Clinical Trials /

Phase I Trial of Adjuvant Pembrolizumab After Radiation Therapy for Lung-Intact Malignant Pleural Mesothelioma

NCT02959463

Description:

This phase I trial studies the side effects and best way to give pembrolizumab after radiation therapy in treating patients with pleural malignant mesothelioma. Radiation therapy uses high energy radiation to kill tumor cells and shrink tumors. 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. Giving pembrolizumab after radiation therapy may kill more tumor cells.

Related Conditions:
  • Malignant Pleural Mesothelioma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Phase I Trial of Adjuvant Pembrolizumab After Radiation Therapy for Lung-Intact Malignant Pleural Mesothelioma
  • Official Title: Phase I Trial of Adjuvant Pembrolizumab After Radiation Therapy for Lung-Intact Malignant Pleural Mesothelioma

Clinical Trial IDs

  • ORG STUDY ID: 2015-0856
  • SECONDARY ID: NCI-2016-01923
  • SECONDARY ID: 2015-0856
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT02959463

Conditions

  • Pleural Malignant Mesothelioma

Interventions

DrugSynonymsArms
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Cohort 1 (hemithoracic radiation therapy, pembrolizumab)

Purpose

This phase I trial studies the side effects and best way to give pembrolizumab after radiation therapy in treating patients with pleural malignant mesothelioma. Radiation therapy uses high energy radiation to kill tumor cells and shrink tumors. 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. Giving pembrolizumab after radiation therapy may kill more tumor cells.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the safety and tolerability of pembrolizumab administered after radiation
      therapy in patients with malignant pleural mesothelioma (MPM) who have not undergone
      extrapleural pneumonectomy.

      SECONDARY OBJECTIVES:

      I. To assess progression-free and overall survival (progression free survival [PFS] and
      overall survival [OS], respectively) in patients receiving pembrolizumab after radiation
      therapy for malignant pleural mesothelioma (MPM).

      EXPLORATORY OBJECTIVES:

      I. To evaluate biomarkers of interest, including cytokines, measurements of T-cell
      activation, and serum exosome micro ribonucleic acid (RNA)s with the delivery of
      pembrolizumab after radiation therapy for MPM.

      OUTLINE: Patients are assigned to 1 of 2 cohorts.

      COHORT 1: Patients undergo hemithoracic radiation therapy.

      COHORT 2: Patients undergo palliative radiation therapy over 1-3 weeks to only the region of
      palliation (a region that does not include the entire side of the chest or thorax).

      After radiation therapy, both cohorts receive pembrolizumab intravenously (IV) over about 30
      minutes on day 1. Courses repeat every 3 weeks for up to 2 years in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days, every 6 weeks for
      48 weeks, then every 12 weeks for up to 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort 1 (hemithoracic radiation therapy, pembrolizumab)ExperimentalPatients undergo hemithoracic radiation therapy. After radiation therapy, patients receive pembrolizumab IV over about 30 minutes on day 1. Courses repeat every 3 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity.
  • Pembrolizumab
Cohort 2 (palliative radiation therapy, pembrolizumab)ExperimentalPatients undergo palliative radiation therapy over 1-3 weeks to only the region of palliation (a region that does not include the entire side of the chest or thorax). After radiation therapy, patients receive pembrolizumab IV over about 30 minutes on day 1. Courses repeat every 3 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity.
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have a histologic diagnosis of malignant pleural mesothelioma, with
             histologic diagnosis from the pleura or relevant lymph node stations, including
             mediastinal, hilar, or supraclavicular lymph nodes

          -  Be willing and able to provide written informed consent/assent for the trial

          -  Have measurable or non-measurable disease per Response Evaluation Criteria in Solid
             Tumors (RECIST) 1.1; however, note that patients in Cohort 1 that have undergone an R0
             resection will be eligible for the trial

          -  Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
             performance scale

          -  Absolute neutrophil count (ANC) >=1,500 /mcL (within 10-15 days of treatment
             initiation)

          -  Platelets >= 100,000 /mcL (within 10-15 days of treatment initiation)

          -  Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO)
             dependency (within 7 days of assessment) (within 10-15 days of treatment initiation)

          -  Serum 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]) >= 60 mL/min for subject with creatinine
             levels > 1.5 X institutional ULN (within 10-15 days of treatment initiation)

          -  Serum total bilirubin =< 1.5 X ULN or direct bilirubin =< ULN for subjects with total
             bilirubin levels > 1.5 ULN (within 10-15 days of treatment initiation)

          -  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 (within 10-15 days of treatment
             initiation)

          -  Albumin >= 2.5 mg/dL (within 10-15 days of treatment initiation)

          -  International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless
             subject is receiving anticoagulant therapy as long as PT or partial thromboplastin
             time (PTT) is within therapeutic range of intended use of anticoagulants (within 10-15
             days of treatment initiation)

          -  Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving
             anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
             of anticoagulants (within 10-15 days of treatment initiation)

          -  Female subject of childbearing potential should have a negative urine or serum
             pregnancy within 72 hours prior to receiving the first dose of study medication; if
             the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
             will be required

          -  Female subjects of childbearing potential should be willing to use 2 methods of birth
             control or be surgically sterile, or abstain from heterosexual activity for the course
             of the study through 120 days after the last dose of study medication; subjects of
             childbearing potential are those who have not been surgically sterilized or have not
             been free from menses for > 1 year

          -  Male subjects should agree to use an adequate method of contraception starting with
             the first dose of study therapy through 120 days after the last dose of study therapy

          -  COHORT 1 (PATIENTS RECEIVING HEMITHORACIC RADIATION THERAPY)

          -  Patients must not have evidence of metastatic disease per positron emission tomography
             (PET)/ computed tomography (CT) scan; mediastinal lymph node involvement is acceptable

          -  Patients will have received at least 2 cycles of induction chemotherapy with
             pemetrexed/cisplatin or pemetrexed/carboplatin

          -  Forced expiratory volume in 1 second (FEV1) >= 30% of predicted postoperative
             (ppoFEV1, as if patient underwent a pneumonectomy)

          -  Diffusing capacity of the lungs for carbon monoxide (DLCO) > 35% predicted

          -  Patients must be assessed to be a suitable candidate for hemithoracic radiation
             therapy per the treating radiation oncologist; if the patient undergoes
             pleurectomy/decortication, they must initiate hemithoracic radiation therapy within 4
             months of the surgery date; patients that do not meet the dose constraints outlined
             below will be removed from the study prior to radiation therapy

          -  COHORT 2 INCLUSION CRITERIA

          -  Patients must be assessed to be a suitable candidate for radiation therapy by the
             treating radiation oncologist; patients that do not meet the dose constraints outlined
             below will be removed from the study prior to radiation therapy

          -  Any prior number of prior therapies, including prior immunotherapy, is allowed

          -  Patient must have prior treatment with a platinum plus pemetrexed regimen

        Exclusion Criteria:

          -  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; note that patients should not receive steroids
             during pembrolizumab administration

          -  Has a known history of active tuberculosis (TB) (Bacillus tuberculosis)

          -  Hypersensitivity to pembrolizumab or any of its excipients

          -  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 and who have not recovered adequately from this
             treatment (=< grade 2 toxicity at the time of enrollment)

          -  Has a known additional malignancy that is progressing or requires active treatment;
             patients with a stage I-III cancer that has been cured over two years ago are not
             excluded in the study

          -  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 a history of (non-infectious) pneumonitis that required steroids or current
             pneumonitis

          -  Has an active infection requiring systemic therapy

          -  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 trial, starting with the pre-screening or screening visit
             through 120 days after the last dose of trial treatment

          -  Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

          -  Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
             hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is
             detected)

          -  Has received a live vaccine within 30 days of planned start of study therapy

               -  Note: seasonal influenza vaccines for injection are generally inactivated flu
                  vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist)
                  are live attenuated vaccines, and are not allowed

          -  Evidence of interstitial lung disease

          -  COHORT 1 EXCLUSION CRITERIA

          -  Patients undergoing an extrapleural pneumonectomy (EPP); lung sparing surgeries, such
             as pleurectomy/decortication, are acceptable

          -  Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent

          -  COHORT 2 EXCLUSION CRITERIA

          -  Patients in which hemithoracic radiation therapy is planned

          -  Patients who have received EPP for mesothelioma

          -  COHORTS 1 AND 2 EXCLUSION CRITERIA

          -  Patients with inherited syndromes associated with hypersensitivity to ionizing
             radiation, specifically patients with known history of ataxia-telengiectasia, Nijmegen
             breakage syndrome
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of treatment-related adverse events
Time Frame:Up to at least 4 months from start of radiation therapy
Safety Issue:
Description:For each study cohort, will tabulate toxicities by dose, severity, and relationship to the treatment plan. If treatment-related toxicity rate is more than 30%, the trial will stop.

Secondary Outcome Measures

Measure:Progression-free survival assessed according to Response Evaluation Criteria for Solid Tumors version 1.1
Time Frame:Up to 5 years
Safety Issue:
Description:Estimated using the method of Kaplan and Meier.
Measure:Overall survival assessed according to Response Evaluation Criteria for Solid Tumors version 1.1
Time Frame:Up to 5 years
Safety Issue:
Description:Estimated using the method of Kaplan and Meier.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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