Pembrolizumab Before Surgery for the Treatment of Mismatch Repair Deficient Locally Advanced Solid Cancers

NCT04082572 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 2018-1182NCI-2019-05822
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 1

Brief Summary

This phase II trial studies how well pembrolizumab works before surgery in treating patients with mismatch repair deficient solid cancers that have spread to nearby tissue or lymph nodes (locally advanced). Cancer is caused by changes (mutations) to genes (DNA) that control the way cells function, and some of these mutations can cause tumor cells to grow quickly and out of control. Microsatellite instability-high (MSI-H) tumors are made up of cancer cells that have a greater than normal number of genetic markers called microsatellites. These cancers may have defects in the ability to correct mutations that occur when DNA is copied in the cell. Similarly, mismatch repair deficient tumors (dMMR) may have difficulty repairing some type of genetic mutation during cellular replication that may affect tumor's response to cancer therapy. 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.

Conditions

Locally Advanced Malignant Solid Neoplasm

Outcome Measures

Primary Outcomes (3)

• Pathological Complete Response (pCR).

  Number of patients with Pathologic complete response (pCR) as defined by absence of any residual viable tumor of the macroscopically identifiable tumor bed or lymph node after 3 doses.

  1 year

• Safety of Neo-adjuvant Pembrolizumab in Patients With Locally Advanced (Unresectable Primary Cancer or Resectable Primary Cancer With a High Chance of Recurrence) Mismatch Repair Protein Deficiency (dMMR) Solid Organ Tumors.

  Number of patients that developed toxicity as assessed by Common Terminology Criteria for Adverse Events (CTCAE) Version 4.

  At 1 year

• Post-surgical Complication Assessment by the Clavien- Dindo Classification.

  Number of patients with post surgical complication based on the Clavien-Dindo Classification

  Up to 2 years

Secondary Outcomes (2)

• Overall Response Rate

  From treatment start till death or last follow-up, assessed up to 2 years

• Radiographic Tumor Response to Neoadjuvant Pembrolizumab.

  1 year

Study Arms (1)

Treatment (pembrolizumab)

EXPERIMENTAL

Patients receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for 1 year in the absence of disease progression or unacceptable toxicity. Patients who do not respond to pembrolizumab and stop the treatment after 2 doses may undergo surgery within 6 months.

Biological: Pembrolizumab

Interventions

Pembrolizumab BIOLOGICAL

Given IV

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

Treatment (pembrolizumab)

Eligibility Criteria

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

You may qualify if:

• Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of solid cancer
• Solid cancer that is deficient in mismatch repair (dMMR) or microsatellite instability high (MSI-H) as determined by one of three methods:
• Immunohistochemistry determined dMMR by complete loss of MLH1, PMS2, MSH2 or MSH6
• Polymerase chain reaction (PCR) determined microsatellite instability at \> 30% of tested microsatellites
• Next-generation sequencing determined MSI-H based upon instability at multiple microsatellites as determined by the specific next generation sequencing panel
• Locally advanced cancer defined as either an unresectable primary cancer or a resectable primary cancer with a high chance of recurrence (defined as an estimated greater or equal to 20% chance of recurrence by the treating physician). A resectable primary may include locoregional disease, as long as all disease is felt by the treating physician to be in a resectable distribution
• The participant (or legally acceptable representative if applicable) provides written informed consent for the trial
• Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 (unless discussed and approved by study principal investigator \[PI\])
• Have available archival tumor tissue. Availability will be met as long as a request to obtain formalin-fixed, paraffin embedded (FFPE) tissue blocks (preferred) or slides has been made (unless discussed and approved by study PI)
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the date of signing study consent
• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
• Not a woman of childbearing potential (WOCBP) OR
• A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least (120 days \[corresponding to time needed to eliminate any study treatment(s) plus 30 days (a menstruation cycle) for risk of genotoxicity\]) after the last dose of study treatment
• Absolute neutrophil count (ANC) \>= 1500/uL (within 14 days prior to the start of study treatment)
• Platelets \>= 100 000/uL (within 14 days prior to the start of study treatment)

You may not qualify if:

• A woman of childbearing potential (WOCBP) who has a positive urine pregnancy test within 72 hours prior to enrollment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Note: in the event that 72 hours have elapsed between the screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative in order for subject to start receiving study medication
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137)
• Has received prior systemic anti-cancer therapy including investigational agents within 2 weeks of study treatment. Note: Participants must have recovered from all adverse events (AEs) due to previous therapies to =\< grade 1 or baseline. Participants with =\< grade 2 neuropathy may be eligible
• If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment
• Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (=\< 2 weeks of radiotherapy) to non-central nervous system (CNS) disease
• Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment. Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
• Has a known additional malignancy that is progressing or has required active treatment within the past 1 year. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) or other similar good prognosis cancer with recurrence rates expected to be \< 10% that have undergone potentially curative therapy are not excluded
• Known metastatic sites of disease. Note: locoregional lymph nodes or tumor deposits are not considered metastatic disease
• Has severe hypersensitivity (\>= grade 3) to pembrolizumab and/or any of its excipients
• 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 a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
• Has an active infection requiring systemic therapy
• Has a known history of human immunodeficiency virus (HIV)

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (2)

• Ludford K, Ho WJ, Thomas JV, Raghav KPS, Murphy MB, Fleming ND, Lee MS, Smaglo BG, You YN, Tillman MM, Kamiya-Matsuoka C, Thirumurthi S, Messick C, Johnson B, Vilar E, Dasari A, Shin S, Hernandez A, Yuan X, Yang H, Foo WC, Qiao W, Maru D, Kopetz S, Overman MJ. Neoadjuvant Pembrolizumab in Localized Microsatellite Instability High/Deficient Mismatch Repair Solid Tumors. J Clin Oncol. 2023 Apr 20;41(12):2181-2190. doi: 10.1200/JCO.22.01351. Epub 2023 Jan 9.

  PMID: 36623241 DERIVED

• Mendonca Gorgulho C, Krishnamurthy A, Lanzi A, Galon J, Housseau F, Kaneno R, Lotze MT. Gutting it Out: Developing Effective Immunotherapies for Patients With Colorectal Cancer. J Immunother. 2021 Feb-Mar 01;44(2):49-62. doi: 10.1097/CJI.0000000000000357.

  PMID: 33416261 DERIVED

Related Links

• M D Anderson Cancer Center

MeSH Terms

Interventions

pembrolizumab

Results Point of Contact

• Title: Michael J. Overman, MD
• Organization: M.D. Anderson Cancer Center

moverman@mdanderson.org

(713) 792-2828

Study Officials

• Michael J Overman, MD

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

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: September 5, 2019
• First Posted: September 9, 2019
• Study Start: October 31, 2019
• Primary Completion: November 8, 2024
• Study Completion: November 8, 2024
• Last Updated: May 13, 2025
• Results First Posted: May 13, 2025

Record last verified: 2025-05

Locations

US (1)