Pembrolizumab, Capecitabine, and Bevacizumab for Treating Colorectal Cancer

NCT03396926 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 174517NCI-2017-02324
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 1

Brief Summary

This phase II trial studies the side effects and best dose of capecitabine when given together with pembrolizumab and bevacizumab, and investigates how well they work in treating patients with microsatellite stable colorectal cancer that has spread to nearby tissues or lymph nodes, has spread to other places in the body, or that cannot be removed by surgery. Monoclonal antibodies, such as pembrolizumab and bevacizumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving capecitabine together with pembrolizumab and bevacizumab may work better in treating patients with colorectal cancer.

Conditions

Microsatellite Stable; Mismatch Repair Protein Proficient; Stage III Colorectal Cancer AJCC v7; Stage IIIB Colorectal Cancer AJCC v7; Stage IIIC Colorectal Cancer AJCC v7; Stage IV Colorectal Cancer AJCC v7; Stage IVA Colorectal Cancer AJCC v7; Stage IVB Colorectal Cancer AJCC v7

Outcome Measures

Primary Outcomes (2)

• Proportion of Participants With Treatment-related, Dose-limiting Toxicities (DLT) (Safety Lead-In Cohort)

  A DLT evaluation of the first 6 participants will be conducted to confirm the safety of administering pembrolizumab at 200 mg (flat dosing) every three weeks with capecitabine and bevacizumab and include all participants in the safety lead in cohort who received at least 1 dose of study treatment. At least one laboratory or vital sign measurement obtained subsequent to at least one dose of study treatment is required for inclusion in the analysis including a baseline measure. Dose-limiting toxicity (DLT) must be clinically-significant toxicities which are at least possibly treatment-related per the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4

  Up to 1 cycle (each cycle is 21 days)

• Overall Response Rate (ORR)

  ORR is defined as the percentage of the participants in the ASaT population who have a confirmed complete response (CR) or a partial response (PR) (Overall Response (OR) = CR + PR) assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 on Computerized Tomography (CT) or magnetic resonance imaging or (MRI) imaging if a CT cannot be obtained. The ORR and 95% confidence interval will be provided using exact binomial method proposed by Clopper and Pearson (1934).

  Up to 4 years

Secondary Outcomes (4)

• Disease Control Rate (DCR)

  Up to 4 years

• Median Duration of Response (DOR)

  Up to 4 years

• Median Overall Survival (OS)

  Up to 4 years

• Median Progression-Free Survival (PFS)

  Up to 4 years

Study Arms (2)

Safety Lead in Cohort: Treatment (pembrolizumab, bevacizumab, capecitabine)

EXPERIMENTAL

Participants receive pembrolizumab IV over 30 minutes on day 1, bevacizumab IV over 30-90 minutes on day 1, and capecitabine PO BID on days 1-14. Treatment repeats every 3 weeks for up to 35 courses in the absence of disease progression or unacceptable toxicity.

Biological: Bevacizumab; Drug: Capecitabine; Procedure: Specimen collection; Biological: Pembrolizumab

Expansion Cohort: Treatment (pembrolizumab, bevacizumab, capecitabine)

EXPERIMENTAL

Participants receive pembrolizumab IV over 30 minutes on day 1, bevacizumab IV over 30-90 minutes on day 1, and capecitabine PO BID on days 1-14. Treatment repeats every 3 weeks for up to 35 courses in the absence of disease progression or unacceptable toxicity.

Biological: Bevacizumab; Drug: Capecitabine; Procedure: Specimen collection; Biological: Pembrolizumab

Interventions

Bevacizumab BIOLOGICAL

Given intravenously (IV)

Also known as: Anti-VEGF, Anti-VEGF Humanized Monoclonal Antibody, Anti-VEGF rhuMAb, Avastin, Bevacizumab Biosimilar BEVZ92, Bevacizumab Biosimilar BI 695502, Bevacizumab Biosimilar CBT 124, Bevacizumab Biosimilar FKB238, BEVACIZUMAB, LICENSE HOLDER UNSPECIFIED, Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer, Recombinant Humanized Anti-VEGF Monoclonal Antibody, rhuMab-VEGF

Expansion Cohort: Treatment (pembrolizumab, bevacizumab, capecitabine); Safety Lead in Cohort: Treatment (pembrolizumab, bevacizumab, capecitabine)

Capecitabine DRUG

Given orally (PO)

Also known as: Ro 09-1978/000, Xeloda

Expansion Cohort: Treatment (pembrolizumab, bevacizumab, capecitabine); Safety Lead in Cohort: Treatment (pembrolizumab, bevacizumab, capecitabine)

Specimen collection PROCEDURE

For use in correlative studies

Expansion Cohort: Treatment (pembrolizumab, bevacizumab, capecitabine); Safety Lead in Cohort: Treatment (pembrolizumab, bevacizumab, capecitabine)

Pembrolizumab BIOLOGICAL

Given IV

Also known as: Keytruda, Lambrolizumab, MK-3475, SCH 900475

Expansion Cohort: Treatment (pembrolizumab, bevacizumab, capecitabine); Safety Lead in Cohort: Treatment (pembrolizumab, bevacizumab, capecitabine)

Eligibility Criteria

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

You may qualify if:

• Have histologically confirmed, locally advanced unresectable or metastatic (stage IV) colorectal adenocarcinoma
• Have locally confirmed MSS or pMMR CRC; MSS is defined as 0-1 allelic shifts among 3-5 tumor microsatellite loci using a PCR-based assay; pMMR is defined as presence of protein expression of 4 MMR enzymes (DNA mismatch repair protein Mlh1 (MLH1), DNA mismatch repair protein Msh2 (MSH2), mutS homolog 6 (MSH6) and Mismatch repair endonuclease postmeiotic segregation increased 2 (PMS2) by immunohistochemistry.
• Have stable disease or progression on a prior regimen containing infusional 5-FU or capecitabine according to the interpretation of the treating provider
• Be willing and able to provide written informed consent/assent for the trial
• Be 18 years of age on day of signing informed consent
• Have measurable disease based on RECIST 1.1
• Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion (phase II dose expansion cohort only); newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on day 1; subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the Sponsor
• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
• Demonstrate adequate organ function performed within 10 days of treatment initiation as defined below:
• Absolute neutrophil count (ANC) \>= 1,500 /mcL
• Platelets \>= 100,000 / microliter (mcL)
• Hemoglobin \>= 9 g/dL or \>= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)
• Serum creatinine =\< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance \>= 60 mL/min for subject with creatinine levels \> 1.5 X institutional ULN. Glomerular filtration rate (GFR) can also be used in place of creatinine or creatinine clearance (CrCl)). Creatinine clearance should be calculated per institutional standard
• Serum total bilirubin =\< 1.5 X ULN OR direct bilirubin =\< ULN for subjects with total bilirubin levels \> 1.5 ULN. Patients with Gilbert's disease may be included if their direct bilirubin is ≤ 1.5 X ULN.
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase (SGOT)) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase (SGPT)) =\< 2.5 X ULN OR =\< 5 X ULN for subjects with liver metastases

You may not qualify if:

• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
• Has a known history of active tuberculosis (TB) (Bacillus Tuberculosis)
• Hypersensitivity to pembrolizumab or any of its excipients
• Hypersensitivity/intolerance to capecitabine, Infusional 5-Fluorouracil (5-FU), or bevacizumab
• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =\< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
• Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =\< grade 1 or at baseline) from adverse events due to a previously administered agent
• Note: Subjects with =\< grade 2 neuropathy are an exception to this criterion and may qualify for the study
• Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
• Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Has known history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or current pneumonitis/interstitial lung disease.
• Has an active infection at the time of cycle 1 day 1 requiring systemic therapy
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator

Sponsors & Collaborators

• University of California, San Francisco: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (1)

University of California, San Francisco

San Francisco, California, 94143, United States

Location

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Bevacizumab; Immunoglobulin G; Disulfides; Capecitabine; Specimen Handling; pembrolizumab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Immunoglobulin Isotypes; Sulfides; Anions; Ions; Electrolytes; Inorganic Chemicals; Hydrogen Sulfide; Sulfur Compounds; Organic Chemicals; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques

Results Point of Contact

• Title: Dr.Chloe Atreya, MD, PhD
• Organization: University of California, San Francisco

chloe.atreya@ucsf.edu

(415) 353-9888

Study Officials

• Chloe Atreya, MD, PhD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 5, 2018
• First Posted: January 11, 2018
• Study Start: April 18, 2018
• Primary Completion: January 30, 2024
• Study Completion: January 30, 2024
• Last Updated: February 28, 2025
• Results First Posted: February 28, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)