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Merkel Cell Polyomavirus InfectionPhase 1/2NCT02584829

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

A Phase 1/2 study testing Avelumab, Laboratory Biomarker Analysis and MCPyV TAg-specific Polyclonal Autologous CD8-positive T Cells in people with Merkel Cell Polyomavirus Infection and Stage IV Merkel Cell Carcinoma AJCC v7, run by Fred Hutchinson Cancer Center at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Avelumab, Laboratory Biomarker Analysis and MCPyV TAg-specific Polyclonal Autologous CD8-positive T Cells
Could I receive a placebo?
No, everyone receives an active treatment
How many people
8 participants
Where
1 siteUnited States
Study dates
6 Nov 2015to 18 Dec 2018
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Signed written informed consent
  • Confirmation of MCC by internal pathology review of initial or subsequent biopsy or other pathologic material
  • If an accessible lesion is present, a biopsy will be performed within 6 weeks of the start of study intervention; the results of the biopsy must be obtained prior to initiation of study intervention
  • Evidence of MCPyV TAg tumor expression by immunohistochemistry on any prior or current tumor specimen or viral oncoprotein antibody confirmation within 6 weeks of the start of study intervention
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) =< 2 at trial entry
  • Patients must have at least one bi-dimensionally measurable lesion by palpation, clinical exam, or radiographic imaging within 6 weeks of the start of study intervention (X-ray, computed tomography [CT] scan, positron emission tomography [PET] scan, magnetic resonance imaging [MRI], or ultrasound)
  • For patients designated to be treated on Group 2: cardiac ejection fraction >= 35%; for patients with significant risk factors for coronary artery disease (Framingham risk score > 15%), a cardiac stress test is recommended
  • At least 3 weeks must have passed since any of the following: systemic corticosteroids, immunotherapy (for example, T-cell infusions, immunomodulatory agents, interleukins, MCC vaccines, intravenous immunoglobulin, expanded polyclonal tumor infiltrating lymphocytes [TIL] or lymphokine-activated killer [LAK] therapy), pentoxifylline, other small molecule or chemotherapy cancer treatment, other investigational agents or other systemic agents that target Merkel cell carcinoma

Who cannot join

  • Known active infections or oral temperature > 38.2 Celsius (C) fewer than 72 hours prior to receiving study treatment or systemic infection requiring chronic maintenance or suppressive therapy
  • White blood cells (WBC) < 200/mcl
  • Hemoglobin (Hb) < 8 g/dL
  • Absolute neutrophil count (ANC) < 1000/mcl
  • Platelets < 50,000/mcl
  • New York Heart Association functional class III-IV heart failure, symptomatic pericardial effusion, stable or unstable angina, symptoms of coronary artery disease, congestive heart failure, clinically significant hypotension, or history of an ejection fraction of =< 30 % (echocardiogram or multi gated acquisition scan [MUGA])
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  • Clinically significant pulmonary dysfunction, as determined by medical history and physical exam; patients so identified will undergo pulmonary functions testing and those with forced expiratory volume in 1 second (FEV1) < 2.0 L or diffusion capacity of the lung for carbon monoxide (DLco) (corrected [corr] for hemoglobin [Hgb]) < 50% will be excluded
  • Creatinine clearance < 30 ml/min which cannot be attributed to MCC metastasis
  • Total bilirubin > 1.5 x upper limit of normal (ULN)
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 2.5 x ULN; for patients with liver metastases: AST/ALT > 5 x ULN
  • Active autoimmune disease (e.g. systemic lupus erythematosus, vasculitis, infiltrating lung disease, inflammatory bowel disease) whose possible progression during treatment would be considered unacceptable by the investigators
  • Symptomatic and untreated central nervous system (CNS) metastasis; however, patients with 1 to 2 asymptomatic, less than 1 cm brain/CNS metastases without significant edema may be considered for treatment; if sub-centimeter CNS lesions are noted at study entry, then repeat imaging will be performed, if more than 4 weeks have elapsed from the last scan
  • Any condition or organ toxicity that is deemed by the principal investigator (PI) or the attending physician to place the patient at unacceptable risk for treatment on the protocol
  • Pregnant women, nursing mothers, men or women of reproductive ability who are unwilling to use effective contraception or abstinence; women of childbearing potential must have a negative pregnancy test within 2-6 weeks prior to treatment
  • Clinically significant and ongoing immune suppression including, but not limited to, systemic immunosuppressive agents such as cyclosporine or corticosteroids, chronic lymphocytic leukemia (CLL), uncontrolled human immunodeficiency virus (HIV) infection, or solid organ transplantation
  • Patients may not be on any other treatments for their cancer aside from those included in the protocol; patients may not undergo another form of treatment concurrently with this study
  • Known severe hypersensitivity reactions to monoclonal antibodies (grade >= 3 National Cancer Institute [NCI]-Common Terminology Criteria for Adverse Events [CTCAE] version [v] 4.0), any history of anaphylaxis, or uncontrolled asthma
  • Vaccination with live inactivated viral strains for the prevention of infectious diseases within 4 weeks of the start of the study treatment, inactivated influenza vaccines are permitted while on trial
  • Known alcohol or drug abuse
  • Legal incapacity or limited legal capacity

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Fred Hutch/University of Washington Cancer Consortium

    Seattle, Washington, 98109

Other trials in United States

About this study

Official title: 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

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. 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:

  1. 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.

Being tested
Avelumab, Laboratory Biomarker Analysis, MCPyV TAg-specific Polyclonal Autologous CD8-positive T Cells, Radiation Therapy, Recombinant Interferon Beta
Medical subject headings
Carcinoma, Merkel Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AvelumabDrug

    Also called Bavencio, MSB-0010718C, MSB0010718C

    Given IV

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • MCPyV TAg-specific Polyclonal Autologous CD8-positive T CellsBiological

    Given IV

  • Radiation TherapyRadiation

    Also called Cancer Radiotherapy, Irradiate, Irradiated, irradiation

    Undergo radiation therapy

  • Recombinant Interferon BetaBiological

    Also called Beta Interferon, Betantrone, Feron, Human Interferon Beta

    Given via intra-tumor injection

Study groups in NCT02584829
Study groupRoleWhat they receive
Group 1 (avelumab and MHC class I up-regulation)ExperimentalPatients 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.
Receives: Drug: Avelumab; Other: Laboratory Biomarker Analysis; Radiation: Radiation Therapy; Biological: Recombinant Interferon Beta
Group 2 (avelumab, MHC class I up-regulation, T cells)ExperimentalPatients 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.
Receives: Drug: Avelumab; Other: Laboratory Biomarker Analysis; Biological: MCPyV TAg-specific Polyclonal Autologous CD8-positive T Cells; Radiation: Radiation Therapy; Biological: Recombinant Interferon Beta

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Evidence of Response, Based on Median Time to New Metastasis

    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.

    Measured: Up to 1 year

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

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

    Measured: Up to 4 weeks after the last infusion

Secondary outcomes (5)

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

    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).

    Measured: 28 days post infusion

  2. Count of Participants That Displayed Evidence of Epitope Spreading

    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.

    Measured: Up to 3 months

  3. Functional Capacity of Transferred T Cells (Group 2)

    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.

    Measured: Up to 3 months

  4. Merkel Cell Carcinoma (MCC)-Specific Survival

    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.

    Measured: Up to 1 year

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

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

    Measured: Up to 90 days post infusion

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted23 Oct 2015 (estimated)
  2. Study start6 Nov 2015
  3. Primary completion18 Dec 2018
  4. Study completion18 Dec 2018

Why it stopped: Terminated due to loss in funding

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
8 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02584829
Sponsor's protocol ID
9245
Other IDs
NCI-2014-02462, FHCRC 9245, 9245, K24CA139052, P30CA015704, R01CA176841, RG1015013
Status last verified
Feb 2022
First submitted
21 Oct 2015
Last updated
22 Mar 2022
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Avelumab, Laboratory Biomarker Analysis and MCPyV TAg-specific Polyclonal Autologous CD8-positive T Cells in people with Merkel Cell Polyomavirus Infection and Stage IV Merkel Cell Carcinoma AJCC v7, run by Fred Hutchinson Cancer Center at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 8 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 22 Mar 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 22 Mar 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Evidence of Response, Based on Median Time to New Metastasis (time frame: Up to 1 year). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02584829.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Mar 2022.

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