Symptoms and General Pathology

All Conditions

Neoplasms

Skin and Connective Tissue Diseases

Rare Diseases

Recurrence

Melanoma

Melanoma, Cutaneous Malignant

Skin Neoplasms

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

All Drugs and Chemicals

Amino Acids

Ibrutinib

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Patients receive ibrutinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis

Pharmacogenomic Study

Pharmacological Study

Stergios J Moschos

This phase II trial studies how well ibrutinib works in treating patients with stage IV melanoma of the skin that has not responded to previous treatment. Ibrutinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. Estimate rate of objective response (OR: complete response \[CR\] + partial response \[PR\]) to ibrutinib administered as single agent in patients with immune checkpoint inhibitor-refractory, or immune checkpoint inhibitor ineligible and mitogen-activated protein kinase (MAPK) inhibitor-refractory (if B-Raf proto-oncogene, serine/threonine kinase \[BRAF\]V600-mutant) or MAPK inhibitor-intolerant distant metastatic cutaneous melanoma.

SECONDARY OBJECTIVES:

I. Estimate progression-free survival (PFS) rate at 6 months after initiation of ibrutinib in patients with immune checkpoint inhibitor-refractory or immune checkpoint ineligible and MAPK inhibitor-refractory (if BRAFV600-mutant) or MAPK inhibitor-intolerant distant metastatic cutaneous melanoma.

II. Estimate overall survival (OS) after initiation of ibrutinib in patients with immune checkpoint inhibitor-refractory or immune checkpoint ineligible and MAPK inhibitor-refractory (if BRAFV600-mutant) or MAPK inhibitor-intolerant distant metastatic cutaneous melanoma.

III. Explore the association of ITK protein expression with OR and PFS.

TERTIARY OBJECTIVES:

I. Explore association between other putative targets of ibrutinib (e.g. Tec, ErbB4, Hck, Yes, BTK) in melanoma cells, as assessed by 2-color immunofluorescence (IF) in representative tissue sections obtained from pretreatment archived formalin-fixed paraffin-embedded (FFPE) tumor blocks or FFPE blocks obtained from fresh tissue biopsy from enrolled patients, with overall response (OR) and PFS.

II. Explore ibrutinib-mediated effect(s) on immune cell subsets associated with immunomodulation by performing multiparameter flow cytometric analysis in peripheral blood mononuclear cell (PBMC) obtained prior to treatment, on day 29 (i.e., predose day 1 of cycle 2) following initiation of treatment with ibrutinib, and at the time of disease progression (3 time points).

III. Determine pharmacokinetics (PK) of ibrutinib following daily dosing at 840 mg on day 8 of cycle 1 (Css).

OUTLINE:

Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 2 years.

Ibrutinib in Treating Patients With Refractory Metastatic Cutaneous Melanoma

A Phase 2 Study of Ibrutinib (PCI-32765) in Refractory Distant Metastatic Cutaneous Melanoma: Correlation of Biomarkers With Response and Resistance

Assessed by IHC and 2-color IF and analyzed by Aperio imaging. Exploratory analysis will also be performed to assess the predictive ability of each tissue biomarker by fitting logistic model or Cox model with biomarker as a covariate. Antitumor response rate or PFS information will be used to investigate possible cut-points for the biomarker. Logistic regression analysis will be conducted to assess whether a profile of immune response in tumor biopsies (or in peripheral blood) can be developed that distinguishes patients who respond to treatment versus those who do not.

Will be assessed by comparisons using analysis of variance followed by paired t-test or other tests (Wilcoxon rank-sum test), if normality assumption is not satisfied even when data transformation is performed.

The following parameters will be estimated: maximum concentration, time of maximum concentration, area under the concentration verses time curve, half-life, apparent clearance, apparent volume of distribution.

Antitumor response defined as the sum of complete response (CR) and partial response (PR). CR is the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm (\<1 cm). PR is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Progression free survival (PFS) is defined as the duration of time from Day 1 of treatment to time of progression (based on clinical or radiographic grounds) or death as a result of any cause, whichever occurs first.

National Cancer Institute (NCI)

Patients receive ibrutinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Ibrutinib: Given PO

Laboratory Biomarker Analysis: Correlative studies

Pharmacogenomic Study: Correlative studies

Pharmacological Study: Correlative studies

Treatment (Ibrutinib)

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Stergios Moschos

The primary comparison was between the response rate of an ineffective drug, such as investigators' choice chemotherapy (5%), and the response rate of ibrutinib.

Number of Subjects With Antitumor Response as Evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) Criteria 1.1

Progression Free Survival

Overall Survival

Expression Levels of ITK and Putative Targets of Ibrutinib (e.g. Tec, ErbB4, Hck, Yes, BTK)

Change in Th1, Th2, and Various Immune Regulatory Cell Populations in Peripheral Blood Mononuclear Cells and Assessed by Flow Cytometry

Pharmacokinetic Analysis on Ibrutinib Concentrations in Plasma Using WinNonlin

Overall Study

Neoplasm Metastasis

Anti-Infective Agents

Alovudine

Antiviral Agents

NEOADJUVANT TREATMENT: Patients receive 18F-FLT IV and undergo a PET/CT scan approximately 60 minutes later. Within 2 weeks, patients receive encorafenib PO QD and binimetinib PO BID on days 1-28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive 18F-FLT IV and undergo a second PET/CT scan approximately 60 minutes later.

SURGICAL RESECTION: Within 2 weeks of completing therapy with encorafenib and binimetinib, patients undergo surgery.

ADJUVANT TREATMENT: Within 2-7 days after surgery, patients resume treatment with encorafenib PO QD and binimetinib PO BID on days 1-28. Treatment repeats every 28 days for up to 11 cycles in the absence of disease progression or unacceptable toxicity.

Binimetinib

Computed Tomography

Conventional Surgery

Encorafenib

Fluorothymidine F-18

Positron Emission Tomography

Leslie A Fecher

This phase II trial studies how well encorafenib and binimetinib work before surgery in treating patients with BRAF V600-mutated stage IIIB-D melanoma that has spread to the lymph nodes. Encorafenib and binimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. This trial also studies how well 18F-FLT positron emission tomography (PET)/computed tomography (CT) works in predicting the response of melanoma to encorafenib and binimetinib. 18F-FLT is an imaging agent, sometimes called a tracer. PET and CT are types of imaging scans. Using 18F-FLT PET/CT together with encorafenib and binimetinib may provide more information on melanoma over time.

PRIMARY CLINICAL OBJECTIVE:

I. To evaluate the pathologic complete response (pCR) rate of neoadjuvant treatment with encorafenib and binimetinib.

SECONDARY CLINICAL OBJECTIVES:

I. To determine response rate (RR) (Response Evaluation Criteria in Solid Tumors \[RECIST\]), disease-free survival (DFS) and overall survival (OS).

II. To describe correlation of pCR with RR, DFS and OS. III. To assess safety and toxicity.

CORRELATIVE SCIENCE OBJECTIVES:

I. To evaluate CD8 positive (+) T cell infiltration and Ki-67 status in tumor or tumor bed pre, during, and post neoadjuvant treatment and the change in CD8+ tumor infiltrating lymphocyte (TIL) with neoadjuvant treatment and correlate with clinical response.

II. To compare local review for pathologic response with central pathology review.

III. To assess the correlation between change in fluorothymidine F-18 (18F-FLT) PET/CT uptake and change in Ki-67.

IMAGING OBJECTIVES:

I. To compare the change in 18F-FLT PET/CT uptake (from baseline to post-neoadjuvant therapy) among patients with and without pathologic complete response.

II. To compare post-neoadjuvant 18F-FLT PET/CT uptake among patients with and without pathologic complete response.

III. To estimate an optimal threshold for prediction of pathologic complete response using i) change in 18F-FLT PET/CT uptake, and ii) post-neoadjuvant 18F-FLT PET/CT uptake.

IV. To assess the correlation between change in 18F-FLT PET/CT uptake and change in Ki-67.

OUTLINE:

NEOADJUVANT TREATMENT: Patients receive 18F-FLT intravenously (IV) and undergo a PET/CT scan approximately 60 minutes later. Within 2 weeks, patients receive encorafenib orally (PO) once daily (QD) and binimetinib PO twice daily (BID) on days 1-28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive 18F-FLT IV and undergo a second PET/CT scan approximately 60 minutes later.

SURGICAL RESECTION: Within 2 weeks of completing therapy with encorafenib and binimetinib, patients undergo surgery.

ADJUVANT TREATMENT: Within 2-7 days after surgery, patients resume treatment with encorafenib PO QD and binimetinib PO BID on days 1-28. Treatment repeats every 28 days for up to 11 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year, then every 6 months for 3 years.

Testing Treatment With Encorafenib and Binimetinib Before Surgery for Melanoma With Lymph Node Involvement

A Phase II Neoadjuvant Study of Encorafenib With Binimetinib in Patients With Resectable Locoregional Metastases From Cutaneous or Unknown Primary Melanoma (Stages III N1B/C/D)

Ki-67 immunohistochemistry in tumor cells will be graded as a percentage of total number of tumor cells with nuclear staining (to the nearest 10%) over 10 high powered fields (at 20 x magnification).

Will be estimated and 90% confidence intervals (CI) adjusting for the first stage analysis will be provided.

Will be compared among patients with and without a pCR. Distributional summaries of the continuous percent change in 18F-FLT PET/CT maximum standardized uptake value (SUVmax) will be reported, where percent change is defined as (baseline SUVmax - post-neoadjuvant SUVmax)/(baseline SUVmax)\*100%. The comparison of percent change in SUVmax between pCR and non-pCR patients will be performed using a one-sided nonparametric Wilcoxon rank sum test with an alpha level of 0.05. Will also report distributional summaries and comparisons for percent change in 18F-FLT PET/CT peak SUV (SUVpeak); however, the prespecified primary comparison will be based on 18F-FLT PET/CT SUVmax.

OS distributions will be estimated using the Kaplan-Meier method. Median OS will be described with 95% confidence intervals. Clinical data from unevaluable patients will be summarized separately.

DFS distributions will be estimated using the Kaplan-Meier method. Median DFS will be described with 95% confidence intervals. Clinical data from unevaluable patients will be summarized separately.

Will be evaluated based on international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors guideline (version 1.1) and estimated with 95% confidence interval. Clinical data from unevaluable patients will be summarized separately.

Will be graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version(v.) 5.0. All treatment-emergent and baseline adverse events and hematological/biochemical toxicities based on laboratory measurements, as well as drug related AEs, will be summarized by NCI CTCAE v. 5.0 worst grade. The incidence of deaths and treatment-emergent serious adverse events (defined as number of patients experiencing the AE divided by all treated patients) will be summarized. Also, the incidence of adverse events leading to discontinuation of investigational product and/or withdrawal from the study will be summarized and listed.

Will be based on the two-sample t-test using two-sided type I error rate of 0.1. If normality assumption is not appropriate, Wilcoxon rank sum test will be used during the analysis. Using the median change value, cases will be divided to high and low change groups. Will be assessed and summarized using the descriptive statistics. Will be compared among patients achieving a pCR versus no pCR.

Will be based on the two-sample t-test using two-sided type I error rate of 0.1. If normality assumption is not appropriate, Wilcoxon rank sum test will be used during the analysis. Using the median change value, cases will be divided to high and low change groups. Will be assessed and summarized using the descriptive statistics

The concordance of pCR assessed based on local review versus central pathology review will be evaluated. Kendall's Tau test will be used for this comparison.

Will be compared among patients with and without a pCR. Distributional summaries of the post-neoadjuvant 18F-FLT PET/CT SUVmax will be reported. The comparison SUVmax between pCR and non-pCR patients will be performed using a one-sided nonparametric Wilcoxon rank sum test with an alpha level of 0.05. Will also report distributional summaries and comparisons for post-neoadjuvant in 18F-FLT PET/CT peakSUV.

Will be estimated using change in 18F-FLT PET/CT uptake. Diagnostic performance of percent change in 18F-FLT PET/CT SUVmax (from the baseline scan to the post-neoadjuvant scan) as a marker for pCR status will be assessed using receiver operating characteristic curve (ROC) analysis. In particular, the empirical area. The corresponding performance of the optimal threshold (measured via sensitivity and specificity) will be estimated using cross-validation under the receiver operating characteristic curve (ROC AUC) will be reported, along with corresponding 95% confidence interval. In addition, will formally test if the ROC AUC exceeds 0.5 using a one-sided test with an alpha level of 0.05. The optimal threshold (binary cutpoint) of continuous percent change in SUVmax will be estimated by means of the Youden index. A 95% confidence interval for the optimal threshold will be estimated using the bootstrap technique to properly reflect sampling variability.

The correlation between percent change in continuous SUVmax and percent change in the continuous Ki67 score will be estimated using the Spearman correlation coefficient. A one-sided correlation test with null hypothesis of zero correlation will be conducted at alpha level of 0.05. The corresponding confidence interval for the estimated Spearman correlation coefficient will also be reported. Correlation between change in 18F-FLT PET/CT and the early change in tumor cell Ki-67 (from baseline to the week 2 interim biopsy) will also be separately estimated. The corresponding correlation with percent change in 18F-FLT PET/CT SUVpeak will also be reported.

ECOG-ACRIN Cancer Research Group

Disease Attributes

Antineoplastic Agents

Pembrolizumab

Antibodies

Antibodies, Monoclonal

Ipilimumab

Immunoglobulins

Interferons

Interferon-alpha

Interferon alpha-2

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Immunologic Factors

INDUCTION THERAPY: Patients receive high-dose recombinant interferon alfa-2B intravenously (IV) over 20 minutes on days 1-5. Treatment repeats weekly for 4 weeks in the absence of disease progression or unacceptable toxicity. Or patients receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 3 weeks for a total of 4 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive high-dose recombinant interferon alfa-2B subcutaneously (SC) on days 1, 3, and 5. Treatment repeats every 6 weeks for up to 48 weeks in the absence of disease progression or unacceptable toxicity. Or patients receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 12 weeks for 3 years in the absence of disease progression or unacceptable toxicity.

Patients undergo CT scan, PET scan, MRI and blood sample collection throughout the study.

Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 52 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, PET scan, MRI and blood sample collection throughout the study.

Biospecimen Collection

Magnetic Resonance Imaging

Quality-of-Life Assessment

Recombinant Interferon Alfa-2b

Sapna Patel

This randomized phase III trial studies how well pembrolizumab works compared with the current standard of care, physician/patient choice of either high-dose recombinant interferon alfa-2B or ipilimumab, in treating patients with stage III-IV melanoma that has been removed by surgery but is likely to come back or spread. High-dose recombinant interferon alfa-2B may help shrink or slow the growth of melanoma. Immunotherapy with monoclonal antibodies, such as ipilimumab and pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether pembrolizumab is more effective than the current standard of care in treating patients with melanoma.

PRIMARY OBJECTIVES:

I. To compare overall survival (OS) of patients with resected stage III and IV melanoma treated with physician/patient choice of either high dose interferon recombinant interferon alfa-2b (alfa-2b) or ipilimumab versus MK-3475 (pembrolizumab).

II. Among patients who are PD-L1 positive, to compare OS of patients with resected stage III and IV melanoma treated with physician/patient choice of either high dose interferon alfa-2b or ipilimumab versus MK-3475 (pembrolizumab).

III. To compare relapse-free survival (RFS) of patients with resected stage III and IV melanoma treated with physician/patient choice of either high dose interferon alfa-2b or ipilimumab to MK-3475 (pembrolizumab).

SECONDARY OBJECTIVES:

I. To estimate OS and RFS for patients who are PD-L1 negative or PD-L1 indeterminate in this population.

II. To compare OS and RFS of patients between the two arms within PD-L1 positive and negative subgroups and to look at the interaction between PD-L1 (positive versus negative) and treatment arm.

III. To assess the safety and tolerability of the regimens.

ADDITIONAL OBJECTIVES:

I. To bank tissue and whole blood in anticipation of future correlative studies in this patient population.

II. To evaluate PD-L1 expression through immunohistochemistry assay. III. To evaluate the effect of treatment-related side effects that may have an impact on the health-related domains of quality of life (QOL) using the Functional Assessment of Cancer Therapy (FACT)-Biological Response Modifiers (BRM), European Quality of Life Five Dimension Three Level Scale (EQ-5D-3L), and Functional Assessment of Chronic Illness Therapy Diarrhea (FACIT-D) between patients treated with physician/patient choice of either high-dose interferon alfa-2b or ipilimumab and MK-3475 (pembrolizumab).

IV. Pharmacokinetic (PK) and anti-drug antibody (ADA) testing will be performed on all patients receiving MK-3475 (pembrolizumab).

TRANSLATIONAL OBJECTIVES RELATED TO T-CELL RECEPTOR BETA CHAIN SEQUENCING:

I. To evaluate the association between TCR beta variable gene (TRBV) haplotype and grade 3-4 immune-related adverse events (irAEs) among stage III melanoma patients treated with adjuvant ipilimumab or pembrolizumab.

II. To describe the TRBV haplotype distribution among this cohort of patients studied.

TRANSLATIONAL MEDICINAL OBJECTIVE RELATED TO ASSOCIATION OF CIRCULATING TUMOR DNA (ctDNA) WITH RELAPSE-FREE SURVIVAL IN HIGH-RISK, RESECTED MELANOMA PATIENTS.

I. To evaluate associations between pretreatment ctDNA (present versus absent) and relapse within 2 years of randomization in a case-control analysis across treatment arms.

II. To evaluate associations between pretreatment ctDNA (present versus absent) and relapse within 2 years of randomization in a case-control analysis across treatment arms.

III. To evaluate associations between pretreatment ctDNA and relapse within 2 years of randomization in a case-control analysis within each treatment arm (after treatment arm data are unblinded to investigators).

IV. To evaluate associations between "early-on treatment" ctDNA levels and relapse within 2 years of randomization.

V. To describe ctDNA levels at end of therapy and time of relapse.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I:

INDUCTION THERAPY: Patients receive high-dose recombinant interferon alfa-2B intravenously (IV) over 20 minutes on days 1-5. Treatment repeats weekly for 4 weeks in the absence of disease progression or unacceptable toxicity. Or patients receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 3 weeks for a total of 4 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive high-dose recombinant interferon alfa-2B subcutaneously (SC) on days 1, 3, and 5. Treatment repeats every 6 weeks for up to 48 weeks in the absence of disease progression or unacceptable toxicity. Or patients receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 12 weeks for 3 years in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 52 weeks in the absence of disease progression or unacceptable toxicity.

Patients undergo computed tomography (CT) scan, positron emission tomography (PET) scan, magnetic resonance imaging (MRI) and blood sample collection throughout the study.

After completion of study treatment, patients are followed up at 30 days, 6 and 12 weeks, every 3 months for 2 years, every 6 months for 3 years, and then every 12 months for 5 years.

Physician/Patient Choice of Either High-Dose Recombinant Interferon Alfa-2B or Ipilimumab, Versus Pembrolizumab in Treating Patients With Stage III-IV High Risk Melanoma That Has Been Removed by Surgery

A Phase III Randomized Trial Comparing Physician/Patient Choice of Either High Dose Interferon or Ipilimumab to MK-3475 (Pembrolizumab) in Patients With High Risk Resected Melanoma

From date of randomization to date of death due to any cause. Patients last known to be alive were censored at date of last contact. OS estimates will be calculated using the method of Kaplan-Meier. Comparison between arms will be performed using a stratified log-rank test in the intent-to-treat population.

From date of randomization to date of first documentation of disease recurrence (relapse) or death due to any cause. On study disease assessments by imaging were to be performed every 12 weeks until 2 years from randomization, and then every 6 months until 5 years from randomization. Patients last known to be alive and relapse-free were censored at date of last contact. RFS estimates will be calculated using the method of Kaplan-Meier. Comparison between arms will be performed using a stratified log-rank test in the intent-to-treat population.

From date of randomization to date of death due to any cause. Patients last known to be alive were censored at date of last contact. OS estimates will be calculated using the method of Kaplan-Meier. Comparison between arms will be performed using a stratified log-rank test in the intent-to-treat population among those patients with PD-L1 positive tumors.

PD-L1 expression was evaluated by immunohistochemistry (IHC) assay on archival or fresh tumor tissue using the 22C3 antibody and was scored on a scale of 0 to 5 (with higher numbers reflecting a higher level of PD-L1 expression); a score of 2 or higher (staining on greater than 1% of cells) was considered to indicate PD-L1 positivity.

From date of randomization to date of first documentation of disease recurrence (relapse) or death due to any cause. On study disease assessments by imaging were to be performed every 12 weeks until 2 years from randomization, and then every 6 months until 5 years from randomization. Patients last known to be alive and relapse-free were censored at date of last contact. RFS estimates will be calculated using the method of Kaplan-Meier. Comparison between arms will be performed using a stratified log-rank test in the intent-to-treat population among those patients with PD-L1 positive tumors.

PD-L1 expression was evaluated by immunohistochemistry (IHC) assay on archival or fresh tumor tissue using the 22C3 antibody and was scored on a scale of 0 to 5 (with higher numbers reflecting a higher level of PD-L1 expression); a score of 2 or higher (staining on greater than 1% of cells) was considered to indicate PD-L1 positivity.

From date of randomization to date of death due to any cause. Patients last known to be alive will be censored at date of last contact. OS estimates will be calculated using the method of Kaplan-Meier. Cox regression models will be used to estimate hazard ratios and calculate confidence intervals to compare treatment arms in the PD-L1 negative subgroup. In addition Cox regression models for OS will be used to estimate interaction terms between PD-L1 status and treatment arm.

PD-L1 expression was evaluated by immunohistochemistry (IHC) assay on archival or fresh tumor tissue using the 22C3 antibody and was scored on a scale of 0 to 5 (with higher numbers reflecting a higher level of PD-L1 expression); a score of 0-1 (staining on ≤ 1% of cells) was considered to indicate PD-L1 negative status.

From date of randomization to date of first documentation of disease recurrence (relapse) or death due to any cause. On study disease assessments by imaging were to be performed every 12 weeks until 2 years from randomization, and then every 6 months until 5 years from randomization. Patients last known to be alive and relapse-free were censored at date of last contact. RFS estimates will be calculated using the method of Kaplan-Meier. Cox regression models will be used to estimate hazard ratios and calculate confidence intervals to compare treatment arms in the PD-L1 negative subgroup. In addition Cox regression models for RFS will be used to estimate interaction terms between PD-L1 status and treatment arm.

PD-L1 expression was evaluated by IHC assay on archival or fresh tumor tissue using the 22C3 antibody and was scored on a scale of 0 to 5; a score of 2 or higher was considered to indicate PD-L1 positivity. a score of 0-1 was considered to indicate PD-L1 negative status.

The proportion of patients experiencing a particular adverse event (AE), as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (CTCAE version 5.0 beginning April 1, 2018), for each treatment regimen using the number of patients who received at least one dose of that regimen as the denominator. AEs are AE proportions will be estimated along with a 95% confidence intervals.

NEOADJUVANT PHASE: Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.

SURGERY: Patients undergo surgery 1-2 weeks after completion of neoadjuvant phase.

ADJUVANT PHASE: After recovery from surgery, patients receive pembrolizumab IV over 30 minutes on day 1 of every other cycle. Treatment repeats every 21 days for up to 16 cycles in the absence of disease progression or unacceptable toxicity.

Patients also undergo CT or PET/CT throughout the trial and may undergo optional biopsy at baseline and disease progression and optional collection of blood samples throughout the trial.

NEOADJUVANT PHASE: Patients receive CMP-001 SC on day 1 of cycle 1 and then intratumorally on days 8 and 15 of cycle 1, days 1, 8, and 15 of cycle 2, and day 1 of cycle 3. Patients also receive pembrolizumab IV over 30 minutes on day 8 of each cycle. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.

SURGERY: Patients undergo surgery 1-2 weeks after completion of neoadjuvant phase.

ADJUVANT PHASE: After recovery from surgery, patients receive pembrolizumab IV over 30 minutes on day 1 of every other cycle. Treatment repeats every 21 days for up to 16 cycles in the absence of disease progression or unacceptable toxicity.

Patients also undergo CT or PET/CT throughout the trial and may undergo optional biopsy at baseline and disease progression and optional collection of blood samples throughout the trial.

Biopsy

Surgical Procedure

VLP-encapsulated TLR9 Agonist CMP-001

Ahmad Tarhini

This phase II trial studies the effect of pembrolizumab alone or in combination with CMP-001 in treating patients with melanoma that can be treated by surgery (operable). 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. Immunotherapy with CMP-001 may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. The addition of CMP-001 to pembrolizumab could improve the ability of the immune system to shrink tumors and to prevent them from returning.

PRIMARY OBJECTIVE:

I. To evaluate the rate of pathologic complete response (pCR) rate in patients in each arm.

SECONDARY OBJECTIVES:

I. To evaluate the rate of pathologic near-complete/major response (pMR) of the neoadjuvant therapy in each arm.

II. To evaluate the pathologic response rate of un-injected lesions on the combination arm (Arm B).

III. To evaluate relapse-free survival (RFS) in each arm. IV. To evaluate overall survival (OS) in each arm. V. To evaluate the preoperative radiographic response rate in each arm. VI. To evaluate safety and toxicity of neoadjuvant therapy in each arm.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A:

NEOADJUVANT PHASE: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.

SURGERY: Patients undergo surgery 1-2 weeks after completion of neoadjuvant phase.

ADJUVANT PHASE: After recovery from surgery, patients receive pembrolizumab IV over 30 minutes on day 1 of every other cycle. Treatment repeats every 21 days for up to 16 cycles in the absence of disease progression or unacceptable toxicity.

Patients also undergo computed tomography (CT) or positron emission tomography (PET)/CT throughout the trial and may undergo optional biopsy at baseline and disease progression and optional collection of blood samples throughout the trial.

ARM B:

NEOADJUVANT PHASE: Patients receive VLP-encapsulated TLR9 agonist CMP-001 (CMP-001) subcutaneously (SC) on day 1 of cycle 1 and then intratumorally on days 8 and 15 of cycle 1, days 1, 8, and 15 of cycle 2, and day 1 of cycle 3. Patients also receive pembrolizumab IV over 30 minutes on day 8 of each cycle. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.

SURGERY: Patients undergo surgery 1-2 weeks after completion of neoadjuvant phase.

ADJUVANT PHASE: After recovery from surgery, patients receive pembrolizumab IV over 30 minutes on day 1 of every other cycle. Treatment repeats every 21 days for up to 16 cycles in the absence of disease progression or unacceptable toxicity.

Patients also undergo CT or PET/CT throughout the trial and may undergo optional biopsy at baseline and disease progression and optional collection of blood samples throughout the trial.

After completion of study treatment, patients are followed up at 30 days and then every 3 months if \< 2 years from study entry, every 6 months if 2-5 years from study entry, and every 12 months if \> 5 years from study entry for up to 10 years (15 years total follow up).

A Study Evaluating Whether Pembrolizumab Alone or in Combination With CMP-001 Improves Efficacy in Patients With Operable Melanoma

Phase II Randomized Study of Neoadjuvant Pembrolizumab Alone or in Combination With CMP-001 in Patients With Operable Melanoma: Efficacy and Biomarker Study

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Will be estimated by the percentage of patients who achieve complete response, partial response or stable disease by Response Evaluation Criteria in Solid Tumors (RECIST) and Immune-Modified (i)RECIST criteria, with exact 90% confidence intervals.

Patients will be monitored for adverse events using the National Cancer Institute's Common Terminology Criteria for Adverse Events.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Ibrutinib in Treating Patients With Refractory Metastatic Cutaneous Melanoma	NCT02581930	Metastatic Mela... Recurrent Cutan... Stage IV Cutane...	Ibrutinib Laboratory Biom... Pharmacogenomic... Pharmacological...	18 Years -	National Cancer Institute (NCI)
Testing Treatment With Encorafenib and Binimetinib Before Surgery for Melanoma With Lymph Node Involvement	NCT04221438	Melanoma of Unk... Metastatic Mali... Pathologic Stag... Pathologic Stag... Pathologic Stag... Recurrent Cutan...	Binimetinib Computed Tomogr... Conventional Su... Encorafenib Fluorothymidine... Positron Emissi...	18 Years -	Eastern Cooperative Oncology Group
Testing Treatment With Encorafenib and Binimetinib Before Surgery for Melanoma With Lymph Node Involvement	NCT04221438	Melanoma of Unk... Metastatic Mali... Pathologic Stag... Pathologic Stag... Pathologic Stag... Recurrent Cutan...	Binimetinib Computed Tomogr... Conventional Su... Encorafenib Fluorothymidine... Positron Emissi...	18 Years -	Eastern Cooperative Oncology Group
Physician/Patient Choice of Either High-Dose Recombinant Interferon Alfa-2B or Ipilimumab, Versus Pembrolizumab in Treating Patients With Stage III-IV High Risk Melanoma That Has Been Removed by Surgery	NCT02506153	Clinical Stage ... Clinical Stage ... Metastatic Cuta... Metastatic Muco... Metastatic Non-... Non-Cutaneous M... Recurrent Cutan... Recurrent Mucos... Recurrent Non-C...	Biospecimen Col... Computed Tomogr... Ipilimumab Magnetic Resona... Pembrolizumab Positron Emissi... Quality-of-Life... Recombinant Int...	18 Years -	National Cancer Institute (NCI)
A Study Evaluating Whether Pembrolizumab Alone or in Combination With CMP-001 Improves Efficacy in Patients With Operable Melanoma	NCT04708418	Clinical Stage ... Melanoma of Unk... Pathologic Stag... Pathologic Stag... Pathologic Stag... Recurrent Cutan...	Biopsy Biospecimen Col... Computed Tomogr... Pembrolizumab Positron Emissi... Surgical Proced... VLP-encapsulate...	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for recurrent cutaneous melanoma