Neoadjuvant MEDI 4736 +/- Tremelimumab in Locally Advanced Renal Cell Carcinoma
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|ClinicalTrials.gov Identifier: NCT02762006|
Recruitment Status : Recruiting
First Posted : May 4, 2016
Last Update Posted : June 21, 2019
|Condition or disease||Intervention/treatment||Phase|
|Renal Cell Carcinoma Kidney Cancer||Drug: Durvalumab Drug: Tremelimumab||Phase 1|
• To investigate the safety and feasibility of neoadjuvant plus adjuvant dosing of durvalumab +/- tremelimumab in patients with localized renal cell carcinoma (RCC).
- 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.
- 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).
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||45 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase Ib Trial of Neoadjuvant Durvalumab (MEDI4736) +/- Tremelimumab in Locally Advanced Renal Cell Carcinoma|
|Actual Study Start Date :||December 20, 2016|
|Estimated Primary Completion Date :||January 2020|
|Estimated Study Completion Date :||January 2020|
Experimental: 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.
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.
Durvalumab is a programmed cell death ligand-1 monoclonal antibody which has demonstrated anti-tumor efficacy renal cell carcinoma and other malignancies via activation of the immune system.
Other Name: MEDI4736
Tremelimumab is a CTLA-4 monoclonal antibody.
- 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.
- Average estimated blood loss during nephrectomy [ Time Frame: Up to 56 days after screening ]
- Average operative time (hours) [ Time Frame: Up to 56 days after screening ]
- Average length of hospital stay (days) [ Time Frame: Up to 56 days after screening ]
- Average days in the intensive care unit (ICU) [ Time Frame: Up to 56 days after screening ]
- Average volume of post operative blood transfusion [ Time Frame: Up to 56 days after screening ]
- Number of patients with perioperative complications by grade of the Clavien-Dindo Classification System [ Time Frame: Up to 56 days after screening ]
- Any deviation from the normal postoperative course without the need for pharmacological treatment or surgical, endoscopic, and radiological interventions
- Allowed therapeutic regimens are: drugs as antiemetics, antipyretics, analgetics, diuretics, electrolytes, and physiotherapy. This grade also includes wound infections opened at the bedside
-- Requiring pharmacological treatment with drugs other than such allowed for grade I complications
Blood transfusions and total parenteral nutrition are also included
--Grade III - Requiring surgical, endoscopic or radiological intervention
- Grade IIIa - Intervention not under general anesthesia
- Grade IIIb - Intervention under anesthesia
- Grade IV - Life-threatening complication (including CNS complications) requiring IC/ICU management
- Grade IVa - Single organ dysfunction (including dialysis)
- Grade IVb - Multiorgan dysfunction
- Grade V - Death of a patients
- Percentage of tumor-infiltrating CD8+ T-cells after treatment [ Time Frame: Up to 12 months after screening ]The primary readout here will be increased CD8 infiltration versus a large historical control cohort already in our possession. Preliminary studies will focus on peri-tumoral and inter-tumoral CD8 infiltration, as those parameters are associated with responsiveness to immunotherapy in melanoma patients. Secondary efforts will focus on the induction of a pro-inflammatory infiltrate by comparing the surgical specimen to pre-treatment biopsies. Those assays will be challenged by the small amount of tissue generally available from biopsy, but are important since the biopsy could potentially serve as a valuable prediction tool to guide early treatment.
- Tumor response rate according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) [ Time Frame: Up to 12 months after screening ]
RECIST 1.1 Criteria Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
- Proportion of patients with measurable disease according to RECIST 1.1 [ Time Frame: Up to 12 months after screening ]
- Best overall response rate (BOR) according to RECIST 1.1 [ Time Frame: Up to 12 months after screening ]o The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02762006
|Contact: Brian Rini, MDfirstname.lastname@example.org|
|United States, Ohio|
|Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center||Withdrawn|
|Cleveland, Ohio, United States, 44106|
|Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center||Recruiting|
|Cleveland, Ohio, United States, 44195|
|Contact: Brian Rini, MD 216-444-9567 email@example.com|
|Principal Investigator:||Brian Rini, MD||Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center|