Combination Immunotherapy for the Treatment of Chemotherapy-refractory Metastatic MSS CRC

February 17, 2026 updated by: Dan Feng

A Phase 1b/2 Study of Combination Immunotherapy for the Treatment of Chemotherapy-refractory Metastatic Microsatellite Stable (MSS) Colorectal Cancer (CRC)

Phase 1b/2 open-label study evaluates the safety, tolerability, and efficacy of combination immunotherapy with nadunolimab (anti-IL-1RAP) and toripalimab (anti-PD-1) in patients with chemotherapy-refractory metastatic microsatellite stable (MSS) colorectal cancer. Phase 1b will assess dose-limiting toxicity (DLT), while Phase 2 will evaluate objective response rate (ORR), including progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and duration of response (DOR). Exploratory analyses will investigate immunomodulatory effects through tumor and peripheral blood studies, and treatment will continue every 3 weeks for up to 1 year or until disease progression.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

This is a Phase 1b/2, open-label study evaluating the safety, tolerability, and efficacy of nadunolimab (anti-IL-1RAP) in combination with toripalimab (anti-PD-1) in adults with chemotherapy-refractory metastatic microsatellite stable (MSS) colorectal cancer. The Phase 1b portion serves as a safety run-in with up to 6 subjects to assess the safety of a single dose of the combination therapy. Following this, Phase 2 will enroll up to 21 subjects, with the first 6 from Phase 1b included in the Phase 2 analysis to assess the primary efficacy endpoint. Eligible participants must have biopsy-confirmed MSS colorectal cancer (non-MSI-high or pMMR), whose disease has progressed during or following 5-FU, oxaliplatin and/or irinotecan-based chemotherapy with or without a biological agent. Subjects must have have measurable disease and tumor accessible for core needle biopsy. Participants will receive nadunolimab 5 mg/kg and toripalimab 240 mg intravenously every three weeks, continuing for up to one year or until disease progression. Primary objectives: For Phase 1/b, to determine the safety and tolerability of combination immunotherapy in subjects with chemotherapy-refractory metastatic non-MSI-high/pMMR CRC. For Phase 2, to determine the efficacy of combination immunotherapy in subjects with chemotherapy-refractory metastatic non-MSI-high/pMMR CRC as measured by the objective response rate (ORR) achieved. Subjects will undergo core needle biopsies, blood collection, and repeat imaging throughout the study. This study is conducted at Mount Sinai Hospital under IRB and PRMC oversight. The results will provide important information on the safety and potential efficacy of combining nadunolimab and toripalimab in a population with limited treatment options.

Study Type

Interventional

Enrollment (Estimated)

24

Phase

  • Phase 2
  • 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 Backup

Study Locations

  • United States
    • New York
      • New York, New York, United States, 10029
        • Recruiting
        • ICAHN School of Medicine at Mount Sinai
        • Contact:
        • Principal Investigator:
          • Dan Feng
        • Contact:

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

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Patients must have a pathologically confirmed diagnosis of non-MSI-H/pMMR CRC.
  • Patients must have progressed (clinically or radiographically) on or after standard chemotherapy, including fluoropyrimidines, oxaliplatin, and irinotecan, or are intolerant to standard chemotherapy. Patients may have received, if eligible, anti-VEGF or anti-EGFR antibodies in combination with chemotherapy.
  • Patients must have at least 1 measurable target lesion at baseline ≥ 10mm in the longest diameter.
  • Patient must be willing and able to provide blood samples (6 heparinized, and two streck tubes, roughly 70 - 80 mL) at the time points indicated in the Study Calendar.
  • Patients must have at least 1 lesion suitable for core needle biopsies.
  • Patients must be willing and able to have core needle biopsies, if clinically feasible (Goal 3-6 biopsies, final number to be determined by the interventionalist performing the procedure as safe), of tumor prior to initiation of study drug. Should patients undergo pre-treatment or on-treatment biopsy procedure and inadequate number of biopsies are obtained, they may proceed with initiation/continuation of treatment at the discretion of the investigator and treating physician.
  • Age ≥ 18 years.
  • ECOG Performance Status 0-1 (Karnofsky ≥60%, see https://ecog-acrin.org/resources/ecog-performance-status/). o Patients with performance status >1 carrying long-term disability (such as cerebral palsy) where the disability is not acute nor progressive, and unlikely to significantly affect their response to therapy may be enrolled at the investigator's discretion
  • Women of child-bearing potential (WOCBP) and men must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 4 months following completion of therapy. Should a study participant become pregnant or suspect pregnancy while participating in this study, the study participant should inform the treating physician immediately. A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: o Has not undergone a hysterectomy or bilateral oophorectomy; or o Has not been naturally postmenopausal for at least 12 consecutive months
  • Ability to understand and the willingness to sign a written informed consent. • Adequate organ and marrow function

Exclusion Criteria:

  • Patients who have had chemotherapy within 14 days from start of therapy.
  • Palliative radiotherapy is permitted at anytime, if deemed in the best interest of the patient.
  • Patients may not be receiving any other investigational agents.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring antibiotics (exception is a brief (≤10days) course of antibiotics to be completed before initiation of treatment), symptomatic congestive heart failure, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Patients who have undergone major surgery within 4 weeks prior to the first dose of treatment.
  • Patients who are pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.
  • Patients who discontinued prior immune checkpoint inhibitors due to immune-related adverse events are not eligible for enrollment.
  • Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Patients on chronic steroids (more than 4 weeks at stable dose) equivalent to ≤ 10mg prednisone will not be excluded.
  • Has active autoimmune disease that has required systemic treatment in the past 1 year (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is acceptable.
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator.
  • HIV positive with detectable viral load, or anyone not on stable anti-viral (HAART) regimen, or with <200 CD4+ T cells/microliter in the peripheral blood. HIV testing is mandatory for patients with no known history of HIV. For such patients HIV testing will be considered SOC.
  • Has known active Hepatitis B (e.g., HBV detected by PCR or active Hepatitis C (e.g., HCV RNA [qualitative] is detected). Patients with hepatitis B (HepBsAg+) who have controlled infection (serum hepatitis B virus DNA PCR that is below the limit of detection AND receiving anti-viral therapy for hepatitis B) are permitted. Patients with controlled infections must undergo periodic monitoring of HBV DNA. Patients must remain on anti-viral therapy for at least 6 months beyond the last dose of investigational study drug.
  • History of allogeneic hematopoietic cell transplantation or solid organ transplantation.
  • Receipt of a live vaccine within 28 days of planned start of study medication.
  • Receipt of etanercept or other TNF-α inhibitors within 28 days of planned start of the study medication.
  • Documented allergic or hypersensitivity response to any protein therapeutics (e.g., recombinant proteins, vaccines, intravenous immune globulins, monoclonal antibodies, receptor traps).
  • Principal investigator believes that for one or multiple reasons the patient will be unable to comply with all study visits, or if they believe the trial is not clinically in the best interest of the patient.
  • History of irAE in response to prior immunotherapy that has not improved to a Grade 0 or 1; this does not include chronic conditions such as endocrinopathies which can be treated with hormone replacement therapy.
  • History of interstitial lung disease (e.g., idiopathic pulmonary fibrosis, organizing pneumonia) or active, noninfectious pneumonitis attributed to prior use of cancer immunotherapy that required immune-suppressive doses of glucocorticoids to assist with management. A history of radiation pneumonitis in the radiation field is permitted.

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: Treatment
  • Allocation: N/A
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Nadunolimab and Toripalimab
Participants will receive the investigational combination of nadunolimab and toripalimab. Treatment will continue for up to 1 year or until disease progression, whichever occurs first.
Drug: Nadunolimab
5 mg/kg intravenously (IV) every 3 weeks (Q3W)
Drug: Toripalimab
240 mg IV every 3 weeks (Q3W)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Dose-Limiting Toxicities (DLTs)
Time Frame: The first cycle (day1 - day21) constitutes the DLT window.
For the Phase 1b portion, Dose-Limiting Toxicities (DLTs) will be assessed based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Adverse events are graded on a scale from 1 (mild) to 5 (death related to AE). Permanent discontinuation of study treatment will occur for any severe (Grade 3) drug-related adverse event that recurs or for any life-threatening (Grade 4) event.
The first cycle (day1 - day21) constitutes the DLT window.
Objective Response Rate (ORR)
Time Frame: Treatment initiation through 12 months, or until documented disease progression or initiation of new anti-cancer therapy, whichever occurs first
For the phase 2 portion, ORR will be assessed based on the definition, as the combined percent of the subjects experiencing a partial response (PR) or a complete response (CR) at anytime within the first year from the initiation of therapy, or until the documented progression of disease or start of a new anti-cancer therapy. Radiographic response will be determined by the RECIST v1.1
Treatment initiation through 12 months, or until documented disease progression or initiation of new anti-cancer therapy, whichever occurs first

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression-free Survival (PFS)
Time Frame: From first dose through disease progression, death, or up to 12 months, whichever occurs first.
Progression-free survival (PFS) is defined as the time in days from the first administration of nadunolimab until documented progression of disease on imaging or death.
From first dose through disease progression, death, or up to 12 months, whichever occurs first.
Overall survival (OS)
Time Frame: From first administration of nadunolimab until documented death from any cause, or up to 12 months, whichever occurs first.
Overall survival (OS) is defined as the time in days from the first administration of nadunolimab until documented death from any cause.
From first administration of nadunolimab until documented death from any cause, or up to 12 months, whichever occurs first.
Disease control rate (DCR)
Time Frame: From first administration of nadunolimab until best objective response, or up to 12 months, whichever occurs first.
Disease control rate (DCR) is defined as the percent of the subjects experiencing a best objective response of PR, CR or stable disease (SD).
From first administration of nadunolimab until best objective response, or up to 12 months, whichever occurs first.
Duration of response (DOR)
Time Frame: up to 12 months
Duration of response (DOR) is defined as the time from which a subject achieves either a PR or a CR until subsequent progression of disease is documented radiographically or clinically.
up to 12 months

Collaborators and Investigators

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

Sponsor

Dan Feng

Collaborators

Cantargia AB
Coherus Oncology, Inc.

Investigators

  • Principal Investigator: Dan Feng, MD, PhD, ICAHN School of Medicine at Mount Sinai

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

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 (Actual)

December 1, 2025

Primary Completion (Estimated)

December 15, 2028

Study Completion (Estimated)

December 15, 2028

Study Registration Dates

First Submitted

November 25, 2025

First Submitted That Met QC Criteria

December 4, 2025

First Posted (Actual)

December 15, 2025

Study Record Updates

Last Update Posted (Actual)

February 19, 2026

Last Update Submitted That Met QC Criteria

February 17, 2026

Last Verified

December 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • STUDY-25-00756
  • PRMC-25-046 IIT (Other Identifier: PRMC)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

The completed dataset is the sole property of the Sponsor-Investigator's institution and should not be exported to third parties, except for authorized representatives of appropriate Health/Regulatory Authorities, without permission from the Sponsor-investigator and their institution.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

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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