Durvalumab with or without Tremelimumab in Treating Patients with Localized or Locally Advanced Kidney Cancer before Surgery
This phase Ib trial studies the side effects of durvalumab when given together with tremelimumab in treating patients with kidney cancer that is restricted to the site of origin, without evidence of spreading or has spread from where it started to nearby tissue or lymph nodes before surgery. Immunotherapy with monoclonal antibodies, such as durvalumab and tremelimumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread
- Radiographic evidence of renal cell carcinoma (any histologic subtype) without evidence of distant metastatic disease
- Patients must have clinical stage T2b-4 and/or N1, M0 disease
- Written informed consent and any locally-required authorization (e.g., Health Insurance Portability and Accountability Act [HIPAA]) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Hemoglobin >= 8.0 g/dL
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (>= 1500 per mm^3)
- Platelet count >= 100 x 10^9/L (>= 100,000 per mm^3)
- Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN); this will not apply to subjects 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 the study sponsor
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
- Glomerular filtration rate > 40 ml/min/1.73m^2 as estimated by the Cockcroft-Gault formula or creatinine clearance > 50 ml/min as determined by 24-hour urine collection
- Female subjects must either be of non-reproductive potential (i.e., post-menopausal by history: >= 60 years old and no menses for >= 1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry
- Subject 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
- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site); previous enrollment in the present study
- Participation in another clinical study with an investigational product during the last 30 days
- Prior systemic anti-cancer therapy of any kind for RCC, including but not limited to any approved agent or any previous treatment with a PD1 or PD-L1 inhibitor including durvalumab; no previous treatment with immunotherapy for any malignancy including cytokine, anti-tumor vaccine, T-cell activator, co-stimulator or immune checkpoint inhibitor
- Definitive evidence of metastatic renal cell carcinoma on imaging and/or biopsy; involvement of regional lymph nodes is permitted
- Mean QT interval corrected for heart rate (QTc) >= 470 ms calculated from an electrocardiogram (ECG) using Fridericia’s Correction (QTcF) * At screening, a single ECG will be obtained on which QTcF must be < 470 ms; in case of clinically significant ECG abnormalities, including a QTcF value > 470 ms, 2 additional 12-lead ECGs should be obtained over a brief period (e.g., 30 minutes) to confirm the finding
- Current or prior use of 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
- Active or prior documented autoimmune disease within the past 2 years; NOTE: subjects with vitiligo, Graves’ disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded; patients with autoimmune endocrine disease adequately controlled with hormone replacement therapy are not excluded
- Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis)
- History of primary immunodeficiency
- History of allogeneic organ transplant
- History of hypersensitivity to durvalumab or any excipient
- History of hypersensitivity to tremelimumab or any excipient
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension (defined as > 160/90 mmHg despite medical therapy), unstable angina pectoris (requiring nitrates), cardiac arrhythmia (NOT including controlled atrial fibrillation), active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C (detectable ribonucleic acid [RNA]) or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent
- Known history of previous clinical diagnosis of tuberculosis
- History of leptomeningeal carcinomatosis
- Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab or tremelimumab
- Female subjects who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control * Pregnant or breastfeeding women are excluded from this study; breastfeeding should be discontinued if the mother is treated with either agent
- Subjects with uncontrolled seizures
- Subjects with known HIV, active hepatitis B, or active hepatitis C (detectable RNA); HIV positive subjects on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with durvalumab and/or tremelimumab; in addition, these subjects are at increased risk of lethal infections when treated with immunosuppressive therapy
- Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results
Locations & Contacts
Trial Objectives and Outline
I. To investigate the safety and feasibility of neoadjuvant plus adjuvant dosing of durvalumab +/- tremelimumab in patients with localized renal cell carcinoma (RCC).
I. To assess the immune response to neoadjuvant plus adjuvant dosing of durvalumab +/- tremelimumab in patients with localized RCC as measured density of tumor-infiltrating CD8+ T cells.
II. To assess the antitumor effect of neoadjuvant durvalumab +/- tremelimumab in patients with RCC as measured by change in tumor size.
I. To explore pharmacodynamic and microbiome markers of response to checkpoint inhibition in pre- and post-treatment blood and tissue samples (e.g. infiltration of T cells, regulatory T cells [Treg] and/or myeloid-derived suppressor cell [MDSC]).
II. To understand changes in the immunological milieu mediated by pre-surgical immune checkpoint blockade (e.g. change in T cell repertoire, expression of T cell agonist targets).
OUTLINE: Patients are assigned to 1 of 4 cohorts.
COHORT 1: Patients receive durvalumab intravenously (IV) on day 0, then undergo nephrectomy. Beginning 2-8 weeks after surgery, patients receive durvalumab IV once.
COHORT 2: Patients receive durvalumab IV and tremelimumab IV on day 0, then undergo nephrectomy. Beginning 2-8 weeks after surgery, patients receive durvalumab IV once.
COHORT 2A: Patients receive durvalumab IV and tremelimumab IV on day 0, then undergo nephrectomy. Beginning 2-8 weeks after surgery, patients receive durvalumab IV for up to 1 year.
COHORT 3: Patients receive durvalumab IV and tremelimumab IV on day 0, then undergo nephrectomy. Beginning 2-8 weeks after surgery, patients receive durvalumab and tremelimumab IV once then durvalumab alone for up to 1 year.
After completion of study treatment, patients are followed up periodically.
Trial Phase & Type
Case Comprehensive Cancer Center
Brian I. Rini
Secondary IDs NCI-2017-00016
Clinicaltrials.gov ID NCT02762006