NIMBLE-CRC: NeoImmunoModulation Before Leveraging Excision in Colorectal Rectal Cancer

Starting soon · Phase 2

Conditions studied: Colon Cancer Metastatic

In brief

This is a Phase II, single-arm, open-label trial evaluating the feasibility, safety, and preliminary activity of neoadjuvant Zanzalintinib (a VEGFR-targeting TKI) and Retifanlimab (an anti-PD-1 antibody) in patients with resectable stage II-III mismatch repair-proficient (pMMR) colon cancer. The study's primary objective is to determine the proportion of patients able to undergo curative-intent surgery within 14-35 days after completing two cycles (6 weeks) of neoadjuvant therapy. Secondary objectives include assessment of safety/tolerability and rates of pathologic response, including tumor regression grade (TRG). Two-year relapse-free survival (RFS) will also be evaluated. This trial builds on emerging evidence from neoadjuvant immunotherapy studies-including in pMMR tumors-and the recently positive readout of STELLAR-303, which evaluated Zanzalintinib plus a PD-(L)1 inhibitor in refractory metastatic colorectal cancer. With a favorable safety profile, short treatment window, and rapid post-treatment pathologic readout, this study provides a low-risk opportunity to test whether immunotherapy-based neoadjuvant strategies can improve outcomes and potentially redefine management in early-stage, pMMR colon cancer.

Key facts

Study ID

NCT07677579

Run by

Northwell Health

People needed

26

Starts

2026-08-30

Expected to finish

2028-12-30

Last updated by the study team

2026-07-01

Who can join

Age: 18 and older, up to 80. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. A signed informed consent must be obtained prior to conducting any study-specific procedures.
• Male or female adult 18 to 80 years of age on day of signing informed consent.
• Histological-confirmed adenocarcinoma of the colon that is amenable to curative intent resection.
• Only participants with pMMR/MSS CRC are eligible. Microsatellite status should be performed per local standard of practice. (e.g., IHC and/or PCR, next-generation sequencing). Subjects with unknown or indeterminate results for either test at the time of enrollment are not eligible.
• Adequate organ and marrow function as defined below:
• Absolute neutrophil count: ≥ 1,500/mcl
• Platelets: ≥ 100,000/mcL without transfusion within 2 weeks of screening laboratory sample collection
• Total bilirubin ≤ 1.5 x the upper limit of normal (ULN). This may be up to 3x ULN if Gilbert's syndrome is documented.
• AST and ALT ≤ 3 x institutional ULN.
• Serum creatinine ≤ 1.5 x ULN and EGFR ≥ 40
• ECOG performance status (PS) 0 or 1.
• Urine protein-to-creatinine ratio ≤ 1mg/mg creatinine.
• INR ≤ 1.5 and aPTT ≤ 1.2 x ULN
• Measurable disease as determined by RECIST v1.1.
• Sexually active fertile subjects and their partners must agree to use highly effective method of contraception during the course of the study and for the following durations after the last dose of treatment (whichever is later). An additional contraceptive method, such as a barrier method (listed in addendum), is required. In addition, men must agree not to donate sperm and women must agree not to donate eggs (ova, oocyte) for the purpose of reproduction during these same periods.
• Through 186 days after the last dose of zanzalintinib or 120 days from retifanlimab (whichever is latest) for women of childbearing potential (WOCBP) or through 96 days after the last dose of zanzalintinib or retifanlimab (whichever is latest) for men
• At least T3 disease or with pathologically enlarged local lymph nodes by pre-surgical imaging.

You may not qualify if…

• Symptoms of clinical obstruction or impending clinical obstruction including severe constipation, nausea and vomiting, or other as deemed by the principal investigator.
• Tumor invading GI-tract from external viscera
• Active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, or acute pancreatitis
• Systemic therapy with immunosuppressive agents within 7 days or use of any investigational drug within 28 days before the start of trial treatment
• Prior exposure to any immune checkpoint blockade agent or any other immunomodulatory agent used for antineoplastic therapy within the last two years.
• Previous malignant disease (other than the target malignancy to be investigated in this trial) within 2 years prior to study treatment initiation unless NED for greater than 2 years or deemed to have no possibility of interference with the current study (such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast).
• Receipt of any organ transplantation, including allogeneic stem cell transplantation
• Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent, such as rheumatoid arthritis, which in the opinion of the Investigator might impair the subject's tolerance or ability to participate in the trial
• Known severe hypersensitivity reactions to monoclonal antibodies or drug formulation components of retifanlimab or Zanalintinib
• Subject is pregnant or breast feeding or planning to become pregnant while enrolled in the study, up to the final end of treatment visit
• Congestive heart failure ≥ New York Heart Association (NYHA) class III.
• Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months), myocardial infarction less than 6 months before start of study drug.
• Uncontrolled cardiac arrhythmias.
• Poorly controlled hypertension, defined as a blood pressure consistently above 140/90 mmHg despite optimal medical management.
• Persistent proteinuria of NCI-CTCAE Grade 3 or higher. Urine dipstick result of 3+ or abnormal, based on type of urine test strip used, is allowed if protein excretion (estimated by urine protein/creatinine ratio on a random urine sample) is < 3.5 g/24 hr.
• Non-healing wound, non-healing ulcer, or non-healing bone fracture.
• Significant acute gastrointestinal disorders with diarrhea as a major symptom e.g., Crohn's disease, malabsorption, or NCI CTCAE Grade ≥ 2 diarrhea of any etiology other then secondary to colon cancer.
• Participants with an active, known or suspected autoimmune disease. -Participants with type I diabetes mellitus (T1DM), hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
• Active autoimmune disease requiring systemic immunosuppression in excess of physiologic maintenance doses of corticosteroids (> 10 mg/day of prednisone or equivalent).
• Physiologic corticosteroid replacement therapy at doses ≤ 10 mg/day of prednisone or equivalent for adrenal or pituitary insufficiency and in the absence of active autoimmune disease is permitted.
• Participants with asthma that requires intermittent use of bronchodilators, inhaled corticosteroids, or local corticosteroid injections may participate.
• Participants using topical, ocular, intra-articular, or intranasal corticosteroids (with minimal systemic absorption) may participate.
• Brief courses of corticosteroids for prophylaxis (eg, contrast dye allergy) or study treatment-related standard premedications are permitted.
• Active infections requiring systemic antibiotics or antifungal or antiviral treatment within 7 days before first dose of study treatment
• Has received a live vaccine within 28 days before the planned start of study treatment (mRNA vaccines not considered live vaccines).

Full record on ClinicalTrials.gov

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