Neoplasms

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Carcinoma, Merkel Cell

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Merkel Cell Carcinoma

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Antibodies

Avelumab

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Interferon-beta

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Immunologic Factors

Patients who do not have a HLA type for which T cells can be generated or for whom T cells cannot be generated for technical issues receive avelumab intravenously (IV) over 1 hour every 2 weeks for 12 months. Within 7-10 days after completion of 1-3 doses of avelumab, patients receive MHC class I up-regulation intervention comprising either localized radiation therapy or recombinant interferon beta via intra-tumor injection.

Patients who have an HLA type for which T cells can be generated receive avelumab IV over 1 hour every 2 weeks for 12 months. Patients also receive MHC class I up-regulation intervention as in Group 1 between 7-10 days after the first infusion of avelumab and 2-5 days before the first infusion of MCPyV TAg-specific polyclonal autologous CD8+ T cells. Patients receive two infusions of MCPyV TAg-specific polyclonal autologous CD8+ T cells IV over 60-120 minutes.

Laboratory Biomarker Analysis

MCPyV TAg-specific Polyclonal Autologous CD8-positive T Cells

Radiation Therapy

Recombinant Interferon Beta

Aude Chapuis

This phase I/II trial studies the side effects and how well localized radiation therapy or recombinant interferon beta and avelumab with or without cellular adoptive immunotherapy works in treating patients with Merkel cell carcinoma that has spread to other parts of the body. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Interferon beta is a substance that can improve the body's natural response and may interfere with the growth of tumor cells. Monoclonal antibodies, such as avelumab, may help T lymphocytes kill tumor cells. For cellular adoptive immunotherapy, specific white blood cells are collected from the patient's blood and treated in the laboratory to recognize Merkel cell carcinoma. Infusing these cells back into the patient may help the body build an effective immune response to kill Merkel cell carcinoma. Giving localized radiation therapy or recombinant interferon beta and avelumab with or without cellular adoptive immunotherapy may be a better treatment for Merkel cell carcinoma.

PRIMARY OBJECTIVES:

I. Assess and compare the safety and potential toxicities associated with treating patients with metastatic Merkel cell carcinoma (MCC) with either major histocompatibility complex (MHC) up regulation and programmed cell death 1 (PD1)-axis blockade (Group 1), or MHC up-regulation, PD1-axis blockade and adoptive transfer of Merkel cell polyoma virus (MCPyV) T antigen (TAg)-specific polyclonal autologous cluster of differentiation (CD)8+ T cells (Group 2).

II. Assess and compare the antitumor efficacy associated with treating patients with metastatic MCC with either MHC up-regulation and PD1-axis blockade (Group 1), or MHC up-regulation, PD1-axis blockade and adoptive transfer of MCPyV TAg-specific polyclonal autologous CD8+ T cells (Group 2).

SECONDARY OBJECTIVES:

I. Examine the in vivo persistence and, where evaluable, migration to tumor sites of adoptively transferred polyclonal CD8+ T cells targeting the MCPyV TAg (Group 2).

II. Examine the in vivo functional capacity of adoptively transferred polyclonal CD8+ T cells targeting the MCPyV Tag (Group 2).

III. Examine and compare evidence of epitope spreading with either MHC up-regulation and adoptive transfer of MHC up-regulation and PD1-axis blockade (Group 1), or MHC up regulation, PD1-axis blockade and adoptive transfer of MCPyV TAg-specific polyclonal autologous CD8+ T cells (Group 2).

OUTLINE: Patients are assigned to 1 of 2 groups.

GROUP 1: Patients who do not have a human leukocyte antigen (HLA) type for which T cells can be generated or for whom T cells cannot be generated for technical issues receive avelumab intravenously (IV) over 1 hour every 2 weeks for 12 months. Within 7-10 days after completion of 1-3 doses of avelumab, patients receive MHC class I up-regulation intervention comprising either localized radiation therapy or recombinant interferon beta via intra-tumor injection.

GROUP 2: Patients who have an HLA type for which T cells can be generated receive avelumab IV over 1 hour every 2 weeks for 12 months. Patients also receive MHC class I up-regulation intervention as in Group 1 between 7-10 days after the first infusion of avelumab and 2-5 days before the first infusion of MCPyV TAg-specific polyclonal autologous CD8+ T cells. Patients receive two infusions of MCPyV TAg-specific polyclonal autologous CD8+ T cells IV over 60-120 minutes.

In both groups, MHC class I up-regulation treatment with or without T cell infusions may repeat if indicated.

After completion of study treatment, patients are followed up at 12 months and then periodically thereafter.

Localized Radiation Therapy or Recombinant Interferon Beta and Avelumab With or Without Cellular Adoptive Immunotherapy in Treating Patients With Metastatic Merkel Cell Carcinoma

Study to Evaluate Cellular Adoptive Immunotherapy Using Polyclonal Autologous CD8+ Antigen-Specific T Cells for Metastatic Merkel Cell Carcinoma in Combination With MHC Class I Up-Regulation and the Anti-PD-L1 Antibody Avelumab

Median time to new metastases reported for each group below. Group 1 result is NA, patient had no new detectable metastases in study follow-up period. Arm I is not analyzed because the one patient in Arm I did not experience new metastasis in their followup period, so they are not evaluable.

Evidence and nature of toxicity related to the treatment will be assessed and compared between groups.

Patients were evaluated for their disease response throughout their follow up period. Disease response reported is best response per patient. A complete response (CR) will be defined as total regression of all tumors, a PR as 30% or greater decrease in the sum of the longest diameter of target lesions compared to baseline and PD as 20% increase in the sum of the longest diameter of target lesions compared to the smallest prior diameter (RECIST v1.1 criteria).

Quantiﬁcation of the overall recognition of the MCPyV T-antigen for each patient will likely be performed by testing the reactivity of whole peripheral blood mononuclear cells (PBMC) before and at indicated timepoints after treatment to peptides 15 amino acids (aa) in length offset by 5 aa bases spanning the whole T-antigen protein to include both CD8 and CD4 responses regardless of the HLA type of the patient. Due to changes in assay technology, epitope spreading was detected using a flow cytometric based intracellular cytokine assay.

To evaluate the direct ex vivo function of the transferred cells, where possible, tetramer+ cells within collected peripheral blood mononuclear cells (PBMCs) will be evaluated for production of intracellular cytokines including interferon (IFN), tumor necrosis factor alpha and interleukin-2 in response to cognate antigen using an intracellular cytokine assay. This endpoint was evaluable in 4 of 7 patients, all 4 of whom upregulated interferon, tumor necrosis factor alpha and IL-2 expression in response to cognate antigen using intracellular cytokine assay. Persistence was not detected for 3 out of 7 patients in group 2, making them unevaluable for functional capacity.

Survival status in patients with Merkel cell carcinoma will be evaluated. Data is reported as count of participants that survived past the 1 year follow up period.

Persistence of trasferred T cells was evaluated and assessed after 90 days. Patients were counted if transferred T cells were detected beyond 90 days.

EMD Serono

National Cancer Institute (NCI)

Fred Hutchinson Cancer Center

Associate Professor

All unexpected and serious AEs which may be due to study treatment or intervention must be reported to the FHCRC Institutional Review Office (IRO) per their current reporting requirements.

All grade ≥ 3 CTCAE v.4 AEs will be collected through 4 weeks after each participant's last T-cell infusion and per section 12.C. Beginning 4 weeks after the participant's last infusion, only study related toxicities will be collected.ci

Patients who do not have a HLA type for which T cells can be generated or for whom T cells cannot be generated for technical issues receive avelumab intravenously (IV) over 1 hour every 2 weeks for 12 months. Within 7-10 days after completion of 1-3 doses of avelumab, patients receive MHC class I up-regulation intervention comprising either localized radiation therapy or recombinant interferon beta via intra-tumor injection.

Avelumab: Given IV

Laboratory Biomarker Analysis: Correlative studies

Radiation Therapy: Undergo radiation therapy

Recombinant Interferon Beta: Given via intra-tumor injection

Group 1 (Avelumab and MHC Class I Up-regulation)

Patients who have an HLA type for which T cells can be generated receive avelumab IV over 1 hour every 2 weeks for 12 months. Patients also receive MHC class I up-regulation intervention as in Group 1 between 7-10 days after the first infusion of avelumab and 2-5 days before the first infusion of MCPyV TAg-specific polyclonal autologous CD8+ T cells. Patients receive two infusions of MCPyV TAg-specific polyclonal autologous CD8+ T cells IV over 60-120 minutes.

Avelumab: Given IV

Laboratory Biomarker Analysis: Correlative studies

MCPyV TAg-specific Polyclonal Autologous CD8-positive T Cells: Given IV

Radiation Therapy: Undergo radiation therapy

Recombinant Interferon Beta: Given via intra-tumor injection

Group 2 (Avelumab, MHC Class I Up-regulation, T Cells)

Total

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Aude Chapuis

Patient in group 1 did not experience new metastasis in followup period of 1 year. Only 4 patients in group 2 experienced new metastases in the followup period of 1 year. The other 3 patients in group 2 were omitted due to no new metastases.

Evidence of Response, Based on Median Time to New Metastasis

Count of Participants Who Experienced Adverse Events, Evaluated According to the Current Guidelines in National Cancer Institute (NCI) Common Toxicity Criteria Version 4.0

Disease Response, as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1

Count of Participants That Displayed Evidence of Epitope Spreading

Functional Capacity of Transferred T Cells (Group 2)

Merkel Cell Carcinoma (MCC)-Specific Survival

Count of Participants Who Displayed Persistence of Transferred T Cells in Blood and Tumor (Group Co2)

Overall Study

Recurrence

Analgesics

Amino Acids

Aldesleukin

Interleukin-2

Analgesics, Non-Narcotic

Anti-HIV Agents

Anti-Retroviral Agents

Serine

Patients undergo radiation therapy or recombinant interferon beta intralesional injection within day -3 to day -1.

Patients receive MCPyV TAg-specific polyclonal autologous CD8-positive T cell infusion IV on day 1 and aldesleukin SC every 12 hours on days 1-14. Treatment repeats at least every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.

Patients with continued presence of detectable metastatic disease 8 weeks after the first infusion may repeat the treatment regimen including radiation therapy or recombinant interferon beta injection.

This phase I/II trial studies the side effects and best way to give laboratory treated autologous T cells together with aldesleukin and to see how well it works in treating patients with merkel cell carcinoma that has spread from the primary site (place where it started) to other places in the body. Biological therapies, such as cellular adoptive immunotherapy, may stimulate the immune system in different ways and stop tumor cells from growing. Aldesleukin may stimulate the white blood cells to kill tumor cells. Giving cellular adoptive immunotherapy with aldesleukin may be a better treatment for metastatic merkel cell carcinoma.

PRIMARY OBJECTIVES:

I. Determine the safety and potential toxicities associated with treating patients with metastatic merkel cell carcinoma (MCC) by combined myosin heavy chain (MHC) up-regulation therapy and adoptive transfer of merkel cell polyomavirus (MCPyV) T-antigen (TAg)-specific polyclonal autologous cluster of differentiation (CD)8+ T cells.

II. Determine the antitumor efficacy associated with treating patients with metastatic MCC by combined MHC up-regulation therapy and adoptive transfer of MCPyV TAg-specific polyclonal autologous CD8+ T cells.

SECONDARY OBJECTIVES:

I. Determine the in vivo persistence and where evaluable, migration to tumor sites of adoptively transferred polyclonal CD8+ T cells targeting the MCPyV TAg.

II. Determine the in vivo functional capacity of adoptively transferred polyclonal CD8+ T cells targeting the MCPyV TAg.

OUTLINE:

Patients undergo radiation therapy or recombinant interferon beta intralesional injection within day -3 to day -1.

Patients receive MCPyV TAg-specific polyclonal autologous CD8-positive T cell vaccine intravenously (IV) on day 1 and aldesleukin subcutaneously (SC) every 12 hours on days 1-14. Treatment repeats at least every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.

Patients with continued presence of detectable metastatic disease 8 weeks after the first infusion may repeat the treatment regimen including radiation therapy or recombinant interferon beta injection.

After completion of study treatment, patients are followed up every 3 months.

Viral Oncoprotein Targeted Autologous T Cell Therapy for Merkel Cell Carcinoma

The treatment will be considered to have an acceptable safety profile if the observed toxicity rate is consistent with a true rate that does not exceed 30%.

Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Localized Radiation Therapy or Recombinant Interferon Beta and Avelumab With or Without Cellular Adoptive Immunotherapy in Treating Patients With Metastatic Merkel Cell Carcinoma	NCT02584829	Merkel Cell Pol... Stage IV Merkel...	Avelumab Laboratory Biom... MCPyV TAg-speci... Radiation Thera... Recombinant Int...	18 Years -	Fred Hutchinson Cancer Center
Viral Oncoprotein Targeted Autologous T Cell Therapy for Merkel Cell Carcinoma	NCT01758458	Recurrent Merke... Stage IV Merkel...	Aldesleukin Laboratory Biom... MCPyV TAg-speci... Radiation Thera... Recombinant Int...	18 Years -	Fred Hutchinson Cancer Center
Localized Radiation Therapy or Recombinant Interferon Beta and Avelumab With or Without Cellular Adoptive Immunotherapy in Treating Patients With Metastatic Merkel Cell Carcinoma	NCT02584829	Merkel Cell Pol... Stage IV Merkel...	Avelumab Laboratory Biom... MCPyV TAg-speci... Radiation Thera... Recombinant Int...	18 Years -	Fred Hutchinson Cancer Center
Localized Radiation Therapy or Recombinant Interferon Beta and Avelumab With or Without Cellular Adoptive Immunotherapy in Treating Patients With Metastatic Merkel Cell Carcinoma	NCT02584829	Merkel Cell Pol... Stage IV Merkel...	Avelumab Laboratory Biom... MCPyV TAg-speci... Radiation Thera... Recombinant Int...	18 Years -	Fred Hutchinson Cancer Center

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