Evaluating PD-1/PD-L1 in Locally Advanced Rectal Cancer by Quantitative Fluorescence Molecular Endoscopy (PREDICT)

March 4, 2024 updated by: University Medical Center Groningen

Improving Detection and Treatment of Locally Advanced Rectal Cancer by Dual Wavelength Quantitative Fluorescence Molecular Endoscopy Using Nivolumab-800CW and Durvalumab-680LT

Colorectal cancer (CRC) claims 10% of global cancer-related deaths annually, with rising incidence. Locally advanced rectal cancer (LARC) requires improved diagnostic techniques. This study focuses on dual-wavelength quantitative fluorescence molecular endoscopy (qFME) using PD-1/PD-L1-targeted tracers for LARC patients undergoing neoadjuvant treatment. Eighteen patients will receive nivolumab-800CW and durvalumab-680LT before qFME procedures, assessing programmed death-1/programmed death ligand-1 (PD-1/PD-L1) expression. We want to test the feasibility of qFME and ex vivo fluorescence imaging after intravenous administration of nivolumab-800CW, targeting PD-1, and durvalumab-680LT, targeting PD-L1, to visualize PD-L1 and PD-1 expression before and after CRT in LARC patients. If successful, this method can potentially be used in the future to see which patients most likely benefit from additional immunotherapy beforehand. The non-randomized, prospective phase 1 intervention explores biomarkers' role in treatment response prediction. Tracer administration poses minimal risks. Patients will not directly benefit, but the study aims to establish the utility of nivolumab-800CW and durvalumab-680LT in determining PD-1/PD-L1 expression during endoscopy.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Not yet recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Colorectal cancer (CRC) constitutes a significant global health burden, responsible for 10% of cancer-related deaths annually, with incidence rates escalating by 1-4% annually. Locally advanced rectal cancer (LARC) demands enhanced diagnostic tools, despite various existing modalities. This prospective, non-randomized, phase 1 intervention study addresses this need through dual-wavelength quantitative fluorescence molecular endoscopy (qFME) utilizing PD-1/PD-L1-targeted tracers. The primary goal is to assess the safety and feasibility of using durvalumab-680LT and nivolumab-800CW to assess PD-1 and PD-L1 expression alterations before and after neoadjuvant chemoradiotherapy (nCRT) in LARC patients.

The study's central hypothesis posits that higher PD-1/PD-L1 expression correlates with improved treatment response. To test this, eighteen LARC patients scheduled for nCRT and surgery will receive intravenous nivolumab-800CW and durvalumab-680LT, with qFME procedures conducted before and after nCRT. The tracers, labeled with different near-infrared (NIR) fluorophores (800CW and 680LT), allow separate quantification during simultaneous administration.

The study design is single-center, non-blinded, and non-randomized. Eligible patients, identified at the University Medical Center Groningen (UMCG), undergo qFME during staging endoscopy pre-nCRT and an additional procedure 2-3 weeks post-nCRT. Tracer administration precedes these procedures, involving monitoring for potential side effects. A potential third restaging endoscopy occurs 6-8 weeks post-CRT, without tracer administration, collecting biopsies.

The study population comprises eighteen LARC patients (cT3c-4, N1-2, M0) at UMCG scheduled for nCRT followed by surgery. Tracer administration involves 15 mg nivolumab-800CW and 15 mg durvalumab-680LT, with endoscopy procedures incorporating high-definition white-light endoscopy (HD-WLE), qFME, multi-diameter single fiber reflectance/single fiber fluorescence (MDSFR/SFF) spectroscopy, endoscopic rectal ultrasound (EUS), fine needle aspiration (FNA) biopsy, and ultrasound-guided needle biopsy single-fiber fluorescence (USNB/SFF) spectroscopy.

The main study parameters assess the safety of the combination of durvalumab-680LT and nivolumab-800CW through the evaluation of both vital signs after tracer administration and possible (severe) adverse events (SAE/AE's). Importantly, we will determine the feasibility of fluorescence molecular imaging using the GMP-produced near-infrared fluorescent tracers durvalumab-680LT and nivolumab-800CW for visualizing PD-1 and PD-L1 expression before and after nCRT in LARC patients with dedicated fluorescence imaging systems. Risks include minimal infection and hematoma risks from tracer administration, and the study offers negligible benefits to participants. The study's significance lies in establishing the utility of nivolumab-800CW and durvalumab-680LT in determining PD-1/PD-L1 expression during endoscopy for potential treatment response prediction in LARC.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
18

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

  • Netherlands
      • Groningen, Netherlands, 9713 GZ
        • University Medical Center Groningen
        • Contact:
        • Sub-Investigator:
          • Lisanne E van Heijst, Bsc.
        • Sub-Investigator:
          • Pia Volkmer, Drs.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Diagnosed with LARC (cT3c-4, N1-2, M0);
  • Written informed consent is obtained; (We aim to include only patients who consent to both study procedures, however if some patients (n<9) do not consent to the first or second procedure or withdraw their consent for the second procedure after the first procedure, they can still be included)
  • Be at least 18 years old;
  • Speak the Dutch language.

Exclusion Criteria:

  • Concurrent uncontrolled medical conditions according to treating medical physician;
  • Pregnancy or breast feeding. A negative pregnancy test must be available for women of childbearing potential on the day of tracer administration (i.e. premenopausal women with intact reproductive organs and women less than two years after menopause);
  • Prior irradical endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) of the primary tumor.
  • Received an investigational drug within 30 days prior to administration of nivolumab-800CW and durvalumab-680LT according to the patient's medical history;
  • History of infusion reactions to nivolumab, durvalumab or other monoclonal antibodies according to the patient's medical history;
  • Active episode of inflammatory bowel disease;
  • Use of immunosuppressive agents;
  • Medical or psychiatric conditions that compromise the patient's ability to give informed consent according to treating medical physician.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Durvalumab-680LT and nivolumab-800CW

Study procedure 1: Combined intravenous tracer administration with 15mg IMFINZI and 15mg OPDIVO followed by fluorescence molecular endoscopy

Study procedure 2: Combined intravenous tracer administration with 15mg IMFINZI and 15mg OPDIVO followed by fluorescence molecular endoscopy
Drug: Imfinzi
Durvalumab is labeled to IRDye-680LT and will be administered in combination with fluorescently labelled nivolumab (Opdivo)
Other Names:
  • durvalumab
Drug: Opdivo
Nivolumab is labeled to IRDye-800CW and will be administered in combination with fluorescently labelled durvalumab (Imfinzi)
Other Names:
  • Nivolumab

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Safety of nivolumab-800CW in combination with durvalumab-680LT
Time Frame: Until 24 hours after administration
To evaluate the safety of nivolumab-800CW in combination with durvalumab-680LT through monitoring vital signs, the injection site and evaluating possible tracer-related (severe) adverse events (SAE/AEs) and suspected unexpected serious adverse reactions (SUSARs).
Until 24 hours after administration
To investigate the feasibility of using fluorescence molecular endoscopy (FME) and ex vivo FMI to detect nivolumab-800CW and durvalumab-680LT signals indicating PD1 and PD-L1 expression.
Time Frame: 12 months
Determine in vivo fluorescent signal in tumor and surrounding tissue by noting yes/no and the number of lesions detected by HD-WLE and qFME on recorded location during the endoscopic procedure. Semi-quantification of signal intensities of different areas by collecting the mean and standard deviation for the targeted area and surrounding tissue (looking at intra and inter variability). Afterwards comparisons of TBRs/CNRs can be performed. Durvalumab-680LT and nivolumab-800CW detection by fluorescence microscopy (yes/no). Mean fluorescence intensity (MFI) calculation of biopsies Quantified PD-L1/PD-1 expression by qPCR and Western Blot will be correlated to in vivo fluorescence signals, MDSFR/SFF measurements and MFI calculations of biopsies.
12 months
Heart rate
Time Frame: Until 24 hours after administration
Beats per minute
Until 24 hours after administration
Blood pressure systolic and diastolic
Time Frame: Until 24 hours after administration
Millimeters of mercury (mmHg)
Until 24 hours after administration
Temperature
Time Frame: Until 24 hours after administration
Degrees Celsius
Until 24 hours after administration

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Determine the PD-1 and PD-L1 expression and the changes in PD-1 and PD-L1 expression before and after nCRT in patients with LARC.
Time Frame: 12 months
Quantified PD-L1/PD-1 expression by qPCR will be compared before and after CRT.
12 months
Determine the PD-1 and PD-L1 expression and the changes in PD-1 and PD-L1 expression before and after nCRT in patients with LARC.
Time Frame: 12 months
Quantified PD-L1/PD-1 expression by Western Blot will be compared before and after CRT.
12 months
Quantify in vivo fluorescence signals of nivolumab-800CW and durvalumab-680LT before and after CRT by using MDSFR/SFF spectroscopy/UNSB/SFF spectroscopy and correlate these measurements to, in vivo fluorescence intensities and PD1/PD-L1 expression
Time Frame: 12 months
Evaluation of staining intensities by scored positive/negative in percentages and the H-score will be calculated by two independent researchers to evaluate staining intensities. qPCR and Western Blot quantifications (numerical values) will be compared to H-scores.
12 months
Quantify in vivo fluorescence signals of nivolumab-800CW and durvalumab-680LT before and after CRT by using MDSFR/SFF spectroscopy/UNSB/SFF spectroscopy and correlate these measurements to, in vivo fluorescence intensities and PD1/PD-L1 expression
Time Frame: 12 months
qPCR and Western Blot quantifications and H-scores will be correlated to MDSFR/SFF spectroscopy/UNSB/SFF spectroscopy measurements
12 months
Perform real-time polymerase chain reaction (qPCR) and western blot on biopsies to determine whether there is genetic downregulation or protein degradation of PD-1 and PD-L1 after chemoradiotherapy
Time Frame: 12 months
qPCR and Western Blot quantifications (numerical values) will be compared to each other
12 months
Compare immune cell composition between the radiated and non-radiated area of the bowel.
Time Frame: 12 months
Immune cell composition (percentages)measured by FACS will be compared in biopsies from radiated and non radiated areas and in the blood from before and after CRT.
12 months
Evaluate targeted detection with nivolumab-800CW and durvalumab-680LT of the tumor by ex vivo visualization of the resection specimen with PEARL Trilogy
Time Frame: 12 months
Fluorescence of the resection specimen will be measured with the PEARL Trilogy
12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University Medical Center Groningen

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Wouter B Nagengast, Prof., University Medical Center Groningen

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
April 1, 2024

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
March 1, 2025

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
June 1, 2025

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
November 14, 2023

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 4, 2024

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
March 12, 2024

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
March 12, 2024

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 4, 2024

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
March 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 17651

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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