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

Phase 1

Completed

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

Interventions: Procedure: Cryosurgery
Biological: Dendritic Cell Therapy
Other: Laboratory Biomarker Analysis
Biological: Pembrolizumab
Biological: Pneumococcal 13-valent Conjugate Vaccine
Other: Quality-of-Life Assessment

Registration Number: NCT03035331

Lead Sponsor: 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. 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 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)

CORRELATIVE OBJECTIVES:

I. Assess the effect of combination immunotherapy on patients' immune status and anti-tumor immune response. (Phase II) II. Assess the potential association between PD-1/PD-L1/PD-L2 expression in tumor and blood with clinical efficacy. (Phase II) III. Assess the potential association between tumor antigen mutations and antigen-specific immune response with clinical efficacy. (Phase II) IV. Evaluate patient quality of life. (Phase II)

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 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive dendritic cell therapy intratumorally (IT) on days 2, 8, and 15 of cycles 2 and 3, and day 2 of cycles 4 and 5. Patients undergo cryosurgery on day 2 of cycle 2 and receive pneumococcal 13-valent conjugate vaccine by injection on day 2 of cycles 2-5. Treatment repeats every 21 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. Patients who are CR, PR, or stable disease (SD) after completion of therapy, may receive pembrolizumab for an additional 18 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months during the first year post-treatment, every 4 months during the second year post-treatment, and then every 6 months for up to 2 years.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 11

Inclusion Criteria

Age >= 18 years
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)
Patients with aggressive NHL must have had >= 2 regimens; Note: This includes diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), primary mediastinal large B-cell lymphoma (PMBCL), and T cell lymphoma
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 or 1
Absolute neutrophil count (ANC) >= 1000/mm^3 (obtained =< 14 days prior to registration)
Absolute lymphocyte count >= 200/mm^3 (obtained =< 14 days prior to registration)
Platelet count >= 50,000/mm^3 (obtained =< 14 days prior to registration)
Hemoglobin >= 8.0 g/dL (obtained =< 14 days prior to registration)
Total bilirubin =< 1.5 x upper limit of normal (ULN), unless due to Gilbert's disease (obtained =< 14 days prior to registration)
Aspartate transaminase (AST/serum glutamic-oxaloacetic transaminase [SGOT]) and alanine transaminase (ALT/serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN (obtained =< 14 days prior to registration)
Creatinine =< 1.5 x ULN or calculated creatinine clearance >= 60 mL/min for subject with creatinine ˃ 1.5 x institutional ULN (obtained =< 14 days prior to registration)
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 because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
- 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, Sjogren's disease, systemic lupus erythematosus, 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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (pembrolizumab, dendritic cell therapy, cryosurgery)	Quality-of-Life Assessment	Patients receive pembrolizumab IV on day 1. Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive dendritic cell therapy IT on days 2, 8, and 15 of cycles 2 and 3, and day 2 of cycles 4 and 5. Patients undergo cryosurgery on day 2 of cycle 2 and receive pneumococcal 13-valent conjugate vaccine by injection on day 2 of cycles 2-5. Treatment repeats every 21 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. Patients who are CR, PR, or SD after completion of therapy, may receive pembrolizumab for an additional 18 cycles in the absence of disease progression or unacceptable toxicity.
Treatment (pembrolizumab, dendritic cell therapy, cryosurgery)	Cryosurgery	Patients receive pembrolizumab IV on day 1. Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive dendritic cell therapy IT on days 2, 8, and 15 of cycles 2 and 3, and day 2 of cycles 4 and 5. Patients undergo cryosurgery on day 2 of cycle 2 and receive pneumococcal 13-valent conjugate vaccine by injection on day 2 of cycles 2-5. Treatment repeats every 21 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. Patients who are CR, PR, or SD after completion of therapy, may receive pembrolizumab for an additional 18 cycles in the absence of disease progression or unacceptable toxicity.
Treatment (pembrolizumab, dendritic cell therapy, cryosurgery)	Laboratory Biomarker Analysis	Patients receive pembrolizumab IV on day 1. Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive dendritic cell therapy IT on days 2, 8, and 15 of cycles 2 and 3, and day 2 of cycles 4 and 5. Patients undergo cryosurgery on day 2 of cycle 2 and receive pneumococcal 13-valent conjugate vaccine by injection on day 2 of cycles 2-5. Treatment repeats every 21 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. Patients who are CR, PR, or SD after completion of therapy, may receive pembrolizumab for an additional 18 cycles in the absence of disease progression or unacceptable toxicity.
Treatment (pembrolizumab, dendritic cell therapy, cryosurgery)	Pneumococcal 13-valent Conjugate Vaccine	Patients receive pembrolizumab IV on day 1. Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive dendritic cell therapy IT on days 2, 8, and 15 of cycles 2 and 3, and day 2 of cycles 4 and 5. Patients undergo cryosurgery on day 2 of cycle 2 and receive pneumococcal 13-valent conjugate vaccine by injection on day 2 of cycles 2-5. Treatment repeats every 21 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. Patients who are CR, PR, or SD after completion of therapy, may receive pembrolizumab for an additional 18 cycles in the absence of disease progression or unacceptable toxicity.
Treatment (pembrolizumab, dendritic cell therapy, cryosurgery)	Dendritic Cell Therapy	Patients receive pembrolizumab IV on day 1. Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive dendritic cell therapy IT on days 2, 8, and 15 of cycles 2 and 3, and day 2 of cycles 4 and 5. Patients undergo cryosurgery on day 2 of cycle 2 and receive pneumococcal 13-valent conjugate vaccine by injection on day 2 of cycles 2-5. Treatment repeats every 21 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. Patients who are CR, PR, or SD after completion of therapy, may receive pembrolizumab for an additional 18 cycles in the absence of disease progression or unacceptable toxicity.
Treatment (pembrolizumab, dendritic cell therapy, cryosurgery)	Pembrolizumab	Patients receive pembrolizumab IV on day 1. Treatment repeats every 21 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive dendritic cell therapy IT on days 2, 8, and 15 of cycles 2 and 3, and day 2 of cycles 4 and 5. Patients undergo cryosurgery on day 2 of cycle 2 and receive pneumococcal 13-valent conjugate vaccine by injection on day 2 of cycles 2-5. Treatment repeats every 21 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. Patients who are CR, PR, or SD after completion of therapy, may receive pembrolizumab for an additional 18 cycles in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Number of Patients That Experienced a Dose Limiting Toxicity (DLT)	56 days	Maximum tolerated dose (MTD) will be defined as the dose level that does not induce dose limiting toxicity in at least one-third of patients. DLTs are defined as Grade 4 or 5 ANC or PLT for at least 7 days, grade 3 plus Infections and infestations, febrile neutropenia defined as fever ≥38.5oC (38 \>1 hour) with grade 4 plus neutropenia, at least Grade 3 erythema multiforme, ulceration, or urticaria that does not resolve to Grade 2 or less within \> three weeks, at least grade 3 bronchial obstruction, pneumonitis, or wheezing at least grade 3 allergic reaction or autoimmunity at least grade 3 that does not resolve to less than Grade 2\> less than or equal to 72 hours per NCI Common Terminology Criteria for Adverse Events.
Percentage of Complete Responses of Combination Therapy With Pembrolizumab, Cryoablation, and Intra-tumor Injection of Autologous Dendritic Cells (DC) at Maximum Tolerated Dose (MTD) Dose	24 months	The percentage 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

Name	Time	Method
Progression Free Survival	24 months	The distribution of survival time will be estimated using the method of Kaplan-Meier.
Treatment Free Survival	34 months	The distribution of treatment-free survival will be estimated using the method of Kaplan-Meier.
Duration of Response	11 months	The distribution of duration of complete response will be estimated using the method of Kaplan-Meier.
Disease Free Survival Rate	2 years	The percentage of patients without disease at two years post start of treatment.
Overall Survival	5 years	The distribution of survival time will be estimated using the method of Kaplan-Meier.
Percentage of Patients With Grade 4 or 5 Adverse Events	Up to 4 years	Will be assessed by Common Terminology Criteria for Adverse Events version 4.0.
Percent of Patients With Improved Quality of Life	4 years	Will be measured using the Functional Assessment of Cancer Therapy-lymphoma. 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.