NIMBLE-CRC: NeoImmunoModulation Before Leveraging Excision in Colorectal Rectal Cancer
ConditionColon Cancer Metastatic
Trial statusNot yet recruiting
Trial phasePhase 2
Trial typeInterventional
Biological sexAll
Age18-80
SponsorNorthwell Health
About this trial
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.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
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.
Disqualifiers
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
Trial design
Design model
Single group
Treatments tested in this trial
Retifanlimab
DrugRetifanlimab-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
Zanzalintinib
DrugChemical 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.
Treatment groups
26 Participants
are divided into 1 treatment groupGroup A: Single ArmExperimental treatment 2 interventions
Trial outcomes
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.
Time frame
Within 14-35 days after completion of two cycles of neoadjuvant therapySecondary outcomes
1
Safety And Tolerability of Neoadjuvant Therapy
To evaluate the tolerability and safety (incidence and severity of treatment-emergent adverse events \[TEAEs\]) of neoadjuvant treatment with Zanzalintinib and Retifanlimab
Time frame
From first dose of neoadjuvant therapy through 30 days post-curative intent surgery2
Pathologic Disease Response Following Neoadjuvant Therapy
To measure the rate of pathologic response in resected colon cancer tissue specimen following neoadjuvant (Zanzalinitinib and Retifanlimab) treatment. Tumor Regression Grade (TRG) and pathologic Complete Response (pCR) will be used to describe the disease response to neoadjuvant therapy following collection of resected colon cancer tissue specimen during curative-intent surgery. Pathological downstaging will be evaluated through comparison of pre-treatment radiographic (imaging) TNM classification stage versus post-surgical pathologic TNM stage.
Time frame
At the time of curative-intent surgery3
Disease-Free Survival (DFS) at Two Years
To determine two-year relapse free survival (RFS) rate
Time frame
2 years following curative-intent surgeryLocations
Sponsors and contacts
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Source ClinicalTrials.gov
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