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Renal Cell CarcinomaPhase 1NCT02762006

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

A Phase 1 study testing Durvalumab and Tremelimumab in people with Renal Cell Carcinoma and Kidney Cancer, run by Moshe Ornstein at 2 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Renal Cell Carcinoma, Kidney Cancer
What is being tested?
Durvalumab and Tremelimumab
Could I receive a placebo?
No, everyone receives an active treatment
How many people
29 participants
Where
2 sitesUnited States
Study dates
20 Dec 2016to 6 Nov 2020
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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.

Who cannot join

  • 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.
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  • 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

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • Cleveland Clinic, Case Comprehensive Cancer Center

    Cleveland, Ohio, 44195

  • University of Minnesota

    Minneapolis, Minnesota, 55455

Other trials in United States

About this study

Official title: A Phase Ib Trial of Neoadjuvant Durvalumab (MEDI4736) +/- Tremelimumab in Locally Advanced Renal Cell Carcinoma

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.

Keywords
durvalumab, tremelimumab, Phase Ib, Locally Advanced
Medical subject headings
Carcinoma, Renal Cell, Kidney Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • DurvalumabDrug

    Also called MEDI4736

    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.

  • TremelimumabDrug

    Tremelimumab is a CTLA-4 monoclonal antibody.

Study groups in NCT02762006
Study groupRoleWhat they receive
Durvalumab + Tremelimumab with NephrectomyExperimentalFollowing 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.
Receives: Drug: Durvalumab; Drug: Tremelimumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Up to 12 months after screening

Secondary outcomes (10)

  1. Average estimated blood loss during nephrectomy

    Measured: Up to 56 days after screening

  2. Average operative time (hours)

    Measured: Up to 56 days after screening

  3. Average length of hospital stay (days)

    Measured: Up to 56 days after screening

  4. Average days in the intensive care unit (ICU)

    Measured: Up to 56 days after screening

  5. Average volume of post operative blood transfusion

    Measured: Up to 56 days after screening

  6. 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

    Measured: Up to 56 days after screening

  7. 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.

    Measured: Up to 12 months after screening

  8. 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.

    Measured: Up to 12 months after screening

  9. Proportion of patients with measurable disease according to RECIST 1.1

    Measured: Up to 12 months after screening

  10. Best overall response rate (BOR) according to RECIST 1.1

    • 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.

    Measured: Up to 12 months after screening

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted4 May 2016 (estimated)
  2. Study start20 Dec 2016
  3. Primary completion6 Nov 2020
  4. Study completion6 Nov 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
29 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02762006
Sponsor's protocol ID
CASE12815
Status last verified
Mar 2024
First submitted
2 May 2016
Last updated
18 Mar 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Durvalumab and Tremelimumab in people with Renal Cell Carcinoma and Kidney Cancer, run by Moshe Ornstein at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 14 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 18 Mar 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Patients with Dose Limiting Toxicity (DTL) (time frame: Up to 12 months after screening). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02762006.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Mar 2024.

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