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

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ClinicalTrials.gov Identifier: NCT03035331
Recruitment Status : Recruiting
First Posted : January 30, 2017
Last Update Posted : July 10, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Mayo Clinic

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
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 Procedure: Cryosurgery Biological: Dendritic Cell Therapy Biological: Pembrolizumab Biological: Pneumococcal 13-valent Conjugate Vaccine Other: Quality-of-Life Assessment Phase 1 Phase 2

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 44 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : March 27, 2017
Estimated Primary Completion Date : February 15, 2021
Estimated Study Completion Date : February 15, 2021


Arm Intervention/treatment
Experimental: Treatment (pembrolizumab, dendritic cell therapy, cryosurgery)
Patients 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.
Procedure: Cryosurgery
Undergo cryosurgery
Other Names:
  • CRYOABLATION
  • cryosurgical ablation

Biological: Dendritic Cell Therapy
Given IT
Other Name: Dendritic Cell Vaccine Therapy

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Biological: Pneumococcal 13-valent Conjugate Vaccine
Given by injection
Other Names:
  • PCV 13
  • PCV13 Vaccine
  • Prevnar 13

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment




Primary Outcome Measures :
  1. 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 ]
    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.

  2. Proportion of complete responses of combination therapy with pembrolizumab, cryoablation, and intra-tumor injection of autologous DC at MTD dose [ Time Frame: Up to 4 years ]
    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.


Secondary Outcome Measures :
  1. Complete response [ Time Frame: Up to 4 years ]
    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.

  2. Disease free survival rate [ Time Frame: At 2 years ]
    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

  3. Duration of response [ Time Frame: Up to 4 years ]
    The distribution of duration of complete response will be estimated using the method of Kaplan-Meier.

  4. Incidence of adverse events assessed by Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 4 years ]
    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.

  5. Overall survival [ Time Frame: From registration to death due to any cause, assessed up to 2 years ]
    The distribution of survival time will be estimated using the method of Kaplan-Meier.

  6. Progression free survival [ Time Frame: Up to 4 years ]
    The distribution of survival time will be estimated using the method of Kaplan-Meier.

  7. Quality of life as measured using the Functional Assessment of Cancer Therapy-lymphoma [ Time Frame: Up to 4 years ]
    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.

  8. Treatment free survival [ Time Frame: From registration to next treatment or death due to any cause, assessed up to 4 years ]
    The distribution of treatment-free survival will be estimated using the method of Kaplan-Meier.


Other Outcome Measures:
  1. Change in immunologic correlates [ Time Frame: Baseline up to 4 years ]
    Will be evaluated and summarized both quantitatively and graphically. Each of the correlative endpoints will be summarized individually, but will also be evaluated in terms of their relationships to one another; i.e., will use Spearman rank correlation coefficient to assess the correlations between baseline levels as well as between changes before and after treatment in these immunologic markers. In addition, these immunologic markers will be correlated with cancer and treatment- related outcomes (e.g. response, toxicities). Relationships will also be explored graphically using scatter plots.

  2. Radiologic analysis [ Time Frame: Up to 4 years ]
    Measurements of index lesion(s) (non-cryoablated lesion) will be evaluated over time for each patient as a marker of systemic immune and treatment response to pembrolizumab and localized treatment with cryoablation and dendritic cell therapy. The index lesion(s) will be selected by the treating physician/investigator and are noncryoablated node. The percent change from baseline in index lesion measurements will be assessed over time. Differences in values over time will be summarized descriptively and graphically. The whole body computed tomography (CT) or positron emission tomography/CT will



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03035331


Locations
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Clinical Trials Referral Office    855-776-0015      
Principal Investigator: Yi Lin         
Sponsors and Collaborators
Mayo Clinic
National Cancer Institute (NCI)
Investigators
Principal Investigator: Yi Lin Mayo Clinic

Responsible Party: Mayo Clinic
ClinicalTrials.gov Identifier: NCT03035331     History of Changes
Other Study ID Numbers: MC1685
NCI-2017-00113 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
MC1685 ( Other Identifier: Mayo Clinic )
P30CA015083 ( U.S. NIH Grant/Contract )
First Posted: January 30, 2017    Key Record Dates
Last Update Posted: July 10, 2018
Last Verified: July 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Follicular
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Lymphoma, Mantle-Cell
Lymphoma, B-Cell, Marginal Zone
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, Large B-Cell, Diffuse
Lymphoma, T-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Leukemia, Lymphoid
Leukemia
Vaccines
Pembrolizumab
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents