patients must have pelvic lymph node amenable for biopsy as assessed by treating MD
and interventional radiologist.
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
- Patients must have a life expectancy of at least 12 weeks.
- Patients must have body weight >30 kg.
- Left ventricular ejection fraction ≥ 50%.
- Adequate organ function as defined below:
- Hematological i. Absolute neutrophil count (ANC) ≥ 1,500/mcL. ii. Platelets
≥100,000 / mcL. iii. Hemoglobin ≥9 g/dL
- Renal iv. Creatinine clearance > 50 ml/min as calculated by the Cockgroft Gault
formula as:
1. CLCR = {[(140-age) × weight)]/(72 x SCR) × 0.85 (if female), where CLCR
(creatinine clearance) is measured in mL/min, age is expressed in years, weight
in kilograms (kg), and SCR (serum creatinine) in mg/dL.
- Hepatic v. Serum total bilirubin ≤1.5xULN OR Direct bilirubin ≤ULN for subjects
with total bilirubin levels >1.5xULN. vi. AST and ALT ≤2.5xULN OR ≤5xULN for
subjects with liver metastases.
- Coagulation vii. International Normalized Ratio (INR) or Prothrombin Time (PT)
≤1.5xULN unless subject is receiving anticoagulant therapy as long as PT or PTT
is within therapeutic range of intended use of anticoagulants. viii. Activated
Partial Thromboplastin Time (aPTT) ≤1.5xULN unless subject is receiving
anticoagulant therapy as long as PT or PTT is within therapeutic range of
intended use of anticoagulants.
- Women of child-bearing potential MUST have a negative serum or urine HCG test unless
prior tubal ligation (>/= 1 year before screening), total hysterectomy or menopause
(defined as 12 consecutive months of amenorrhea). Patients should not become pregnant
or breastfeed while on this study. Sexually active patients must agree to use dual
contraception for the duration of study participation and for 90 days after receipt of
last drug on active treatment.
- Ability to understand and willingness to sign informed consent from prior to
initiation of the study and any study procedures.
- Willing and able to comply with scheduled visits, treatment plan, laboratory tests,
and other study procedures.
Exclusion Criteria:
- Has metastatic disease to lymph nodes outside of the pelvis or to visceral sites as
seen on imaging.
- CTCAE v5.0 Grade ≥ 2 neuropathy.
- CTCAE v5.0 Grade ≥ 2 hearing loss.
- New York Heart Association (NYHA) Class III or IV heart failure defined as:
- Class III heart failure is defined as: patients with cardiac disease resulting in
marked limitation of physical activity and/or less than ordinary activity causes
fatigue. Patients are comfortable only at rest.
- Unable to carry on any physical activity without discomfort. Symptoms of heart
failure at rest. If any physical activity is undertaken, discomfort increases
- Known active Hepatitis B, Hepatitis C infection (HCV-DNA positive), or HIV infection.
- Current or prior use of immunosuppressive medication within 28 days before the first
dose of study drug, with the exceptions of intranasal and inhaled corticosteroids or
systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of
prednisone, or an equivalent corticosteroid. Systemic steroid administration required
to manage toxicities arising from chemotherapy and/or immunotherapy delivered as part
of the therapy on trial is allowed.
- Prior exposure to any anti-PD-1 or anti-PD-L1 (including durvalumab) antibody.
- Active or prior documented autoimmune disease within the past 2 years. NOTE: Patients
with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within
the past 2 years) are not excluded.
- History of primary immunodeficiency.
- History of allogeneic organ transplant.
- Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note:
Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30
days after the last dose of IP.
- Active infection requiring intravenous (IV) antibiotics or other uncontrolled
intercurrent illness requiring hospitalization. Minor infections, e.g. periodontal
infection or urinary tract infection (UTI), which may be treated with short-term oral
antibiotics are allowed.
- Active infection of tuberculosis, as determined by clinical signs and symptoms.
- Inability to comply with the study and follow-up procedures.
- History of CVA, myocardial infarction or unstable angina within the previous 6 months
before starting therapy.
- Uncontrolled intercurrent illness, including but not limited to, ongoing or active
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 requirement, substantially increase
risk of incurring AEs or compromise the ability of the patient to give written
informed consent.
- Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin, organ confined adenocarcinoma of the
prostate, squamous cell carcinoma of the skin that has undergone potentially curative
therapy or in situ cervical cancer. Patients may not have received systemic cytotoxic
chemotherapy within 1 year of study entry.
- History of exposure to immunotherapy for previous malignancy.
- Intra-vesicular therapy within 4 weeks of study entry or those who have not recovered
from adverse effects of such agents administered more than 4 weeks earlier.
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to methotrexate, vinblastine, doxorubicin, cisplatin, durvalumab, or any
other agents used in the study.
- Pregnant female patients; breastfeeding female patients; and female or male patients
of childbearing potential who are unwilling or unable to use 2 methods of
contraception for at least 90 days after the last dose of study drugs. Highly
effective methods of contraception are those that alone or in combination, result in a
failure rate of less than 1% per year when used consistently and correctly. These
methods include:
- Established use of oral, inserted, or injected or implanted hormonal methods of
contraception are allowed provided the patient remains on the same treatment
throughout the entire study and has been using that hormonal contraceptive for an
adequate period of time to ensure effectiveness.
- Correctly placed copper containing intrauterine device (IUD).
- Male condom or female condom used with spermicide (i.e. foam, gel, film, cream or
suppository).
- Male sterilization with appropriately confirmed absence of sperm in the post vasectomy
ejaculate.
- Bilateral tubal ligation or bilateral oophorectomy