A Phase Ib Trial of Neoadjuvant Durvalumab (MEDI4736) +/- Tremelimumab in Locally Advanced Renal Cell Carcinoma
Overview
- Phase
- Phase 1
- Intervention
- Durvalumab
- Conditions
- Renal Cell Carcinoma
- Sponsor
- Moshe Ornstein
- Enrollment
- 29
- Locations
- 2
- Primary Endpoint
- Patients with Dose Limiting Toxicity (DTL)
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
The purpose of this study is to investigate the safety and feasibility of administering investigational drugs (meaning not Food and Drug Administration (FDA)-approved for kidney cancer) prior to surgical treatment for kidney cancer. The first drug is called MEDI4736, and the second drug is called tremelimumab. Both of these drugs work by attaching to certain proteins on immune cells with the goal of stimulating an immune response against cancer cells. This is a phase 1 trial, with the primary goal of identifying if this treatment is safe and possible side effects when given prior to surgery for kidney cancer.
Detailed Description
Objectives: Primary Objective • To investigate the safety and feasibility of neoadjuvant plus adjuvant dosing of durvalumab +/- tremelimumab in patients with localized renal cell carcinoma (RCC). Secondary Objectives * To assess the immune response to neoadjuvant plus adjuvant dosing of durvalumab +/- tremelimumab in patients with localized RCC as measured an increased density of tumor-infiltrating CD8 T-cells. * To assess the antitumor effect of neoadjuvant durvalumab +/- tremelimumab in patients with RCC as measured by change in tumor size. Correlative Objectives * 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, T regulatory cells and/or Myeloid-derived suppressor cells). * 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). Study Design: This study will be a single-arm open-label phase Ib study of neoadjuvant durvalumab +/- tremelimumab in localized / locally advanced, non-metastatic RCC patients suitable for nephrectomy. Upon selection as appropriate for study, patients will undergo computed tomography (CT)-guided biopsy of renal mass to obtain histological confirmation of diagnosis, and immunologic characterization of the RCC tumor. Peripheral blood will also be drawn at time of screening. Patients will subsequently receive systemic neoadjuvant treatment in one of 5 cohorts as defined below. Following systemic therapy, patients will undergo nephrectomy. Type of surgery (open vs. minimally invasive, radical vs. partial) and template for lymph node dissection are at the discretion of surgeon. Timing of surgery in relation to adverse events and/or treatment for adverse events from neoadjuvant dosing of study drugs is at the discretion of the surgeon. Adjuvant therapy will be administered within 4-6 weeks of surgery. Subsequent follow-up will then be completed to assess adverse event resolution and long-term outcomes.
Investigators
Moshe Ornstein
MD
Case Comprehensive Cancer Center
Eligibility Criteria
Inclusion Criteria
- •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., 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
- •Adequate normal organ and marrow function as defined below:
- •Hemoglobin ≥ 8.0 g/dL
- •Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (≥ 1500 per mm3)
- •Platelet count ≥ 100 x 109/L (≥100,000 per mm3)
- •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.
- •AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal
Exclusion Criteria
- •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.
- •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).
- •a. 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 (eg, 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.
- •Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)
- •History of primary immunodeficiency
Arms & Interventions
Durvalumab + Tremelimumab with Nephrectomy
Following systemic therapy, patients will undergo nephrectomy. Adjuvant therapy will be administered within 4-6 weeks of surgery. Subsequent follow-up will then be completed to assess adverse event resolution and long-term outcomes. * Cohort 1: Durvalumab x 1 dose (n=6) * Cohort 2: Durvalumab + Tremelimumab x 1 dose (n=6) * Cohort 2a: Durvalumab + Tremelimumab x 1 dose (n=12) * Cohort 3: Durvalumab + Tremelimumab x 1 dose (n=9) Cohorts 1 and 2: Adjuvant dosing of Durvalumab x 1 beginning 2-8 weeks after surgery. Cohort 2a: Durvalumab monotherapy until 1 year after nephrectomy. Cohort 3: Adjuvant dosing of durvalumab + tremelimumab x 1 beginning 2-8 weeks after surgery, then durvalumab monotherapy until 1 year after nephrectomy.
Intervention: Durvalumab
Durvalumab + Tremelimumab with Nephrectomy
Following systemic therapy, patients will undergo nephrectomy. Adjuvant therapy will be administered within 4-6 weeks of surgery. Subsequent follow-up will then be completed to assess adverse event resolution and long-term outcomes. * Cohort 1: Durvalumab x 1 dose (n=6) * Cohort 2: Durvalumab + Tremelimumab x 1 dose (n=6) * Cohort 2a: Durvalumab + Tremelimumab x 1 dose (n=12) * Cohort 3: Durvalumab + Tremelimumab x 1 dose (n=9) Cohorts 1 and 2: Adjuvant dosing of Durvalumab x 1 beginning 2-8 weeks after surgery. Cohort 2a: Durvalumab monotherapy until 1 year after nephrectomy. Cohort 3: Adjuvant dosing of durvalumab + tremelimumab x 1 beginning 2-8 weeks after surgery, then durvalumab monotherapy until 1 year after nephrectomy.
Intervention: Tremelimumab
Outcomes
Primary Outcomes
Patients with Dose Limiting Toxicity (DTL)
Time Frame: Up to 12 months after screening
Dose-limiting toxicities (DLTs) will be evaluated from the first dose of drug through the first adjuvant dose of durvalumab. Grading of DLTs will follow the guidelines provided in the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Secondary Outcomes
- Average estimated blood loss during nephrectomy(Up to 56 days after screening)
- Average length of hospital stay (days)(Up to 56 days after screening)
- Average days in the intensive care unit (ICU)(Up to 56 days after screening)
- Average volume of post operative blood transfusion(Up to 56 days after screening)
- Average operative time (hours)(Up to 56 days after screening)
- Number of patients with perioperative complications by grade of the Clavien-Dindo Classification System(Up to 56 days after screening)
- Percentage of tumor-infiltrating CD8+ T-cells after treatment(Up to 12 months after screening)
- Tumor response rate according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1)(Up to 12 months after screening)
- Proportion of patients with measurable disease according to RECIST 1.1(Up to 12 months after screening)
- Best overall response rate (BOR) according to RECIST 1.1(Up to 12 months after screening)