Clinical Trials /

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

NCT04082572

Description:

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). 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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab Before Surgery for the Treatment of Mismatch Repair Deficient Locally Advanced Solid Cancers
  • Official Title: Neoadjuvant Pembrolizumab for Patients With Mismatch Repair Deficient Locally Advanced Solid Cancers

Clinical Trial IDs

  • ORG STUDY ID: 2018-1182
  • SECONDARY ID: NCI-2019-05822
  • SECONDARY ID: 2018-1182
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT04082572

Conditions

  • High-Frequency Microsatellite Instability
  • Locally Advanced Malignant Solid Neoplasm
  • Loss of MLH1 Expression
  • Loss of MSH2 Expression
  • Loss of MSH6 Expression
  • Loss of PMS2 Expression
  • Mismatch Repair Protein Deficiency

Interventions

DrugSynonymsArms
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (pembrolizumab)

Purpose

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). 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.

Detailed Description

      PRIMARY OBJECTIVES:

      I. 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:

      I. 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.

      V. 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.

      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 12 weeks, and then every 6 months for up to 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
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.
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  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 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)

          -  Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/La (within 14 days prior to the start of study
             treatment)

          -  Creatinine OR measured or calculated creatinine clearance (glomerular filtration rate
             [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) =< 1.5 x
             upper limit of normal (ULN) OR >= 30 mL/min for participant with creatinine levels >
             1.5 x institutional ULN (within 14 days prior to the start of study treatment)

          -  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)

        Exclusion Criteria:

          -  A 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-Guérin (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)

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Pathological complete response
Time Frame:At 1 year
Safety Issue:
Description:Estimated with 95% confidence interval.

Secondary Outcome Measures

Measure:Rate of organ sparing
Time Frame:At 1 year
Safety Issue:
Description:Estimated with 95% confidence interval.
Measure:Incidence of adverse events
Time Frame:Up to 2 years
Safety Issue:
Description:Safety will be recorded according to Common Terminology Criteria for Adverse Events toxicity and also post-operative complications will be classified according to Clavien-Dindo classification1.
Measure:Overall survival
Time Frame:From treatment start till death or last follow-up, assessed up to 2 years
Safety Issue:
Description:Will be estimated using the method of Kaplan and Meier.
Measure:Relapse-free survival
Time Frame:Up to 2 years
Safety Issue:
Description:Defined as the number of days from the date of response to the date of documented treatment failure, relapses or death from any cause, whichever occurs first. Will be estimated using the method of Kaplan and Meier.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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