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. 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.
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
- SECONDARY ID:
P50CA097274
- NCT ID:
NCT03035331
Conditions
- Aggressive Non-Hodgkin Lymphoma
- Indolent Non-Hodgkin Lymphoma
- Recurrent Diffuse Large B-Cell Lymphoma
- Recurrent Follicular Lymphoma
- Recurrent Mantle Cell Lymphoma
- Recurrent Marginal Zone Lymphoma
- Recurrent Non-Hodgkin Lymphoma
- Recurrent Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma
- Recurrent T-Cell Non-Hodgkin Lymphoma
- Small Lymphocytic Lymphoma
Interventions
Drug | Synonyms | Arms |
---|
Dendritic Cell Therapy | Dendritic Cell Vaccine Therapy | Treatment (pembrolizumab, dendritic cell therapy, cryosurgery) |
Pembrolizumab | Keytruda, Lambrolizumab, MK-3475, SCH 900475 | Treatment (pembrolizumab, dendritic cell therapy, cryosurgery) |
Pneumococcal 13-valent Conjugate Vaccine | PCV 13, PCV13 Vaccine, Prevnar 13 | Treatment (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. 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.
Trial Arms
Name | Type | Description | Interventions |
---|
Treatment (pembrolizumab, dendritic cell therapy, cryosurgery) | Experimental | 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. | - Dendritic Cell Therapy
- Pembrolizumab
- Pneumococcal 13-valent Conjugate Vaccine
|
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)
- 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
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Maximum tolerated dose (MTD) |
Time Frame: | Up to 4 years |
Safety Issue: | |
Description: | MTD will be defined as the dose level that does not induce dose limiting toxicity in at least one-third of patients. |
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: | 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: | 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. |
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: | Disease free survival rate |
Time Frame: | At 2 years |
Safety Issue: | |
Description: | |
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: | Incidence of adverse events |
Time Frame: | Up to 4 years |
Safety Issue: | |
Description: | Will be assessed by Common Terminology Criteria for Adverse Events version 4.0. 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: | Quality of life |
Time Frame: | Up to 4 years |
Safety Issue: | |
Description: | 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. |
Details
Phase: | Phase 1/Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | Mayo Clinic |
Last Updated
June 23, 2021