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

NCT07677579 | Not Yet Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: NHCI25-005
• Study Type: interventional
• Target: 26
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Colon Cancer Metastatic

Outcome Measures

Primary Outcomes (1)

• Intent for Curative Surgery Post-Treatment

  To determine the proportion of patients treated with two cycles of neoadjuvant Zanzalintinib and Retifanlimab to proceed to curative intent surgery within 14-35 days of completion of treatment.

  Within 14-35 days after completion of two cycles of neoadjuvant therapy

Secondary Outcomes (3)

• Safety And Tolerability of Neoadjuvant Therapy

  From first dose of neoadjuvant therapy through 30 days post-curative intent surgery

• Pathologic Disease Response Following Neoadjuvant Therapy

  At the time of curative-intent surgery

• Disease-Free Survival (DFS) at Two Years

  2 years following curative-intent surgery

Study Arms (1)

Single Arm

EXPERIMENTAL

Phase II, single arm, open-label study of the feasibility, safety and efficacy of neoadjuvant treatment of colon cancer with Zanzalitinib and Retifanlimab. Zanzalitinib 60mg daily for 21 days for 2 cycles. VEGF TKI. Retifanlimab 375mg once every 21 days for 2 cycles. Anti-PD1 agent

Drug: Retifanlimab; Drug: Zanzalintinib

Interventions

Retifanlimab DRUG

Retifanlimab-dlwr is a programmed death receptor-1 (PD-1)-blocking antibody. Retifanlimab-dlwr is a humanized IgG4 kappa monoclonal antibody produced in Chinese hamster ovary cells. Retifanlimab-dlwr has an approximate molecular weight of 148 kDa. ZYNYZ (retifanlimab-dlwr) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to pale yellow solution for intravenous use. The solution is free from visible particles. Each single-dose vial contains 500 mg of retifanlimab-dlwr in 20 mL of solution. Each mL contains 25 mg of retifanlimab-dlwr, glacial acetic acid (0.18 mg), polysorbate 80 (0.1 mg), sodium acetate (0.57 mg), sucrose (90 mg), and Water for Injection, USP. The pH is 5.1

Single Arm

Zanzalintinib DRUG

Chemical Name: N-(4-fluorophenyl)-N-(4-((7-methoxy-6-(methylcarbamoyl)quinoline-4-yl)oxy)phenyl)cyclopropane-1,1-dicarboxamide hemi-fumarate. Zanzalintinib doses administered reflect salt weight-converted free base equivalent (FBE) doses. Exelixis will provide each Investigator with adequate supplies of zanzalintinib, which will be supplied as 60mg, 40 mg or 20mg film-coated tablets. Tablets should be stored at room temperature.

Single Arm

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

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.

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.

Sponsors & Collaborators

• Northwell Health: lead

Central Study Contacts

GI Referral GI Trial Referral Team

CONTACT

(516) 734-8900; gitrialreferral@northwell.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 6, 2026
• First Posted: July 1, 2026
• Study Start (Estimated): August 30, 2026
• Primary Completion (Estimated): August 30, 2028
• Study Completion (Estimated): December 30, 2028
• Last Updated: July 1, 2026

Record last verified: 2026-06