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
Overview
- Phase
- Phase 1
- Intervention
- Avelumab
- Conditions
- Merkel Cell Polyomavirus Infection
- Sponsor
- Fred Hutchinson Cancer Center
- Enrollment
- 8
- Locations
- 1
- Primary Endpoint
- Count of Participants Who Experienced Adverse Events, Evaluated According to the Current Guidelines in National Cancer Institute (NCI) Common Toxicity Criteria Version 4.0
- Status
- Terminated
- Last Updated
- 4 years ago
Overview
Brief 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. 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.
Detailed Description
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.
Investigators
Aude Chapuis
Associate Professor
Fred Hutchinson Cancer Center
Eligibility Criteria
Inclusion Criteria
- •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
Exclusion Criteria
- •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 \[MUGA\])
- •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
Arms & Interventions
Group 1 (avelumab and MHC class I up-regulation)
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.
Intervention: Avelumab
Group 1 (avelumab and MHC class I up-regulation)
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.
Intervention: Laboratory Biomarker Analysis
Group 1 (avelumab and MHC class I up-regulation)
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.
Intervention: Radiation Therapy
Group 1 (avelumab and MHC class I up-regulation)
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.
Intervention: Recombinant Interferon Beta
Group 2 (avelumab, MHC class I up-regulation, T cells)
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.
Intervention: Avelumab
Group 2 (avelumab, MHC class I up-regulation, T cells)
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.
Intervention: Laboratory Biomarker Analysis
Group 2 (avelumab, MHC class I up-regulation, T cells)
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.
Intervention: MCPyV TAg-specific Polyclonal Autologous CD8-positive T Cells
Group 2 (avelumab, MHC class I up-regulation, T cells)
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.
Intervention: Radiation Therapy
Group 2 (avelumab, MHC class I up-regulation, T cells)
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.
Intervention: Recombinant Interferon Beta
Outcomes
Primary Outcomes
Count of Participants Who Experienced Adverse Events, Evaluated According to the Current Guidelines in National Cancer Institute (NCI) Common Toxicity Criteria Version 4.0
Time Frame: Up to 4 weeks after the last infusion
Evidence and nature of toxicity related to the treatment will be assessed and compared between groups.
Evidence of Response, Based on Median Time to New Metastasis
Time Frame: Up to 1 year
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.
Secondary Outcomes
- Functional Capacity of Transferred T Cells (Group 2)(Up to 3 months)
- Count of Participants Who Displayed Persistence of Transferred T Cells in Blood and Tumor (Group Co2)(Up to 90 days post infusion)
- Count of Participants That Displayed Evidence of Epitope Spreading(Up to 3 months)
- Disease Response, as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1(28 days post infusion)
- Merkel Cell Carcinoma (MCC)-Specific Survival(Up to 1 year)