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

NCT06304597 | Not Yet Recruiting Phase 1

• 1 other identifier: 17651
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Locally Advanced Rectal Carcinoma

Outcome Measures

Primary Outcomes (5)

• Safety of nivolumab-800CW in combination with durvalumab-680LT

  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.

  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

  Beats per minute

  Until 24 hours after administration

• Blood pressure systolic and diastolic

  Millimeters of mercury (mmHg)

  Until 24 hours after administration

• Temperature

  Degrees Celsius

  Until 24 hours after administration

Secondary Outcomes (7)

• 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.

  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.

  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

  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

  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

  12 months

Study Arms (1)

Durvalumab-680LT and nivolumab-800CW

EXPERIMENTAL

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; Drug: Opdivo

Interventions

Imfinzi DRUG

Durvalumab is labeled to IRDye-680LT and will be administered in combination with fluorescently labelled nivolumab (Opdivo)

Also known as: durvalumab

Durvalumab-680LT and nivolumab-800CW

Opdivo DRUG

Nivolumab is labeled to IRDye-800CW and will be administered in combination with fluorescently labelled durvalumab (Imfinzi)

Also known as: Nivolumab

Durvalumab-680LT and nivolumab-800CW

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University Medical Center Groningen: lead

Study Sites (1)

University Medical Center Groningen

Groningen, 9713 GZ, Netherlands

Location

MeSH Terms

Interventions

durvalumab; Nivolumab

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Wouter B Nagengast, Prof.

  University Medical Center Groningen

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Wouter B Nagengast, Prof.

CONTACT

+31503612620; w.b.nagengast@umcg.nl

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 14, 2023
• First Posted: March 12, 2024
• Study Start: April 1, 2024
• Primary Completion: March 1, 2025
• Study Completion: June 1, 2025
• Last Updated: March 12, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)