Durvalumab and Standard Chemotherapy for the Treatment of Lymph Node Positive Bladder Cancer
This phase II trial tests whether durvalumab works with standard chemotherapy (MVAC regimen) in treating patients with bladder cancer that has spread to nearby lymph nodes. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. The standard chemotherapy regimen, MVAC, consists of the following drugs: methotrexate vinblastine sulfate, doxorubicin hydrochloride (Adriamycin), and cisplatin. These drugs work in different ways to stop the growth of tumor cells, either by killing the cells, stopping them from dividing, or by stopping them from spreading. Adding durvalumab to the standard MVAC regimen may help to control bladder cancer when given before surgery.
Inclusion Criteria
- Patients must have histological diagnosis of urothelial carcinoma of the bladder and must meet criteria for stage cTanyN1-3M0 disease via American Joint Committee on Cancer (AJCC) 8th edition staging criteria
- Patients must provide tissue by agreeing to transurethral 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 documenting lymph node positivity, patient may be eligible per principal investigator (PI) discretion
- Patients must be >= 18 years of age
- Patients must have pelvic lymph node biopsy histologic confirmation
- 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 > 30kg
- Left ventricular ejection fraction >= 50%
- Absolute neutrophil count (ANC) >= 1,500/mcL
- Platelets >= 100,000 / mcL
- Hemoglobin >=9 g/dL
- Creatinine clearance > 50 ml/min as calculated by the Cockcroft Gault formula
- Serum total bilirubin =< 1.5x upper limit of normal (ULN) OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 x ULN
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN OR =< 5 x ULN for subjects with liver metastases
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
- Activated partial thromboplastin time (aPTT) =< 1.5 x ULN 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 human chorionic gonadotropin (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
- Common Terminology Criteria for Adverse Events (CTCAE) v5.0 grade >= 2 neuropathy
- CTCAE v5.0 grade >= 2 hearing loss. For patients with grade 3 or higher hearing loss they are allowed to participate if counseled and documented that chemotherapy may provide permanent hearing loss and they wish to proceed despite the risk
- 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 (hepatitis C virus deoxyribonucleic acid [HCV-DNA] positive), or human immunodeficiency virus (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 investigational product (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 cerebrovascular accident (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 adverse events (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
Additional locations may be listed on ClinicalTrials.gov for NCT05137262.
See trial information on ClinicalTrials.gov for a list of participating sites.
PRIMARY OBJECTIVE:
I. To estimate the difference in pathologic complete response rate as defined as ypT0N0 or ypTcisN0 in patients after administration of the combination of dose-dense MVAC and durvalumab versus dose-dense MVAC alone.
SECONDARY OBJECTIVES:
I. To compare the rates of patients eligible for surgical consolidation within 90 days of completion of pre-surgical treatment.
II. To estimate the difference in
III. To compare the proportions of patients with relapse free survival at 12 and 36 months following surgery in each treatment arm.
IV. To compare overall survival for both arms on study.
V. To measure lymph node response with those with measurable disease via Response Evaluation Criteria for Adverse Events (RECIST) version (v)1.1 at baseline, week 6, and week 12 on study.
VI. To evaluate the toxicity of the combination of dose-dense MVAC chemotherapy and durvalumab.
CORRELATIVE OBJECTIVES:
I. 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.
II. To explore lymph node response of non-measurable regional lymph nodes at baseline, week 6, and week 12 on study.
OUTLINE: Patients are randomized into 1 of 2 arms.
ARM A: Patients receive MVAC regimen consisting of methotrexate intravenously (IV) on day 1, vinblastine IV on day 1, doxorubicin IV on day 1, and cisplatin IV on day 1 or days 1 and 2 of each cycle. Treatment repeats every 14 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients who complete 3 cycles of treatment with stable disease or disease response may undergo surgery at the surgeon’s discretion.
ARM B: Patients receive MVAC regimen consisting of methotrexate IV on day 1, vinblastine IV on day 1, doxorubicin IV on day 1, cisplatin IV on day 1 or days 1 or 2 of each cycle. Patients also receive durvalumab IV 7 to 10 days prior to start of MVAC for cycle 1 only, and on day 1 or 2 for cycles thereafter. Treatment repeats every 14 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients who complete 3 cycles of treatment with stable disease or disease response may undergo surgery at the surgeon’s discretion. Patients then receive durvalumab IV every 4 weeks for up to 1 year in the absence of disease progression or unacceptable toxicity.
Patients in both arms also undergo multigated acquisition (MUGA) scan or echocardiography (ECHO) during screening and as clinically indicated throughout the trial. Patients undergo biopsy during screening and may undergo at time of progression on trial. Patients also undergo computed tomography (CT) and/or magnetic resonance imaging (MRI), as well as blood, urine, and stool sample collection throughout the trial.
After completion of study treatment, patients are followed every 3 months for up to 3 years following surgery.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationM D Anderson Cancer Center
Principal InvestigatorMatthew T. Campbell
- Primary ID2020-1091
- Secondary IDsNCI-2021-12884
- ClinicalTrials.gov IDNCT05137262