Durvalumab with or without Oleclumab before Surgery in Treating Patients with Bladder Urothelial Carcinoma
This phase I trial studies how well durvalumab with or without oleclumab works in treating patients with bladder urothelial carcinoma when given before standard of care surgery. Immunotherapy with monoclonal antibodies, such as durvalumab and oleclumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.
- Written informed consent and any locally-required authorization (e.g. Health Insurance Portability and Accountability Act [HIPAA]) obtained from the patient prior to performing any protocol-related procedures, including screening evaluations
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Histologically confirmed bladder transitional cell carcinoma (TCC) * Patients with mixed histology are required to have a component of TCC, and no component of small cell histology
- T2-T4a N0 M0 disease, considered appropriate and planned for radical cystectomy
- Ineligible for cisplatin-based chemotherapy, defined by any of the following: * Creatinine clearance (CL) < 60 mL/min. Glomerular filtration rate (GFR) should be calculated from serum/plasma creatinine using the Cockcroft-gault formula * Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0 grade > 1 hearing loss * CTCAE v5.0 grade > 1 neuropathy * New York Heart Association (NYHA) class > II cardiac dysfunction
- Patients not meeting the above criteria are eligible if she/he declines perioperative cisplatin-based chemotherapy after specific informed consent describing the known benefits of cisplatin-based chemotherapy
- Hemoglobin >= 9.0 g/dL
- Absolute neutrophil count (ANC) >= 1.5 (>= 1500 per mm^3)
- Platelet count >= 100 x 10^9/L
- Albumin >= 2.5 g/dL
- International normalized ratio (INR) or activated partial thromboplastin time (aPTT) =< 1.5 x ULN, unless the patient is receiving anticoagulation therapy provided INR or partial thromboplastin time (PTT) is within the therapeutic range of the intended anticoagulant therapy
- Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN) * This will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
- Measured creatinine clearance (CL) > 30 mL/min or calculated creatinine CL > 30 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance
- Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: * 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)
- Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
- Availability of baseline archival tumor tissue obtained for correlative studies dated within 8 weeks of study registration * Either formalin-fixed paraffin-embedded (FFPE) tumor tissue block or a minimum of fifteen 5 um unstained FFPE slides and fifteen 10 um unstained FFPE slides with an associated pathology report is required * Patients without adequate baseline tumor tissue or have archival tumor tissue > 8 weeks from registration must undergo cystoscopic tumor biopsy, meeting the above tissue criteria
- Patients with primary TCC of the ureter, urethra, or renal pelvis without TCC of the bladder
- Inoperable tumor(s) with fixation to the pelvic wall on clinical exam
- Any previous systemic chemotherapy or radiotherapy for TCC of bladder
- Participation in another clinical study with an investigational product during the last 6 months
- Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
- Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab
- History of another primary malignancy except for: * Malignancy treated with curative intent and with no known active disease >= 5 years before the first dose of study drug and of low potential risk for recurrence * 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)
- Receipt of the last dose of intravesical chemotherapy or biologic therapy =< 42 days (6 weeks) prior to the first dose of study drug for patients who have received prior intravesical chemotherapy or biologic therapy (e.g. Bacillus Calmette-Guerin [BCG])
- Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) >= 470 ms calculated from 3 electrocardiograms (ECGs) (within 15 minutes at 5 minutes apart). Patient safety and the cardiac electrocardiogram (EKG) should be consulted as needed
- Any unresolved toxicity National Cancer Institute (NCI) CTCAE version 5.0 grade >= 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria * Patients with grade >= 2 neuropathy will be evaluated on a case-by-case basis after consultation with the study physician * Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab and/or oleclumab may be included only after consultation with the study physician
- Any concurrent chemotherapy, investigational product (IP), biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g. hormone replacement therapy) is acceptable
- Major surgical procedure (as defined by the investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable
- 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: * Patients with vitiligo or alopecia * Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement * Any chronic skin condition that does not require systemic therapy * Patients without active disease in the last 5 years may be included but only after consultation with the study physician * Patients 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 patient to give written informed consent
- History of leptomeningeal carcinomatosis
- Brain metastases or spinal cord compression. Patients with suspected brain metastases at screening should have an magnetic resonance imaging (MRI) (preferred) or computed tomography (CT) each preferably with IV contrast of the brain prior to study entry
- 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, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA)
- Current or prior use of immunosuppressive medication within 14 days before the first dose of study drug. 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)
- 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
- Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 180 days after the last dose of durvalumab + oleclumab or 90 days after the last dose of durvalumab monotherapy, whichever is the longer time period
- Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
- Prior randomization or treatment in a previous durvalumab and/or oleclumab clinical study regardless of treatment arm assignment
- Judgment by the investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions and requirements
Locations & Contacts
Contact: Guru P. Sonpavde
Contact: Guru P. Sonpavde
Contact: Richard J. Lee
Trial Objectives and Outline
I. To evaluate the feasibility of durvalumab alone and in combination with oleclumab as neoadjuvant therapy preceding radical cystectomy (RC) for patients with muscle-invasive bladder cancer (MIBC) who are ineligible for or decline cisplatin-based perioperative chemotherapy.
I. To determine the rate of pathologic response at the time of RC.
II. To determine the relapse-free survival (RFS) after RC.
III. To determine the progression-free rate pre-RC.
I. To explore the effects of neoadjuvant treatment on the tumor microenvironment.
II. To examine tissue and circulating predictive biomarkers of response and RFS.
OUTLINE: Patients are assigned to 1 of 2 cohorts.
COHORT I: Patients receive durvalumab intravenously (IV) over 60 minutes on day 1. Treatment repeats every 14 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Within 2-4 weeks of treatment completion, patients undergo standard of care radical cystectomy.
COHORT II: Patients receive durvalumab IV over 60 minutes and oleclumab IV over 80-180 minutes on day 1. Treatment repeats every 14 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Within 2-4 weeks of treatment completion, patients undergo standard of care radical cystectomy.
After completion of study treatment, patients are followed up every 12 weeks for 1 year.
Trial Phase & Type
Dana-Farber Harvard Cancer Center
Guru P. Sonpavde
Secondary IDs NCI-2019-01768
Clinicaltrials.gov ID NCT03773666