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Locally Advanced Malignant Solid NeoplasmPhase 2NCT04082572

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

A Phase 2 study testing Pembrolizumab in people with Locally Advanced Malignant Solid Neoplasm, run by M.D. Anderson Cancer Center at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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). Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Pembrolizumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
35 participants
Where
1 siteUnited States
Study dates
31 Oct 2019to 8 Nov 2024
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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)
  • Hemoglobin >= 8.0 g/dL or >= 5.6 mmol/L (within 14 days prior to the start of study treatment)
  • Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks
  • Creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 30 mL/min for participant with creatinine levels > 1.5 x institutional ULN (within 14 days prior to the start of study treatment)
  • Creatinine clearance (CrCl) should be calculated per institutional standard
  • Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with total bilirubin levels > 1.5 x ULN (within 14 days prior to the start of study treatment)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN (=< 5 x ULN for participants with liver metastases) (within 14 days prior to the start of study treatment)
  • International normalized ratio (INR) OR prothrombin time (PT) activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants (within 14 days prior to the start of study treatment)

Who cannot join

  • 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
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  • 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)
  • Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as HCV ribonucleic acid [RNA] [qualitative] is detected) infection. Note: no testing for hepatitis B and hepatitis C is required unless mandated by local health authority
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
  • Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment

Trial locations and contacts

1 site in 1 country.

United States1 site

  • M D Anderson Cancer Center

    Houston, Texas, 77030

Other trials in United States

About this study

Official title: Neoadjuvant Pembrolizumab for Patients With Mismatch Repair Deficient Locally Advanced Solid Cancers

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To assess the 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 by Common Terminology Criteria for Adverse Events (CTCAE) assessed toxicity and post-surgical complication assessment by the Clavien-Dindo classification.

II. To assess the rate of complete pathological response for patients who undergo surgical resection following at least 3 doses of neoadjuvant pembrolizumab.

SECONDARY OBJECTIVES:

  1. To quantify the rate of organ sparing at 1 year for all patients treated with one dose of pembrolizumab (intent to treat) and those patients who receive at least 3 doses of neoadjuvant pembrolizumab and decline to undergo surgical resection and opt to continue receiving pembrolizumab for a total of 1 year.

II. To assess radiographic tumor response to neoadjuvant pembrolizumab. III. To estimate the relapse-free survival and overall survival in all enrolled participants.

IV. To determine the overall rates of pathological response to neoadjuvant pembrolizumab.

  1. To assess the rate of complete pathological response (intent to treat) for patients who undergo surgical resection following at least 1 dose of neoadjuvant pembrolizumab.

EXPLORATORY OBJECTIVE:

  1. To explore the predictive ability of changes in circulating tumor-derived deoxyriboucleic acid (ctDNA) for efficacy endpoints.

II. To determine if total mutational burden correlate with response and extent of benefit from pembrolizumab.

III. To correlate pre-treatment tumor samples tumor-immune microenvironment (for example Teffector cell populations; CD4 subsets; T-regulatory populations; B cell populations; dendritic and macrophage populations) with efficacy endpoints.

IV. To compare targeted gene expression profiles of immune related genes and genes pertaining to common cancer signaling pathways in pre-treatment samples and also the change in these factors for cases with both pre and on-treatment (i.e. at time of resection) tumor samples of responders (stable disease or radiographic response prior to resection) versus non-responders (progression prior to resection).

OUTLINE:

Patients receive pembrolizumab intravenously (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.

After completion of study treatment, patients are followed up at 30 days, every 6 weeks for 1 year, every 9-12 weeks thereafter.

Being tested
Pembrolizumab

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PembrolizumabBiological

    Also called Keytruda, Lambrolizumab, MK-3475, SCH 900475

    Given IV

Study groups in NCT04082572
Study groupRoleWhat they receive
Treatment (pembrolizumab)ExperimentalPatients 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.
Receives: Biological: Pembrolizumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 1 year

  2. 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.

    Measured: At 1 year

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

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

    Measured: Up to 2 years

Secondary outcomes (2)

  1. Overall Response Rate

    The ORR was estimated using Recist 1.1. ORR (Complete response + Partial response)

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

  2. Radiographic Tumor Response to Neoadjuvant Pembrolizumab.

    Best overall RECIST response as determined by the number of patients with Partial Response and or Complete Response measured using Recist v1.1

    Measured: 1 year

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted9 Sep 2019
  2. Study start31 Oct 2019
  3. Primary completion8 Nov 2024
  4. Study completion8 Nov 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
35 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04082572
Sponsor's protocol ID
2018-1182
Other IDs
NCI-2019-05822, 2018-1182
Status last verified
May 2025
First submitted
5 Sep 2019
Last updated
13 May 2025
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • 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.

    PubMed 36623241

  • 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.

    PubMed 33416261

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Pembrolizumab in people with Locally Advanced Malignant Solid Neoplasm, run by M.D. Anderson Cancer Center at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 22 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 13 May 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 13 May 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Pathological Complete Response (pCR). (time frame: 1 year). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04082572, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 May 2025.

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