PRIMARY OBJECTIVES:
I. To assess the safety and tolerability of durvalumab in combination with chemotherapy in
subjects with variant histology bladder cancer.
SECONDARY OBJECTIVES:
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) (cell free DNA) at
baseline, during treatment and following post treatment cystectomy using Natera sequencing
platform.
OUTLINE: Patients are assigned to 1 of 3 cohorts.
COHORT I: Patients receive durvalumab intravenously (IV) over 60 minutes on day 1.
Chemotherapeutic agents will be administered as an IV infusion according to prescribing
information or treatment guidance in general use by the Investigating site. Methotrexate on
day 1, vinblastine IV on day 2, doxorubicin IV on day 2, and cisplatin IV 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. Chemotherapeutic agents
will be administered as an IV infusion according to prescribing information or treatment
guidance in general use by the Investigating site. Cisplatin IV over 60 minutes on day 1, and
gemcitabine IV 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.Chemotherapeutic agents
will be administered as an IV infusion according to prescribing information or treatment
guidance in general use by the Investigating site. Carboplatin IV on day 1, and gemcitabine
IV 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.
Inclusion Criteria:
- 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 X 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 (CG), 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.
- Clinical T stage 2 (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 30 days prior to
registration.
- 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 registration.
- Resting 12 lead electrocardiogram (ECG) documenting Fridericia's correction formula
(QTcF) =< 470 ms.
- Consent to 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).
Exclusion Criteria:
- Prior treatment with systemic cytotoxic chemotherapy for muscle invasive bladder
cancer (MIBC).
- Class III or IV heart failure, according to New York Heart Association
Classifications. For patient on the dd MVAC or Cis-Gem arm, left ventricular ejection
fraction of less than 50%
- Administration of an investigational therapeutic agent within 28 days of protocol
registration.
- Current participation in a trial using an investigational agent. Subjects may
participate in non-interventional, observational studies.
- Prior treatment with an anti-programmed cell death 1(PD1) or anti--programmed cell
death ligand 1(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 (known positive hepatitis B virus (HBV) surface antigen (HBsAg)
result)
- Hepatitis C
- Human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies).
- 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. Subjects
positive for hepatitis C (HCV) antibody are eligible only if polymerase chain
reaction is negative for HCV ribonucleic acid (RNA).
- 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
monotherapy.
- 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.
