CompletedNCT02762006Updated Mar 18, 2024

Neoadjuvant MEDI 4736 +/- Tremelimumab in Locally Advanced Renal Cell Carcinoma

A Phase 1 interventional study of Durvalumab and Tremelimumab in Renal Cell Carcinoma and Kidney Cancer, sponsored by Moshe Ornstein. Completed at 2 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2024-03-18.

Sponsored by Moshe Ornstein · Phase 1, Interventional, and Treatment

From the registry’s dates

Primary completion was Nov 2020, 5 years 11 months ago, and no results have been posted to the registry.

Phase: Phase 1
Study type: Interventional
Enrollment: 29
Allocation: Not applicable
Ages: 18 Years and older
Sex: All

Study 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.

Read the 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.

Conditions studied

Renal Cell Carcinoma
Kidney Cancer

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Keywords

durvalumab
tremelimumab
Phase Ib
Locally Advanced

In context

Carcinoma

6,741 studies on the registry are indexed under Carcinoma; 1,161 are open to participants now.

This study's enrollment of 29 is below the median of 45 across 5,170 interventional studies indexed under Carcinoma.

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Lead sponsor

This is the only study on the registry with Moshe Ornstein as lead sponsor.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years and older
Sexes eligible: All
Accepts healthy volunteers: No

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
- Glomerular filtration rate > 40ml/min/1.73m2 as estimated by the Cockcroft-Gault formula or creatinine clearance >50ml/min as determined by 24-hour urine collection:
- Estimated creatinine clearance (Clcr) in mL/min by the Cockcroft-Gault (C-G): {[140 - age ( years)]× weight (kg)}/{72 × serum creatinine (mg / dL)} ×0.85 for female patients
Female subjects must either be of non-reproductive potential (ie, 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.

Exclusion criteria

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
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 diathesis including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C (detectable 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.
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

Study design

Phase: Phase 1
Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Enrollment: 29 participants (actual)

Study arms

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. * 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.
Drug: Durvalumab · Drug: Tremelimumab

Interventions

DrugDurvalumab
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.
Also known as: MEDI4736
DrugTremelimumab
Tremelimumab is a CTLA-4 monoclonal antibody.

What researchers measure

Primary outcomes

Patients with Dose Limiting Toxicity (DTL)
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.
Time frame: Up to 12 months after screening

Secondary outcomes

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
* Grade 1 * 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 * Grade II -- 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
Time frame: Up to 56 days after screening
Percentage of tumor-infiltrating CD8+ T-cells after treatment
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.
Time frame: Up to 12 months after screening
Tumor response rate according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
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.
Time frame: Up to 12 months after screening
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
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.
Time frame: Up to 12 months after screening

Study locations

2 sites

University of Minnesota
Minneapolis, Minnesota 55455, United States
Cleveland Clinic, Case Comprehensive Cancer Center
Cleveland, Ohio 44195, United States

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Mar 18, 2024, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT02762006
Lead sponsor: Moshe Ornstein
Responsible party: Moshe Ornstein (MD, Case Comprehensive Cancer Center) — Sponsor-investigator
First posted: May 4, 2016
Start date: Dec 20, 2016
Primary completion: Nov 6, 2020
Completion: Nov 6, 2020
Last update: Mar 18, 2024

Study contacts

Moshe Ornstein, MD, MA

principal investigator · Cleveland Clinic, Case Comprehensive Cancer Center

Oversight

Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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