clear-cell renal cell carcinoma (ccRCC) kidney cancer
Conditions
Interventions
Sponsors
MedImmune, LLC, a wholly-owned subsidiary of AstraZeneca PLC
Eligibility
Age
18 Years to 64 Years
Inclusion criteria
Inclusion criteria: 1. Age * 18 years at the time of screening. 2. ECOG performance status of 0 - 1. 3. N/A for NLD as only dose expansion 4. For dose-expansion: a. Histological confirmation of advanced or metastatic RCC with a clear-cell component b. Must have received at least 1 and no more than 2 prior anti-angiogenic therapy regimens (including, but not limited to, sunitinib, sorafenib, pazopanib, axitinib, tivozanib, and bevacizumab), in the advanced or metastatic setting. c.Must have received no more than 3 total prior systemic treatment regimens in the advanced or metastatic setting, and must have evidence of radiographic progression on or after the last treatment regimen received and within 6 months prior to study enrollment. d. No prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways e. No prior treatment with an mammalian target of rapamycin (mTOR) inhibitor (including, but not limited to everolimus, temsirolimus, sirolimus, and ridaforolimus) f. Prior cytokine therapy (eg, IL-2, IFN-*) or treatment with cytotoxics is allowed. g. Subjects must have at least 1 measurable lesion according to RECIST v1.1. A previously irradiated lesion cannot be considered a target lesion. Radiographic disease assessment can be performed up to 28 days prior to the first dose.;5.Biopsy requirements: a. N/A for NLD as only dose-expansion b. Able and willing to give valid written consent for fresh tumor samples if required. Fresh tumor biopsies should be preferentially obtained from tumor tissues that are safely accessible as determined by the investigator and achieved via non-significant risk procedures (refer to Section 4.3.2.1). c.. For dose-expansion: i. Tumor tissue (formalin fixed paraffin embedded [FFPE] archival or fresh tumor tissue) must be received by the central vendor (block or unstained slides) and evaluable for PD-L1 expression status in order to randomize a subject to study treatment. ii. All subjects are encouraged to consent to and provide both pre-treatment and on- treatment fresh tumor biopsies;however, on-treatment biopsies are optional.;6. For dose-escalation and dose-expansion: (If evaluations performed as part of standard of care for other purposes prior to obtaining informed consent are suitable for screening and occurred within 7 days prior to starting treatment, those evaluations do not need to be repeated if the subject consents to their use): a. Adequate organ and marrow function, as defined below: i. Hemoglobin * 9 g/dL ii. Absolute neutrophil count * 1,500/mm3 iii. Platelet count * 100,000/mm3 iv. Total bilirubin * 1.5 × ULN except subjects with documented Gilbert*s syndrome (> 3 × ULN) or liver metastasis, who must have a baseline total bilirubin * 3.0 mg/dL v. Alanine aminotransferase (ALT) and AST * 2.5 × ULN; for subjects with hepatic metastases, ALT and AST * 5 × ULN vi. Calculated creatine clearance or 24-hour urine creatine clearance * 40mL/min determined by the Cockroft-Gault formula (using actual body weight);7. Written informed consent and any locally required authorization obtained from the subject/legal representative prior to performing any protocol-related procedures, including screening evaluations.;8. Female subjects of childbearing potential who are sexually active with a
Exclusion criteria
Exclusion criteria: 1. Concurrent enrollment in another clinical study, unless in a follow-up period or it is an observational study 2. Central Nervous system (CNS) metastatic disease and leptomeningeal disease are exclused. (NOTE: spinal cord compression which has been stabilized is allowed). 3. Any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormones for non-cancer-related conditions (eg, insulin for diabetes and hormone replacement therapy) is acceptable (NOTE: Local treatment of isolated lesions for palliative intent is acceptable [eg, by local surgery or radiotherapy]) 4. Any investigational anticancer therapy received within 28 days prior to the first dose of durvalumab and MEDI0680 or nivolumab. 5. Major surgical procedure (as defined by the investigator) within 28 days prior to the first dose of durvalumab and MEDI0680 or nivolumab or still recovering from prior surgery. 6. Unresolved toxicities from prior anticancer therapy, defined as having not resolved to NCI CTCAE v4.03 Grade 0 or 1 with the exception of alopecia and laboratory values listed per the inclusion criteria. Subjects with prior endocrine toxicities (eg, hypothyroidism) who are stable on replacement therapy are not excluded. Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by durvalumab and MEDI0680 or nivolumab may be included (eg, hearing loss). 7. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab and MEDI0680 or nivolumab with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent 8. Active or prior documented autoimmune or inflammatory disease (including inflammatory bowel disease, diverticulitis with the exception of diverticulosis, celiac disease, irritable bowel disease; Wegener*s granulomatosis; Hashimoto syndrome) within the past 3 years. Subjects with vitiligo, alopecia, Grave*s disease, or psoriasis not requiring systemic treatment (within the past 3 years) are not excluded. 9. History of primary immunodeficiency or tuberculosis 10. Test results indicating active infection with human immunodeficiency virus (HIV), or hepatitis A, B, or C 11. Receipt of live, attenuated vaccine within 28 days prior to the first dose of durvlumab and MEDI0680 or nivolumab. NOTE: Subjects, if enrolled, should not receive live vaccine during the study and 90 days after the last dose of durvalumab and MEDI0680 or nivolumab. 12. Females who are pregnant, lactating, or intend to become pregnant during the participation to the study 13. Uncontrolled inter-current illness including, but not limited to, ongoing or active infection, current pneumonitis, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, or psychiatric illness/social situations that would limit compliance with study requirement substantially increase risk of incurring AEs from durvalumab or MEDI0680 or nivolumab, or compromise the ability of the subject to give written informed consent 14. Diagnosis of a second malignancy within the last 2 years prior to Cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death, treated with expected curative outcome (such as adequately treated carcinoma in sit
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary objectives endpoints: Dose-expansion: The primary endpoint is objective response (OR) of MEDI0680 in combination with durvalumab versus nivolumab monotherapy. Secondary endpoints include best overall response (BOR), disease control (DC), time to response (TTR), duration of response (DR), progression free survival (PFS), change from baseline in tumor size and overall survival (OS). Efficacy endpoints except OS are based on an application of RECIST v1.1 to investigator-assessed tumor measurements. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary objectives endpoints: Dose-expansion: The endpoints for assessment of safety include the presence of AEs and SAEs, as well as changes from baseline in laboratory parameters, vital signs, physical examination, and ECG results. The endpoints for assessment of antitumor activity include BOR, OR, DC, TTR, DR, PFS, and change from baseline in tumor size as based on BICR-assessed response using RECIST v1.1. Dose-escalation and Dose-expansion: - The endpoints for assessment of PK include individual MEDI0680 and durvalumab concentrations in serum. PK parameters include peak concentration (Cmax) and trough concentration (Cmin) - The endpoints for assessment of immunogenicity of MEDI0680 and durvalumab include the presence of detectable anti-drug antibodies (ADAs). - PD-L1 expression / localization on tumor membrane and tumor-infiltrating immune cells within the tumor microenvironment Exploratory endpoints: 1. The endpoints related to candidate predictive and/or prognostic biomarkers in dose-expansion will focus on tissue-based, protein or gene expression measures and peripheral gene signatures including, but not limited to immunohistochemistry (IHC) measures of markers associated with infiltrating immune cells (eg, cluster of differentiation 80) 2. Gene expression signatures associated with response to therapy will include expression of messengerribonucleic acid in blood and tumor samples before and after treatment to examine gene expression patterns at baseline and changes in response to treatment. Analysis may also include but is not limited to: evaluation of key oncogenic mutations and/or mutations in immune-related molecules. 3. Levels of circulating free DNA and/or circulating soluble factors which may include cytokines, chemokines, growth factors, soluble receptors, and antibodies against tumor and self-antigens, may be evaluated before and after treatment to evaluate response to treatment with MEDI0680 and durvalumab c | — |
Countries
Australia, Canada, France, Korea (the Republic of), Netherlands, United Kingdom, United States of America
Outcome results
None listed