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Pembrolizumab

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Interferon-gamma

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Patients receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 3 weeks for up to 2 years in the absence of disease progression or unexpected toxicity. Patients also receive interferon gamma-1b SC 3 times per week for 12 weeks, and then follow 3 weeks on and 3 weeks off schedule for up to 2 years in the absence of disease progression or unexpected toxicity.

Patients pembrolizumab IV over 30 minutes on day 1 and interferon gamma-1b SC once a week. Cycles repeat every 3 weeks for up to 2 years in the absence of disease progression or unexpected toxicity.

Interferon Gamma-1b

Laboratory Biomarker Analysis

Michael S Khodadoust, MD

This phase II trial studies how well pembrolizumab and interferon gamma-1b work in treating patients with stage IB-IVB mycosis fungoides and Sezary syndrome that has come back (relapsed) or has not responded to previous treatment (refractory). 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. Interferon gamma-1b may boost the immune system activity. Giving pembrolizumab and interferon gamma-1b together may work better in treating patients with stage IB-IVB mycosis fungoides and Sezary syndrome.

PRIMARY OBJECTIVES:

I. To assess the overall response rate (ORR) of MK-3475 (pembrolizumab) and interferon gamma-1b (IFN-G) (Actimmune) combination immunotherapy in subjects with previously treated mycosis fungoides or Sezary syndrome. (Treatment Group 1) II. To determine whether the combination of interferon gamma-1b (ACTIMMUNE) and MK-3475 (pembrolizumab) improves the ORR of pembrolizumab in patients with unresectable or metastatic synovial sarcoma. (Treatment Group 2)

SECONDARY OBJECTIVES:

I. To explore the safety/tolerability and clinical activity of MK-3475 (pembrolizumab) and IFN-G (Actimmune) in subjects with previously treated mycosis fungoides or Sezary syndrome with respect to (Treatment Group 1):

Ia. Safety and tolerability. Ib. Time to response (TTR). Ic. Duration of response (DOR). Id. Progression-free survival (PFS). Ie. Event-free survival (EFS). If. Percentage of all patients who have a response duration of at least 12 months (ORR12).

II. To determine the progression-free survival (PFS) and overall survival (OS) for patients with advanced synovial sarcoma receiving interferon gamma-1b and MK-3475 (pembrolizumab). (Treatment Group 2) III. To determine the tolerability of the combination of interferon gamma-1b and MK-3475 (pembrolizumab) based on Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. (Treatment Group 2)

EXPLORATORY OBJECTIVES:

I. To investigate the relationship between the following putative biomarkers for combination immunotherapy of MK-3475 pembrolizumab) and IFN-gamma (Actimmune) and clinical outcomes (as measured by safety/tolerability and ORR, DOR, PFS, EFS) in subjects with previously treated mycosis fungoides or Sezary syndrome, including tumor/microenvironment (PD-1/PD-L1/PD-L2 expression, cytotoxic T lymphocyte \[CTL\]s, regulatory T cell \[Treg\]s, macrophages, dendritic cell \[DC\]s; nanostring gene expression profile), systemic immune response (flow cytometry, mass cytometry \[CyTOF\], Luminex multiplexed cytokine profile), and molecular/genomic immune correlates (exome sequencing, high throughput sequencing \[HTS\] for T cell receptor \[TCR\]). (Treatment Group 1)

II. To investigate paired, serial biopsy specimens from pre-treatment and 8-12 weeks after starting treatment for the following (Treatment Group 2):

IIa. MHC class I expression (scored by pathologist). IIb. Number of infiltrating T cells per mm\^2. IIc. Tumor associated macrophage number and phenotype using multiplex immunohistochemistry.

IId. T cell clonality. IIe. Gene expression profiling.

III. To investigate peripheral blood samples from patients to determine (Treatment Group 2):

IIIa. The number and phenotype of T cells specific for computed tomography (CT) antigens and potential neo-antigens.

IIb. The phenotype and activation state of circulating monocytes and peripheral blood mononuclear cell (PBMC).

IIc. Cytokines associated with response.

OUTLINE: Patients are assigned to 1 of 2 groups.

GROUP I: Patients with Mycosis Fungoides and Sezary Syndrome receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 3 weeks for up to 2 years in the absence of disease progression or unexpected toxicity. Patients also receive interferon gamma-1b subcutaneously (SC) 3 times per week for 12 weeks, and then follow 3 weeks on and 3 weeks off schedule for up to 2 years in the absence of disease progression or unexpected toxicity.

GROUP II: Patients with advanced synovial sarcoma receive pembrolizumab IV over 30 minutes on day 1 and interferon gamma-1b SC once a week. Cycles repeat every 3 weeks for up to 2 years in the absence of disease progression or unexpected toxicity.

After completion of study treatment, patients are followed up for 30 days and then every 12 weeks for up to 1 year.

Testing the Combination of Two Experimental Drugs MK-3475 (Pembrolizumab) and Interferon-gamma for the Treatment of Mycosis Fungoides and Sézary Syndrome and Advanced Synovial Sarcoma

A Phase II Trial of MK-3475 (Pembrolizumab) and Interferon Gamma 1-b Combination Immunotherapy in Patients With Previously Treated Mycosis Fungoides and Sezary Syndrome (Treatment Group 1) and in Patients With Advanced Synovial Sarcoma (Treatment Group 2)

Clinical response (as measured by the primary and secondary endpoints) to combination immunotherapy regimen as a function of biomarkers will be evaluated. All biomarker assays will be run on the clinical trial samples in a blinded manner. Time to event endpoints (DOR, PFS, EFS) will be evaluated using Kaplan-Meier curves generated by biomarker scoring group using the log-rank test. Exploratory outcomes will be summarized with descriptive statistics (primarily proportions and medians) for all biomarkers described above, and additionally, serum IL-10, regulatory T-cells, and activated CD8 T cells. Scatterplots and Kendall's tau estimates will be produced for estimating correlation of PD-1, PDL1, or PD-L2 expression measures and clinical outcome across compartments (skin, lymph node, blood). Comparison of tissue immunohistochemistry markers between pre-treatment and with clinical response or disease progression will be assessed using Wilcoxon signed-rank test.

Participants in Treatment Group 1 will be assessed for response and progression using standard response criteria in patients with Mycosis Fungoides and Sezary syndrome. Per Global Response Score determined by evaluating skin, lymph nodes, internal organs (viscera), and blood specimens: Complete Response (CR), complete disappearance of all clinical evidence of disease; Partial Response (PR), regression of measurable disease.

Participants in Treatment Group 2 will be assessed for response and progression using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Complete Response (CR) disappearance of all lesions and no new lesion; Partial Response (PR), 30% or greater reduction in tumor size and no new lesions.

The ORR is defined as CR combined with PR. Will be assessed using binomial proportion.

Best response at any timepoint was used to determine ORR.

Will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Will be assessed using the Kaplan-Meier method.

Will be assessed using the Kaplan-Meier method

Will be assessed per global assessment of mycosis fungoides and Sezary syndrome (confirmed \& investigator assessed). Will use binomial distribution.

National Cancer Institute (NCI)

Patients with Mycosis Fungoides and Sezary Syndrome receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 3 weeks for up to 2 years in the absence of disease progression or unexpected toxicity. Patients also receive interferon gamma-1b SC 3 times per week for 12 weeks, and then follow 3 weeks on and 3 weeks off schedule for up to 2 years in the absence of disease progression or unexpected toxicity.

Interferon Gamma-1b: Given SC

Laboratory Biomarker Analysis: Ancillary studies

Pembrolizumab: Given IV

Group I (Pembrolizumab, Interferon Gamma-1b)

Patients with advanced synovial sarcoma receive pembrolizumab IV over 30 minutes on day 1 of each cycle, and interferon gamma-1b SC once a week. Cycles repeat every 3 weeks for up to 2 years in the absence of disease progression or unexpected toxicity.

Interferon Gamma-1b: Given SC

Laboratory Biomarker Analysis: Ancillary studies

Pembrolizumab: Given IV

Group II (Pembrolizumab, Interferon Gamma-1b)

Patients receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 3 weeks for up to 2 years in the absence of disease progression or unexpected toxicity. Patients also receive interferon gamma-1b SC 3 times per week for 12 weeks, and then follow 3 weeks on and 3 weeks off schedule for up to 2 years in the absence of disease progression or unexpected toxicity.

Interferon Gamma-1b: Given SC

Laboratory Biomarker Analysis: Ancillary studies

Pembrolizumab: Given IV

Patients pembrolizumab IV over 30 minutes on day 1 and interferon gamma-1b SC once a week. Cycles repeat every 3 weeks for up to 2 years in the absence of disease progression or unexpected toxicity.

Interferon Gamma-1b: Given SC

Laboratory Biomarker Analysis: Ancillary studies

Pembrolizumab: Given IV

Total

Age, Categorical

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

Patients do not have to complete the study in order to be included in the analysis population for the primary outcome measure.

Anna Wright

Both Treatment Group 1 and Treatment Group 2 study participants received at least one dose of IV pembrolizumab on study, and 27 participants received at least one dose of Interferon gamma on study. While not all participants reached the first disease assessment timepoint specified in the protocol, all had documented disease status at the time of treatment or study discontinuation. Therefore, no study participants were excluded from ORR analysis due to missing data.

Overall Response Rate (ORR)

Incidence of Adverse Events

Per Global Response Score used in Mycosis Fungoides and Sezary Syndrome, Response is assessed by the standard response criteria: Complete Response (CR), complete disappearance of all clinical evidence of disease where all categories (i.e., skin, lymph nodes, viscera, blood) have complete response/noninvolved; Partial Response (PR), regression of measurable disease; Stable Disease (SD), failure to attain CR, PR, or PD.

Simple statistics. Non-responders excluded from analysis.

Non-responders are excluded in the analysis.

Time to Response (TTR)

Non-responders are excluded in analysis; censored at last follow-up or start of new significant therapy

Duration of Response (DOR)

Progression is assessed by the standard response criteria used in Mycosis Fungoides and Sezary Syndrome (skin, lymph nodes, viscera, blood, global). Per Global Response Score, progression is defined as Progressive Disease (PD) in any category (i.e., skin, lymph nodes, viscera, blood).

All efficacy or safety evaluable patients. Censored at last follow-up or start of new significant therapy.

Progression-free Survival (PFS)

All efficacy or safety evaluable patients. Event is defined by early termination due to toxicity, start of new significant therapy, PD, or death of any cause.

Event-free Survival (EFS)

Evaluable duration of response beyond 12 months for evaluable population.

Rate of Overall Response Duration Beyond 12 Months (ORR12)

Biomarkers in Tumor and Blood Assessed by Immunohistochemistry, Mass Spectrometry, Nanostring, Sequencing, and Enzyme-linked Immunosorbent Assay

Overall Study

Histiocytoma, Malignant Fibrous

Chondrosarcoma

Leiomyosarcoma

Histiocytoma

Neoplasms, Fibrous Tissue

Undifferentiated Pleomorphic Sarcoma

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

Itacitinib

Lee Cranmer

This pilot phase I trial studies how well itacitinib works in treating patients with sarcomas that do not respond to treatment (refractory) and have spread to other parts of the body (advanced/metastatic). Itacitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

OUTLINE:

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

After completion of study treatment, patients are followed up at 7 and 30 days, every 12 weeks from baseline for up to 1 year, and then every 6 months thereafter.

Itacitinib in Treating Patients With Refractory Metastatic/Advanced Sarcomas

A Pilot Study Examining the Impact of the Jak1 Inhibitor Itacitinib on the Sarcoma Tumor Immune Microenvironment

Evaluation of the change in percentages of cells against the null hypothesis of no difference will be performed using a 1-sided t-test at the 0.05 level.

Will be graded according to Common Terminology Criteria for Adverse Events version 5.0. The frequency and severity of toxicities will be evaluated by proportions and associated 95% confidence intervals.

Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Distributions and percentages at landmark times for time to event outcomes will be estimated using the method of Kaplan-Meier. Confidence intervals about medians will be estimated using the method of Brookmeyer-Crowley. With 12 LMS patients, binary proportions can be estimated to within 29% with 95% confidence. With 8 (SS or MRCL) and PUS, respectively, binary proportions can be estimated to within 36% with 95% confidence.

Distributions and percentages at landmark times for time to event outcomes will be estimated using the method of Kaplan-Meier. Confidence intervals about medians will be estimated using the method of Brookmeyer-Crowley. With 12 LMS patients, binary proportions can be estimated to within 29% with 95% confidence. With 8 (SS or MRCL) and PUS, respectively, binary proportions can be estimated to within 36% with 95% confidence.

CR and PR will be defined as per RECIST 1.1 Distributions and percentages at landmark times for time to event outcomes will be estimated using the method of Kaplan-Meier. Confidence intervals about medians will be estimated using the method of Brookmeyer-Crowley. With 12 LMS patients, binary proportions can be estimated to within 29% with 95% confidence. With 8 (SS or MRCL) and PUS, respectively, binary proportions can be estimated to within 36% with 95% confidence.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Testing the Combination of Two Experimental Drugs MK-3475 (Pembrolizumab) and Interferon-gamma for the Treatment of Mycosis Fungoides and Sézary Syndrome and Advanced Synovial Sarcoma	NCT03063632	Metastatic Myxo... Metastatic Roun... Metastatic Syno... Recurrent Mycos... Refractory Myco... Stage IB Mycosi... Stage II Mycosi... Stage IIA Mycos... Stage IIB Mycos... Stage III Mycos... Stage IIIA Myco... Stage IIIB Myco... Stage IV Mycosi... Stage IVA Mycos... Stage IVB Mycos... Unresectable Sy...	Interferon Gamm... Laboratory Biom... Pembrolizumab	12 Years -	National Cancer Institute (NCI)
Itacitinib in Treating Patients With Refractory Metastatic/Advanced Sarcomas	NCT03670069	Metastatic Leio... Metastatic Syno... Metastatic Undi... Advanced Myxoid... Advanced Soft T... Metastatic Myxo... Metastatic Roun... Metastatic Soft... Refractory Leio... Refractory Myxo... Refractory Roun... Refractory Soft... Refractory Syno... Refractory Undi... Advanced Leiomy... Advanced Synovi... Advanced Undiff... Metastatic Chon...	Itacitinib Laboratory Biom...	18 Years -	Fred Hutchinson Cancer Center

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