Neoadjuvant Chemotherapy, Anti-PD-1 Antibody and Sitagliptin for Locally Advanced pMMR CRC (Neo-CD)

Zhejiang University

Status and phase: Not yet enrolling; Phase 2; Phase 1

Conditions: Colorectal Cancer

Treatments: Drug: Sitagliptin (DPP4 inhibitor); Drug: Oxaliplatin; Drug: Anti-PD-1 monoclonal antibody; Drug: Capecitabine

Study type: Interventional

Funder types: Other

Identifiers

NCT07365592

SAHZU Jun LI

Details and patient eligibility

About

This is an open-label, multicenter, phase Ib/II combined trial of sitagliptin, XELOX chemotherapy regimen, and PD-1 monoclonal antibody in the treatment of proficient mismatch repair locally advanced colorectal cancer.

Full description

Most colorectal cancer (CRC) cases are classified as proficient mismatch repair (pMMR) CRC. This subtype is insensitive to single-agent immunotherapy, with chemotherapy remaining the primary pharmacotherapeutic intervention. Approximately 30% of colon cancer patients develop recurrence and metastasis following initial radical resection combined with 6 months of adjuvant chemotherapy.

Neoadjuvant chemotherapy (NACT) for tumor downstaging and survival improvement represents a standard approach for locally advanced tumors. However, its application is limited to select rectal cancer populations, and its role in colon cancer remains controversial-primarily due to inadequate tumor regression observed with current regimens. Given that deep tumor regression correlates with improved survival, there is a critical need to enhance NACT efficacy.

Neo-CD adopts a combined phase Ib/II study design. Phase Ib Component

• Design: Single-center trial utilizing the traditional 3+3 dose-escalation principle.

• Objectives:

  1. Evaluate the safety of sitagliptin in combination with XELOX (oxaliplatin + capecitabine) and anti-PD-1 monoclonal antibody as neoadjuvant therapy for CRC.
  2. Determine the recommended phase II dose (RP2D) of sitagliptin.
  3. Explore the combination's potential for significant tumor regression and modulation of the tumor immune microenvironment.

Phase II Component

• Design: Prospective, multicenter, randomized controlled superiority trial.
• Objective: Compare the efficacy of neoadjuvant XELOX + sitagliptin + anti-PD-1 versus standard neoadjuvant XELOX in locally advanced CRC, with a focus on significant tumor regression (TRG 0/1 rate).

Study Procedures All participants will receive 2 cycles of the assigned neoadjuvant treatment, followed by radical surgery.

Primary Endpoints

• Phase Ib: Incidence of adverse events (AEs), serious adverse events (SAEs), and dose-limiting toxicity (DLT).
• Phase II: Proportion of patients achieving tumor regression grade 0/1 (TRG 0/1).

Enrollment: 138 estimated patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Pathologically diagnosed colorectal adenocarcinoma
• Age ≥18 years old and ≤75 years old
• MRI/CT stage T3-4aNany and TanyN1-2, without distant metastasis
• Life expectancy of 1 year The above
• Informed consent, no contraindications to chemotherapy exist
• pMMR diagnosed by IHC

Exclusion criteria

• Refused to participate in this study
• Multifocal colorectal cancer
• Past history of malignant tumors, except for basal cell carcinoma/papillary thyroid carcinoma/various types of carcinoma in situ
• Unable to receive chemotherapy , such as but not limited to bone marrow suppression, etc
• Major organ diseases (such as but not limited to COPD, coronary heart disease and renal insufficiency, etc.) acute attack and or severe acute infectious diseases (such as but not limited to hepatitis, pneumonia and myocarditis, etc.),
• ASA score> 3
• Mental disorder or illiteracy or language and communication barriers cannot understand the research plan
• Colorectal tumor has obstruction or high risk of obstruction and or there is bleeding and/or perforation
• Peripheral sensory nerve disorder, unable to receive oxaliplatin chemotherapy
• Lateral pelvic lymph node metastasis (mainly supplied by internal iliac artery)
• Pregnancy or breastfeeding
• Unable to accept MRI examination
• Consecutive use of glucocorticoids for more than 3 days within 1 month before signing the consent form
• Diabetes or impaired glucose tolerance who may require drug intervention
• Other scenarios deemed inappropriate by the investigators

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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138 participants in 2 patient groups

XELOX+sitagliptin+anti-PD-1

Experimental group

Description:

XELOX (oxaliplatin + capecitabine), sitagliptin and PD-1 monoclonal antibody

Treatment:

Drug: Capecitabine

Drug: Anti-PD-1 monoclonal antibody

Drug: Sitagliptin (DPP4 inhibitor)

Drug: Oxaliplatin

XELOX

Active Comparator group

Description:

XELOX (oxaliplatin + capecitabine)

Treatment:

Drug: Capecitabine

Drug: Oxaliplatin