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

NCT07281716 | Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: STUDY-25-00756PRMC-25-046 IIT
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Metastatic Microsatellite Stable Colorectal Carcinoma

Keywords

Colorectal Cancer(CRC); Chemotherapy-refractory colorectal cancer; Microsatellite stable colorectal cancer (MSS CRC); Metastatic colorectal cancer; Chemotherapy-resistant CRC

Outcome Measures

Primary Outcomes (2)

• Dose-Limiting Toxicities (DLTs)

  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)

  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 Outcomes (4)

• Progression-free Survival (PFS)

  From first dose through disease progression, death, or up to 12 months, whichever occurs first.

• Overall survival (OS)

  From first administration of nadunolimab until documented death from any cause, or up to 12 months, whichever occurs first.

• Disease control rate (DCR)

  From first administration of nadunolimab until best objective response, or up to 12 months, whichever occurs first.

• Duration of response (DOR)

  up to 12 months

Study Arms (1)

Nadunolimab and Toripalimab

EXPERIMENTAL

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; Drug: Toripalimab

Interventions

Nadunolimab DRUG

5 mg/kg intravenously (IV) every 3 weeks (Q3W)

Nadunolimab and Toripalimab

Toripalimab DRUG

240 mg IV every 3 weeks (Q3W)

Nadunolimab and Toripalimab

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Dan Feng: lead
• Coherus Oncology, Inc.: collaborator
• Cantargia AB: collaborator

Study Sites (1)

Icahn School of Medicine at Mount Sinai

New York, New York, 10029, United States

RECRUITING

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  BACKGROUND

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

toripalimab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Study Officials

• Dan Feng, MD, PhD

  Icahn School of Medicine at Mount Sinai

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jordan Cuevas

CONTACT

(212) 824-7945; Jordan.Cuevas@mssm.edu

Rashmi Unawane

CONTACT

(212) 824-2385; rashmi.unawane@mssm.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor in Medicine, Hematology and Medical Oncology

Model Details: 3+3 run-in subjects, first 3 subjects will be enrolled and the first constitutes the DLT window. If there are 2 or more subjects experiencing a DLT, the trial will be halted and the treatment plan discussed with the Tisch Cancer Institute DSMC. If 0 or 1 subject experience a DLT, 3 more subjects will be enrolled. If 2+ subjects experience a DLT the trial will be halted and the treatment plan discussed with the DSMC. If at most 1 out of 6 subjects experiences a DLT, Phase 2 of the trial will open. The 6 subjects from the Phase 1b portion will be evaluable as part of the Phase 2 cohort of 21 subjects and will follow a two-stage minimax design, with 12 subjects in Stage 1 and 9 subjects in Stage 2. A safety stopping rule for futility will be applied and expect that 10% of participants could be expected to drop out either in the phase 1b or phase 2 and will be replaced. Therefore, the total number of subjects that could be enrolled in order to obtain 21 evaluable subjects will be 24

Study Record Dates

• First Submitted: November 25, 2025
• First Posted: December 15, 2025
• Study Start: December 1, 2025
• Primary Completion (Estimated): December 15, 2028
• Study Completion (Estimated): December 15, 2028
• Last Updated: February 19, 2026

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)