Dendritic Cell Therapy With Pembrolizumab for Metastatic or Unresectable Melanoma

Phase 1

Terminated

Conditions: Stage III Cutaneous Melanoma AJCC v7
Stage IIIB Cutaneous Melanoma AJCC v7
Stage IV Cutaneous Melanoma AJCC v6 and v7
Stage IIIA Cutaneous Melanoma AJCC v7
Stage IIIC Cutaneous Melanoma AJCC v7

Interventions: Procedure: Cryosurgery
Biological: Pembrolizumab
Procedure: Pheresis
Biological: Therapeutic Autologous Dendritic Cells

Registration Number: NCT03325101

Lead Sponsor: Mayo Clinic

Brief Summary: This phase Ib/II trial studies how well dendritic cell therapy after cryosurgery in combination with pembrolizumab works in treating patients with stage III-IV melanoma that cannot be removed by surgery. Vaccines made from a person's white blood cells mixed with tumor proteins may help the body build an effective immune response to kill tumor cells. Cryosurgery, also known as cryoablation or cryotherapy, kills tumor cells by freezing them. Monoclonal antibodies, such as pembrolizumab, may block tumor growth in different ways by targeting certain cells. Giving dendritic cell therapy after cryosurgery in combination with pembrolizumab may work better in treating patients with melanoma.

Detailed Description: PRIMARY OBJECTIVES OF PHASE I portion of the trial: To establish the safety and tolerability of the proposed treatment schedule in order to move it forward into the Phase II portion of the trial.

PRIMARY OBJECTIVES OF PHASE II portion of the trial:

I. To determine the objective response rate (ORR) of pembrolizumab combined with cryoablation and intratumoral mature dendritic cells (mDCs) in patients with metastatic melanoma that has failed to respond or has stopped responding to initial therapy with a PD-1 axis-blocking monoclonal antibody.

SECONDARY OBJECTIVES:

I. To assess the safety profile of pembrolizumab combined with cryoablation and intratumoral mDCs in patients with metastatic melanoma that have failed to respond or have stopped responding to initial therapy with a PD-1 axis-blocking monoclonal antibody.

II. To determine median progression-free survival (PFS) obtained with this approach in this patient population.

III. To determine median overall survival (OS) obtained with this approach in this patient population.

TERTIARY OBJECTIVES:

I. To quantitate tumor infiltrating lymphocytes (TILs) in tumor biopsies prior to and following cryoablation and intratumoral mDCs.

II. To measure PD-L1 levels in tumor biopsies and blood biopsies prior to and following cryoablation and to assess whether a change in PD-L1 levels differ among those patients who met the criteria for clinical benefit (progression-free and on study for at least 6 months) and those who do not.

III. To measure peripheral blood mononuclear cells (PBMC) proliferation and function after coculture with frozen tumor before and after intratumoral mDC injection.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 7

Inclusion Criteria

Histologically or cytologically confirmed diagnosis of unresectable stage III or metastatic melanoma (stage IV) not amenable to curative local therapy
Documented progression of disease after initiation of therapy with OR lack of response to therapy with a PD-1- or PD-L1-targeting monoclonal antibody (pembrolizumab, nivolumab, etc) after at least 18 weeks; NOTE: This treatment could have been at any time prior to registration
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
Minimum of 3 radiographically apparent lesions such that there is:
- Minimum of one lesion in areas that have not been previously irradiated that is considered measurable by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria AND
- Minimum of two lesions in areas that have not been previously irradiated that are determined by interventional radiology to be of a size and in a location that a single probe could ablate at least 75% of the lesion; Note: Hepatic lesions measuring =< 3 cm may be treated, as determined by interventional radiology; Note: Brain metastases are not acceptable as lesions defining measurable disease, nor are they candidate lesions for cryoablation
Adequate venous access for apheresis as assessed by apheresis team; NOTE: If a central venous catheter is required for apheresis, the patient is not eligible
Absolute neutrophil count (ANC) >= 1000/mm^3 obtained =< 14 days prior to registration
Absolute lymphocyte count >= 500/mm^3 obtained =< 14 days prior to registration
Platelet count >= 100,000/mm^3 obtained =< 14 days prior to registration
Hemoglobin >= 10 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 persons of childbearing potential =< 7 days prior to registration
Provide written informed consent
Willing to return to the enrolling institution for follow-up (during active treatment and active monitoring phase of the study)
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 persons
- Nursing persons
History of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C
Active tuberculosis or active, non-infectious pneumonitis
Evidence of interstitial lung disease
Active infection requiring the use of systemic antibiotics
Symptomatic congestive heart failure (New York Heart Association classification III or IV cardiovascular disease, myocardial infarction =< 6 months prior to registration, unstable angina pectoris or cardiac arrhythmia =< 3 months prior to registration, or cardiac arrhythmia
Currently receiving or have received any other investigational agent considered as a treatment for the primary neoplasm =< 21 days prior to registration
History of other primary malignancy requiring systemic treatment =< 3 years prior to registration; patients must not be receiving chemotherapy or immunotherapy for another cancer; patients must not have another active malignancy requiring active treatment; EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix
Failure to recover from prior side effects of immune checkpoint inhibitor therapy to =< grade 1; NOTE: Patients will not be excluded for adrenal insufficiency or hypothyroidism secondary to immunotherapy provided they are receiving hormonal replacement
Major surgery =< 4 weeks prior to registration
Prior chemotherapy, targeted therapy, 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 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 (the following are allowed):
- 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
- Secondary adrenal insufficiency from previous hypophysitis, currently on physiologic replacement steroid dosing only
Coagulopathy, including the use of therapeutic 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 =< 14 days prior to registration; NOTE: Patients must be off systemic corticosteroids for at least 2 weeks prior to registration; this includes oral or IV route of administration; patients on chronic corticosteroids for adrenal insufficiency or other reasons may enroll if they receive less than 10 mg/day of prednisone (or equivalent); patients receiving inhaled or intranasal or intra-articular steroids are not excluded
Active central nervous system (CNS) metastasis; NOTE: Patients with prior brain metastases that are asymptomatic without corticosteroid use and stable or improved >= 90 days after treatment with surgery or radiation are not excluded
Receipt of a live vaccine =< 30 days prior to registration

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase I Schedule -1	Therapeutic Autologous Dendritic Cells	Phase I Schedule -1: Cycle length is 21 days with the exception of cycle 1 which may be extended an additional 7 days to allow for dendritic cell production. Cycle 1 Day 1: Patients undergo apheresis over 4 hours and pembrolizumab IV over 30 minutes. Cycle 2 \& Cycle 3 either Day 1 or Day 2 (within 36 hours of receiving pembrolizumab): patients undergo cryosurgery (injection of 30-60 x 10\^6 mDCs and an injection of 0.5 ml Prenar13 such that two distinct metastatic lesions are cryoablated, one during cycle 2 and the other during cycle 3. Cycle 4 Day 1 and all subsequent cycles for a maximum of 2 years: Pembrolizumab 200 mg is administered by IV over 30 minutes
Phase II Schedule	Cryosurgery	Regimen depends upon the results of the Phase I portion of the study.
Phase II Schedule	Pembrolizumab	Regimen depends upon the results of the Phase I portion of the study.
Phase II Schedule	Pheresis	Regimen depends upon the results of the Phase I portion of the study.
Phase II Schedule	Therapeutic Autologous Dendritic Cells	Regimen depends upon the results of the Phase I portion of the study.
Phase I Schedule 1	Cryosurgery	Phase I Schedule 1: Cycle length is 21 days with the exception of cycle 1 which may be extended an additional 7 days to allow for dendritic cell production. Cycle 1 Day 1: Patients undergo apheresis over 4 hours and pembrolizumab IV over 30 minutes. Cycle 2 \& Cycle 3 Day 1: Pembrolizumab 200 mg is administered by IV over 30 minutes. Cycle 2 \& Cycle 3 either Day 1 or Day 2 (within 36 hours of receiving pembrolizumab): patients undergo cryosurgery (injection of 30-60 x 10\^6 mDCs and an injection of 0.5 ml Prenar13 such that two distinct metastatic lesions are cryoablated, one during cycle 2 and the other during cycle 3. Cycle 4 Day 1 and all subsequent cycles for a maximum of 2 years: Pembrolizumab 200 mg is administered by IV over 30 minutes
Phase I Schedule 1	Pembrolizumab	Phase I Schedule 1: Cycle length is 21 days with the exception of cycle 1 which may be extended an additional 7 days to allow for dendritic cell production. Cycle 1 Day 1: Patients undergo apheresis over 4 hours and pembrolizumab IV over 30 minutes. Cycle 2 \& Cycle 3 Day 1: Pembrolizumab 200 mg is administered by IV over 30 minutes. Cycle 2 \& Cycle 3 either Day 1 or Day 2 (within 36 hours of receiving pembrolizumab): patients undergo cryosurgery (injection of 30-60 x 10\^6 mDCs and an injection of 0.5 ml Prenar13 such that two distinct metastatic lesions are cryoablated, one during cycle 2 and the other during cycle 3. Cycle 4 Day 1 and all subsequent cycles for a maximum of 2 years: Pembrolizumab 200 mg is administered by IV over 30 minutes
Phase I Schedule 1	Pheresis	Phase I Schedule 1: Cycle length is 21 days with the exception of cycle 1 which may be extended an additional 7 days to allow for dendritic cell production. Cycle 1 Day 1: Patients undergo apheresis over 4 hours and pembrolizumab IV over 30 minutes. Cycle 2 \& Cycle 3 Day 1: Pembrolizumab 200 mg is administered by IV over 30 minutes. Cycle 2 \& Cycle 3 either Day 1 or Day 2 (within 36 hours of receiving pembrolizumab): patients undergo cryosurgery (injection of 30-60 x 10\^6 mDCs and an injection of 0.5 ml Prenar13 such that two distinct metastatic lesions are cryoablated, one during cycle 2 and the other during cycle 3. Cycle 4 Day 1 and all subsequent cycles for a maximum of 2 years: Pembrolizumab 200 mg is administered by IV over 30 minutes
Phase I Schedule 1	Therapeutic Autologous Dendritic Cells	Phase I Schedule 1: Cycle length is 21 days with the exception of cycle 1 which may be extended an additional 7 days to allow for dendritic cell production. Cycle 1 Day 1: Patients undergo apheresis over 4 hours and pembrolizumab IV over 30 minutes. Cycle 2 \& Cycle 3 Day 1: Pembrolizumab 200 mg is administered by IV over 30 minutes. Cycle 2 \& Cycle 3 either Day 1 or Day 2 (within 36 hours of receiving pembrolizumab): patients undergo cryosurgery (injection of 30-60 x 10\^6 mDCs and an injection of 0.5 ml Prenar13 such that two distinct metastatic lesions are cryoablated, one during cycle 2 and the other during cycle 3. Cycle 4 Day 1 and all subsequent cycles for a maximum of 2 years: Pembrolizumab 200 mg is administered by IV over 30 minutes
Phase I Schedule -1	Cryosurgery	Phase I Schedule -1: Cycle length is 21 days with the exception of cycle 1 which may be extended an additional 7 days to allow for dendritic cell production. Cycle 1 Day 1: Patients undergo apheresis over 4 hours and pembrolizumab IV over 30 minutes. Cycle 2 \& Cycle 3 either Day 1 or Day 2 (within 36 hours of receiving pembrolizumab): patients undergo cryosurgery (injection of 30-60 x 10\^6 mDCs and an injection of 0.5 ml Prenar13 such that two distinct metastatic lesions are cryoablated, one during cycle 2 and the other during cycle 3. Cycle 4 Day 1 and all subsequent cycles for a maximum of 2 years: Pembrolizumab 200 mg is administered by IV over 30 minutes
Phase I Schedule -1	Pembrolizumab	Phase I Schedule -1: Cycle length is 21 days with the exception of cycle 1 which may be extended an additional 7 days to allow for dendritic cell production. Cycle 1 Day 1: Patients undergo apheresis over 4 hours and pembrolizumab IV over 30 minutes. Cycle 2 \& Cycle 3 either Day 1 or Day 2 (within 36 hours of receiving pembrolizumab): patients undergo cryosurgery (injection of 30-60 x 10\^6 mDCs and an injection of 0.5 ml Prenar13 such that two distinct metastatic lesions are cryoablated, one during cycle 2 and the other during cycle 3. Cycle 4 Day 1 and all subsequent cycles for a maximum of 2 years: Pembrolizumab 200 mg is administered by IV over 30 minutes
Phase I Schedule -1	Pheresis	Phase I Schedule -1: Cycle length is 21 days with the exception of cycle 1 which may be extended an additional 7 days to allow for dendritic cell production. Cycle 1 Day 1: Patients undergo apheresis over 4 hours and pembrolizumab IV over 30 minutes. Cycle 2 \& Cycle 3 either Day 1 or Day 2 (within 36 hours of receiving pembrolizumab): patients undergo cryosurgery (injection of 30-60 x 10\^6 mDCs and an injection of 0.5 ml Prenar13 such that two distinct metastatic lesions are cryoablated, one during cycle 2 and the other during cycle 3. Cycle 4 Day 1 and all subsequent cycles for a maximum of 2 years: Pembrolizumab 200 mg is administered by IV over 30 minutes

Primary Outcome Measures

Name	Time	Method
Number of Participants Who Developed a DLT During the First 3 Cycles of Treatment.	Up to 3 months (3 cycles of 21 days and an additional 7 days for Cycle 1)	The primary outcome of the Phase I portion of this trial was to establish the tolerability of the proposed treatment schedule in order to move it forward into the Phase II portion of the trial. A maximum of 6 patients was to be enrolled onto the Schedule 1. If at most one of these 6 patients developed a DLT during the first 3 treatment cycles, then Schedule #1 would be carried forward to the Phase II portion of the trial. If not, then an additional 6 patients would be treated with a modified Schedule 1 where Pembrolizumab was eliminated from cycles 2 \& 3. Dose-limiting toxicity (DLT) were defined as the following possibly, probably, or definitely related AEs to protocol therapy during first 3 treatment cycles: Grade 3+ infusion reactions, acute kidney injury, chronic kidney disease, pneumonitis; or Grade 2 infusion reactions, acute kidney injury, chronic kidney disease or pneumonitis that does not resolve to Grade 0-1 within 21 days.

Secondary Outcome Measures

Name	Time	Method
Incidence of Adverse Events	30 months (through study completion)	Assessed using Common Terminology Criteria for Adverse Events (CTCAE).
Overall Survival	30 months (through study completion)	Time from registration to death due to any cause