Neoplasms

Symptoms and General Pathology

All Conditions

Digestive System Diseases

Neoplasm Metastasis

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Neoplastic Processes

Antineoplastic Agents

All Drugs and Chemicals

Hematinics

Pembrolizumab

Immunomodulating Agents

Liver Extracts

Vactosertib

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Neoadjuvant pembrolizumab will be administered at a fixed dose of 200 mg (IV) for 1 cycle plus 200 mg vactosertib (PO QD, 5 days per week x 2 weeks).

Adjuvant pembrolizumab (400 mg IV) + vactosertib (200 mg PO QD Cycle 1, 5 days per week, Cycles 2 and beyond (200 mg BID, 5 days per week) will be administered for up to eight 6-week cycles

Hepatectomy

Given orally once a day (QD) for cycle 1, and twice a day (BID) for cycle 2 and beyond

UCSF HDFCCC Cancer Immunotherapy Program (CIP)

UCSF HDFCCC Cancer Immunotherapy Program

Chloe E. Atreya, MD, PhD

Chloe Atreya, MD, Ph.D.

This phase II trials studies how well pembrolizumab and vactosertib work after standard of care chemotherapy in patients with colorectal cancer that has spread to the liver that can be removed by surgery (resectable hepatic metastases). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Vactosertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and vactosertib after standard of care chemotherapy, but before liver metastases surgery, may help shrink the cancer prior to surgery. This study also investigates pembrolizumab and vactosertib after liver metastases surgery, decrease the risk of the cancer recurring (coming back).

PRIMARY OBJECTIVE:

I. To characterize the change in the populations of tumor infiltrating lymphocytes (TILs) induced by neoadjuvant pembrolizumab plus vactosertib in patients with metastatic colorectal cancer (mCRC).

SECONDARY OBJECTIVES:

I. To establish the safety/toxicity profile of pembrolizumab-based treatment in the perioperative setting for patients with colorectal cancer (CRC) with resectable hepatic metastases.

II. To explore the efficacy of pembrolizumab plus vactosertib in patients with CRC with resectable hepatic metastases.

EXPLORATORY OBJECTIVES:

I. To determine the impact of pembrolizumab-based treatment on PD-L1 expression in tumor cells and tumor-infiltrating immune cells (TIICs), in patients with mCRC.

II. To determine the change in T cell repertoire within the tumor and blood induced by neoadjuvant pembrolizumab-based treatment in patients with mCRC.

III. To explore molecular profiles to identify potentially predictive biomarkers for patients with metastatic CRC treated with immunotherapy (including but not limited to microsatellite instability (MSI) testing).

IV. To correlate change in TIICs, PDL-1 expression, and T cell repertoires as well as molecular profiles with response/resistance and toxicity.

V. To identify immune response messenger ribonucleic acid (mRNA) expression analysis to derive signatures associated with tumor response.

VI. To identify genomic mutations and gene copy aberrations associated with response and resistance to therapy.

VII. To correlate changes in microbiome composition and diversity with diet and lifestyle factors.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and vactosertib orally (PO) once a day (QD) for the first cycle 5 days a week and twice daily (BID) 5 days a week for cycle 2 and greater followed by a 2-day resting period for 2 weeks in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care surgical removal of liver metastases approximately 2 weeks (minimum 1 week) after last dose of vactosertib.

OPTIONAL ADJUVANT TREATMENT: After surgery, eligible patients may also receive pembrolizumab and vactosertib every 6 weeks for up to 1 year in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients who do not undergo optional adjuvant treatment are followed up at 14 days and then every 90 days for up to 1 year. Patients who undergo optional adjuvant treatment are followed up at 30 days and then every 90 days for up to 2 years.

Preoperative Immunotherapy (Pembrolizumab) for Patients With Colorectal Cancer and Resectable Hepatic Metastases

A Phase II Study of Preoperative Immunotherapy in Patients With Colorectal Cancer and Resectable Hepatic Metastases

Tumor-infiltrating immune cells (TIICs) will be analyzed by immunohistochemistry (IHC) in pre- and post-pembrolizumab treatment tumor specimens. The proportion of patients with a \>= 2-fold increase (from pre- to post-treatment) in the number of TIICs per unit area (5 high power fields) will be calculated.

Adverse events (AEs) will be analyzed including but not limited to all AEs, serious (S)AEs, and fatal AEs using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5 for classification. Due to the potential for late toxicities from pembrolizumab, patients will be followed for 1 year after their last dose of pembrolizumab.

Specific immune-related AEs (irAEs) will be collected and designated as immune-related events of clinical interest (ECIs). The study will use descriptive statistics to report on the safety/toxicity. Due to the potential for late toxicities from pembrolizumab, patients will be followed for 1 year after their last dose of pembrolizumab

The proportion of participants with reported perioperative complications related to study treatment will be reported.

Participants who undergo surgical resection of liver metastases will be evaluable and the proportion of participants requiring an R0 resection will be reported

Participants who undergo surgical resection of liver metastases will be evaluable and the proportion of participants with a pathological tumor response will be reported

Participants with a complete response (CR) or partial response (PR) using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 will be reported.

The time from objective response to progression or death will be used to determine relapse-free survival.

Spots Global Cancer Trial Database for resectable hepatic metastases