Clinical Trials /

Dendritic Cell Therapy, Cryosurgery, and Pembrolizumab in Treating Patients With Non-Hodgkin Lymphoma

NCT03035331

Description:

This phase I/II trial studies the best dose and side effects of dendritic cell therapy, cryosurgery and pembrolizumab in treating patients with non-Hodgkin lymphoma. Vaccines, such as dendritic cell therapy made from a person's tumor cells and white blood cells may help the body build an effective immune response to kill tumor cells. Cryosurgery kills cancer cells by freezing them. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Giving dendritic cell therapy, cryosurgery and pembrolizumab may work better at treating non-Hodgkin lymphoma.

Related Conditions:
  • Non-Hodgkin Lymphoma
  • Small Lymphocytic Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Dendritic Cell Therapy, Cryosurgery, and Pembrolizumab in Treating Patients With Non-Hodgkin Lymphoma
  • Official Title: Phase I/II Study of Dendritic Cell Therapy Delivered Intratumorally After Cryoablation and Anti-PD-1 Antibody (Pembrolizumab) for Patients With Non-Hodgkin Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: MC1685
  • SECONDARY ID: NCI-2017-00113
  • SECONDARY ID: MC1685
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT03035331

Conditions

  • Aggressive Non-Hodgkin Lymphoma
  • Indolent Non-Hodgkin Lymphoma
  • Recurrent Adult Non-Hodgkin Lymphoma
  • Recurrent Diffuse Large B-Cell Lymphoma
  • Recurrent Follicular Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Recurrent Marginal Zone Lymphoma
  • Recurrent Mediastinal (Thymic) Large B-Cell Cell Lymphoma
  • Recurrent T-Cell Non-Hodgkin Lymphoma
  • Small Lymphocytic Lymphoma

Interventions

DrugSynonymsArms
Dendritic Cell TherapyDendritic Cell Vaccine TherapyTreatment (pembrolizumab, dendritic cell therapy, cryosurgery)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (pembrolizumab, dendritic cell therapy, cryosurgery)
Pneumococcal 13-valent Conjugate VaccinePCV 13, PCV13 Vaccine, Prevnar 13Treatment (pembrolizumab, dendritic cell therapy, cryosurgery)

Purpose

This phase I/II trial studies the best dose and side effects of dendritic cell therapy, cryosurgery and pembrolizumab in treating patients with non-Hodgkin lymphoma. Vaccines, such as dendritic cell therapy made from a person's tumor cells and white blood cells may help the body build an effective immune response to kill tumor cells. Cryosurgery kills cancer cells by freezing them. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Giving dendritic cell therapy, cryosurgery and pembrolizumab may work better at treating non-Hodgkin lymphoma.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Evaluate the optimal dose schedule, safety and tolerability as measured by the incidence
      of significant toxicity of combination therapy with anti-PD-1 monoclonal antibody,
      cryoablation, and intra-tumor injection of autologous dendritic cell into the cryoablated
      tumor. (Phase I) II. Test the efficacy (overall response rate) of combination therapy with
      anti-PD-1 monoclonal antibody, cryoablation, and intra-tumor injection of autologous
      dendritic cell vaccine. (Phase II)

      SECONDARY OBJECTIVES:

      I. Evaluate the feasibility of this combination immunotherapy. (Phase I) II. Evaluate
      patient quality of life. (Phase I) III. Evaluate the partial response (PR) and complete
      response (CR) rate of this combination immunotherapy. (Phase II) IV. Evaluate the
      progression free survival, treatment free survival, duration of response, disease-free rate
      at 2 years, and overall survival of this combination immunotherapy. (Phase II) V. Evaluate
      the safety of this combination immunotherapy. (Phase II)

      TERTIARY OBJECTIVES:

      I. Assess the effect of combination immunotherapy on patients' immune status and anti-tumor
      immune response.

      II. Assess the potential association between PD-1/PD-L1/PD-L2 expression in tumor and blood
      with clinical efficacy.

      III. Assess the potential association between tumor antigen mutations and antigen-specific
      immune response with clinical efficacy.

      IV. Evaluate patient quality of life.

      OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

      Patients receive pembrolizumab intravenously (IV) on day 1. Treatment repeats every 21 days
      for up to 18 courses in the absence of disease progression or unacceptable toxicity.
      Patients also receive dendritic cell therapy intratumorally (IT) on days 2, 8, and 15 of
      courses 2 and 3, and day 2 of courses 4 and 5. Patients undergo cryosurgery on day 2 of
      course 2 and receive pneumococcal 13-valent conjugate vaccine by injection on day 2 of
      courses 2-5. Treatment repeats every 21 days for up to 5 courses in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 4 months during the
      second year post-treatment, and then every 6 months for up to 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (pembrolizumab, dendritic cell therapy, cryosurgery)ExperimentalPatients receive pembrolizumab IV on day 1. Treatment repeats every 21 days for up to 18 courses in the absence of disease progression or unacceptable toxicity. Patients also receive dendritic cell therapy IT on days 2, 8, and 15 of courses 2 and 3, and day 2 of courses 4 and 5. Patients undergo cryosurgery on day 2 of course 2 and receive pneumococcal 13-valent conjugate vaccine by injection on day 2 of courses 2-5. Treatment repeats every 21 days for up to 5 courses in the absence of disease progression or unacceptable toxicity.

    Eligibility Criteria

            Inclusion Criteria:
    
              -  Histological confirmation of biopsy-proven non-Hodgkin lymphoma, excluding chronic
                 lymphocytic leukemia, primary central nervous system (CNS) lymphoma and Burkitt's
                 lymphoma; Note: small lymphocytic lymphoma (SLL) is allowed
    
              -  Patients with indolent non-Hodgkin lymphoma (NHL) must have had >= 1 regimen of
                 rituximab-containing regimen; Note: this includes follicular lymphoma (FL), marginal
                 lymphoma and mucosa-associated lymphoid tissue (MALT)
    
              -  Patient with aggressive NHL must have received prior therapy - at a minimum:
    
                   -  Anti-CD20 monoclonal antibody unless tumor is CD20 negative and
    
                   -  An anthracycline containing regimen
    
                   -  Transformed FL must have had therapy for FL and be refractory to chemotherapy
                      for DLBCL
    
              -  Chemotherapy refractory disease in aggressive NHL is defined as
    
                   -  Stable disease of =< 12 months or progressive disease as best response to most
                      recent chemotherapy containing regimen
    
                   -  Disease progression or recurrence =< 12 months of prior autologous stem cell
                      transplantation (SCT)
    
              -  Patients with aggressive NHL must have failed autologous hematopoietic stem cell
                 transplantation (HSCT), or are ineligible or not consenting to autologous HSCT
    
              -  Patient must have at least 3 measurable lesions that are >= 1.5 cm in one dimension;
                 one of the lesions must be >= 2.0 cm and is amenable to image-guided cryoablation and
                 multiple vaccine injections as determined by interventional radiology and principal
                 investigator (PI) (including tumors that can be safely accessed using imaging
                 guidance and treated with minimal risk to adjacent structures)
    
              -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, 2
    
              -  Absolute neutrophil count (ANC) >= 1000/mm3
    
              -  Absolute lymphocyte count >= 500/mm3
    
              -  Platelet count >= 75,000/mm3
    
              -  Hemoglobin >= 8.0 g/dL
    
              -  Total bilirubin =< 1.5 x upper limit of normal (ULN), unless due to Gilbert's disease
    
              -  Aspartate transaminase (AST/serum glutamic-oxaloacetic transaminase [SGOT]) and
                 alanine transaminase (ALT/serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN
    
              -  Creatinine =< 1.5 x ULN or calculated creatinine clearance >= 60 mL/min for subject
                 with creatinine ˃ 1.5 x institutional ULN
    
              -  Negative serum pregnancy test for women of childbearing potential =< 7 days prior to
                 registration; Note: a second pregnancy test may be required =< 72 hours prior to
                 receiving the first dose of study medication
    
              -  Negative human immunodeficiency virus (HIV), hepatitis B and C, and tuberculosis (TB)
                 test
    
              -  Provide written informed consent
    
              -  Willing to return to the enrolling institution for follow-up (during active treatment
                 and active monitoring phase of the study)
    
              -  Ability to complete questionnaire(s) by themselves or with assistance
    
              -  Willing to provide tissue and blood samples for research purposes
    
              -  Willing to use adequate contraception while on the study and until 120 days after the
                 last dose of study drug
    
            Exclusion Criteria:
    
              -  Any of the following:
    
                   -  Pregnant women
    
                   -  Nursing women
    
              -  Co-morbid systemic illnesses or other severe concurrent disease which, in the
                 judgment of the investigator, would make the patient inappropriate for entry into
                 this study or interfere significantly with the proper assessment of safety and
                 toxicity of the prescribed regimens
    
              -  Serious non-malignant disease such as active infection, symptomatic congestive heart
                 failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social
                 situations or other conditions which in the opinion of the investigator would
                 compromise protocol objectives
    
              -  Currently receiving or have received any other investigational agent considered as a
                 treatment for the primary neoplasm =< 28 days or within 4 half-lives (whichever is
                 shorter) of the agent prior to registration
    
              -  History of other primary malignancy requiring systemic treatment within 6 months of
                 protocol enrollment; patients must not be receiving chemotherapy or immunotherapy for
                 another cancer; patients must not have another active malignancy requiring active
                 treatment with the following acceptable EXCEPTIONS:
    
                   -  Basal cell carcinoma, squamous cell carcinoma, or melanoma of the skin that has
                      undergone or will undergo potentially curative therapy
    
                   -  In situ cervical cancer that has undergone or will undergo potentially curative
                      therapy
    
              -  Prior allogeneic bone marrow or peripheral blood stem cell transplantation
    
              -  Prior autologous bone marrow or peripheral blood stem cell transplantation =< 100
                 days prior to registration or if recovery from the transplant is inadequate
    
              -  Major surgery other than diagnostic surgery =< 4 weeks prior to registration
    
              -  Prior chemotherapy or radiation therapy =< 2 weeks prior to registration or who has
                 not recovered (i.e. to =< grade 1 or baseline) from an adverse event due to the
                 previously administered therapy
    
              -  History of hypersensitivity and anaphylactoid reactions to pneumococcal vaccine or
                 any component of the formulation, including diphtheria toxoid
    
              -  Active autoimmune disease such as Crohn's disease, rheumatoid arthritis, Sjogrens'
                 disease, systemic lupus erythematosis, or similar conditions requiring systemic
                 treatment within the past 3 months or a documented history of clinically severe
                 autoimmune disease/syndrome difficult to control in the past
    
                   -  EXCEPTIONS:
    
                        -  Vitiligo or resolved childhood asthma/atopy
    
                        -  Intermittent use of bronchodilators or local steroid injections
    
                        -  Hypothyroidism stable on hormone replacement,
    
                        -  Diabetes stable with current management
    
                        -  History of positive Coombs test but no evidence of hemolysis
    
                        -  Psoriasis not requiring systemic treatment
    
                        -  Conditions not expected to recur in the absence of an external trigger
    
              -  Coagulopathy, including the use of Coumadin or heparin anticoagulants that cannot be
                 discontinued for the cryoablation procedure; NOTE: heparin for line patency without
                 detectable lab abnormalities for coagulation will be allowed
    
              -  Corticosteroid use =< 2 weeks prior to registration; NOTE: patients must be off
                 corticosteroids for at least 2 weeks prior to registration; this includes oral, IV,
                 subcutaneous, or inhaled route of administration; patients on chronic corticosteroid
                 for adrenal insufficiency or other reasons may enroll if they receive less than 10
                 mg/day of prednisone (or equivalent)
    
              -  Active CNS malignancy
    
              -  Evidence of interstitial lung disease or active, non-infectious pneumonitis
    
              -  Received a live vaccine =< 30 days prior to registration
    
              -  New York Heart Association classification III or IV cardiovascular disease or recent
                 myocardial infarction or unstable angina pectoris or cardiac arrhythmia =< 30 days
                 prior to registration
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Maximum tolerated dose (MTD) defined as the dose level that does not induce dose limiting toxicity in at least one-third of patients
    Time Frame:Up to 4 years
    Safety Issue:
    Description:Measured by the incidence of significant toxicity of combination therapy with anti-PD-1 monoclonal antibody, cryoablation, and intra-tumor injection of autologous dendritic cell into the cryoablated tumor.

    Secondary Outcome Measures

    Measure:Complete response
    Time Frame:Up to 4 years
    Safety Issue:
    Description:The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated. The response rate will be calculated, in each individual cohort as supplementary.
    Measure:Disease free survival rate
    Time Frame:At 2 years
    Safety Issue:
    Description:The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated. The response rate will be calculated, in each individual cohort as supplementary
    Measure:Duration of response
    Time Frame:Up to 4 years
    Safety Issue:
    Description:The distribution of duration of complete response will be estimated using the method of Kaplan-Meier.
    Measure:Incidence of adverse events assessed by Common Terminology Criteria for Adverse Events version 4.0
    Time Frame:Up to 4 years
    Safety Issue:
    Description:The maximum grade for each type of adverse event at each evaluation will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. Longitudinal analysis techniques will be utilized to determine the effect of time on treatment adverse events.
    Measure:Overall survival
    Time Frame:From registration to death due to any cause, assessed up to 2 years
    Safety Issue:
    Description:The distribution of survival time will be estimated using the method of Kaplan-Meier.
    Measure:Progression free survival
    Time Frame:Up to 4 years
    Safety Issue:
    Description:The distribution of survival time will be estimated using the method of Kaplan-Meier.
    Measure:Quality of life as measured using the Functional Assessment of Cancer Therapy-lymphoma
    Time Frame:Up to 4 years
    Safety Issue:
    Description:The assessment will be scored according to the scoring algorithm. Changes from baseline will be calculated at each assessment time points. Mean change scores at each time point will be calculated to determine if quality of life is reduced over the course of treatment. Longitudinal techniques will be employed to describe changes over time.
    Measure:Treatment free survival
    Time Frame:From registration to next treatment or death due to any cause, assessed up to 4 years
    Safety Issue:
    Description:The distribution of treatment-free survival will be estimated using the method of Kaplan-Meier.

    Details

    Phase:Phase 1/Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Mayo Clinic

    Last Updated

    April 10, 2017