Durvalumab and Standard Chemotherapy before Surgery in Treating Patients with Variant Histology Bladder Cancer
- Signed informed consent.
- Eastern Collaborative Oncology Group (ECOG) performance status score of 0 or 1.
- Body weight > 30 kg.
- Absolute neutrophil count (ANC) >= 1500 mm^3 (within 28 days before the first study treatment).
- Hemoglobin >= 9.0 g/dL (within 28 days before the first study treatment).
- Platelet count >= 100,000 per mm^3 (within 28 days before the first study treatment).
- Serum bilirubin =< 1.5 x upper limit of normal (ULN) (within 28 days before the first study treatment). Subjects with Gilbert’s syndrome will be considered after consultation with the principal investigator (PI).
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 × ULN (within 28 days before the first study treatment).
- For subjects who will be treated with dose dense methotrexate, vinblastine, doxorubicin, and cisplatin (DD MVAC) or cisplatin and gemcitabine (Cis-Gem), creatinine clearance >= 50 mL/min as measured based on Cockcroft-Gault glomerular filtration rate estimation (within 28 days before the first study treatment).
- For subjects who will be treated with carboplatin and gemcitabine (Carbo Gem), creatinine clearance >= 30 mL/min as measured based on Cockcroft-Gault glomerular filtration rate estimation (within 28 days before the first study treatment).
- Anticipated life expectancy of >= 12 weeks as assessed by the investigator.
- Histologically proven carcinoma of the bladder of variant urothelial carcinoma histologies which include squamous, adenocarcinoma, nested, plasmacytoid, micropapillary, glandular differentiation, lipid cell, clear cell, undifferentiated, giant cell, trophoblastic, sarcomatoid, carcinosarcoma; subjects with mixed cell types are eligible.
- Stage cT2 T4a, N0 N1, M0 disease. Clinical T stage is based on the transurethral resection of bladder tumor (TURBT) sample and imaging studies. Subjects must undergo cystoscopy and TURBT as part of screening within 60 days prior to start of cycle 1 day 1
- Abdominal/pelvic imaging by computed tomography (CT) or magnetic resonance imaging (MRI) scan; chest imaging by CT scan or x-ray (CT/positron emission tomography [PET]) within 30 days prior to start of cycle 1 day 1
- Resting 12 lead electrocardiogram (ECG) documenting Fridericia's correction formula (QTcF) =< 470 ms.
- Must provide a formalin fixed paraffin embedded (FFPE) tissue block and 1 hematoxylin and eosin (H and E) slide (preferred) or one of the following: * 10 unstained slides and 1 H and E slide OR * Tissue block punches and 1 H and E slide, OR * 4 to 6 cores and 1 H and E slide.
- Willing and able to comply with the protocol for the duration of the study including undergoing treatment, scheduled visits and examinations including follow up.
- For female subjects: * Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy). * Women >= 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation induced menopause with last menses > 1 year ago, had chemotherapy induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
- Prior treatment with systemic cytotoxic chemotherapy for muscle invasive bladder cancer (MIBC).
- For carboplatin patients only: Class III or IV heart failure, according to New York Heart Association classifications
- For cisplatin patients only: Left ventricular ejection fraction of less than normal
- Administration of an investigational therapeutic agent within 28 days of protocol start of cycle 1 day 1
- Current participation in a trial using an investigational agent. Subjects may participate in non-interventional, observational studies.
- Prior treatment with an anti-PD1 or anti-PDL1 inhibitor including durvalumab.
- Receiving chronic systemic steroid therapy in dosing exceeding 10 mg daily of prednisone or equivalent per day within 7 days prior to the first dose of study treatment.
- History of another malignancy within 5 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. Subjects with the following are allowed on study: * Adequately treated non melanoma skin cancer or lentigo maligna without evidence of disease * Adequately treated carcinoma in situ without evidence of disease e.g., cervical cancer in situ.
- Immunosuppressive medication within 28 days before the first dose of durvalumab, 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. The following are exceptions to this criterion: * Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection) * Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent * Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) or anti emetic during chemotherapy.
- History of allogenic organ transplantation.
- Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease]), diverticulitis (with the exception of diverticulosis), systemic lupus erythematosus, sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc). The following are exceptions to this criterion: * Subjects with vitiligo or alopecia * Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement * Any chronic skin condition that does not require systemic therapy * Subjects with celiac disease controlled by diet alone.
- 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 subject to give written informed consent.
- History of active primary immunodeficiency.
- Active infection including: * Tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis (TB) testing in line with local practice) * Hepatitis B (positive hepatitis B virus [HBV] surface antigen (HBsAg) result) ** Subjects with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti HBc] and absence of HBsAg) are eligible * Hepatitis C **Subjects positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA) * Human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies)
- Receipt of live attenuated vaccine within 30 days prior to the first dose of study medication. Note: subjects, if enrolled, should not receive live vaccine while receiving study medication and up to 30 days after the last dose of study medication.
- Pregnant or lactating.
- Male or female subject of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab
- Known allergy or hypersensitivity to any of the study medications or any of the study medication excipients.
- Judgment by the investigator that the subject is unsuitable to participate in the study and the subject is unlikely to comply with study procedures, restrictions and requirements.
I. To assess the safety and tolerability of durvalumab in combination with chemotherapy in subjects with variant histology bladder cancer.
I. To determine the percent of subjects post-neoadjuvant chemo-immunotherapy who achieve tumor stage of pT2 N0 M0 or better (pT1 N0 or pT0) at cystectomy.
II. To assess the response rate (RR) in post-neoadjuvant chemo immunotherapy as assessed by the investigator using imaging at screening and post treatment.
III. To assess the molecular characterization of tumor tissue pre-neoadjuvant therapy and at post treatment cystectomy (for subject who have persistent disease).
IV. To determine circulating free deoxyribonucleic acid (DNA) (cfDNA) (alternate term “cell free DNA”) at baseline, during treatment and following post treatment cystectomy using Natera platform.
OUTLINE: Patients are assigned to 1 of 3 cohorts.
COHORT I: Patients receive durvalumab intravenously (IV) over 60 minutes on day 1, methotrexate over 3 minutes on day 1, vinblastine IV over 3 minutes on day 2, doxorubicin IV over 5 minutes on day 2, and cisplatin IV over 60 minutes on day 2. Cycles repeat every 14 days up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo cystectomy within 6 weeks.
COHORT II: Patients receive durvalumab IV over 60 minutes on day 1, cisplatin IV over 60 minutes on day 1, and gemcitabine IV over 60 minutes on days 1 and 8. Cycles repeat every 21 days up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo cystectomy within 6 weeks.
COHORT III: Patients receive durvalumab IV over 60 minutes on day 1, carboplatin IV over 60 minutes on day 1, and gemcitabine IV over 60 minutes on days 1 and 8. Cycles repeat every 21 days up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo cystectomy within 6 weeks.
After surgery, patients are followed up at 30 and 90 days.
Trial Phase Phase II
Trial Type Treatment
Stanford Cancer Institute Palo Alto
- Primary ID BLDR0028
- Secondary IDs NCI-2019-01364
- Clinicaltrials.gov ID NCT03912818