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Gene-Modified Immune Cells (FH-MCVA2TCR) in Treating Patients With Metastatic or Unresectable Merkel Cell Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03747484
Recruitment Status : Recruiting
First Posted : November 20, 2018
Last Update Posted : July 28, 2020
Sponsor:
Collaborators:
National Cancer Institute (NCI)
bluebird bio
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center

Brief Summary:
This phase I/II trial studies the side effects of gene-modified immune cells (FH-MCVA2TCR) and to see how well they work in treating patients with Merkel cell cancer that has spread to other parts of the body (metastatic) or that cannot be removed by surgery (unresectable). Placing a gene that has been created in the laboratory into immune cells may improve the body's ability to fight Merkel cell cancer.

Condition or disease Intervention/treatment Phase
Other Skin Biological: Autologous MCPyV-specific HLA-A02-restricted TCR-transduced CD4+ and CD8+ T-cells FH-MCVA2TCR Drug: Avelumab Biological: Pembrolizumab Drug: Fludarabine Drug: Cyclophosphamide Phase 1 Phase 2

Detailed Description:

OUTLINE: This is a dose escalation study of FH-MCVA2TCR autologous T-cells.

LYMPHODEPLETING CHEMOTHERAPY: Between 2-7 days prior to receiving FH-MCVA2TCR T-cells, patients receive fludarabine intravenously (IV) over 30 minutes and cyclophosphamide for 3 days.

Patients receive FH-MCVA2TCR T-cells IV over 60-120 minutes. Patients also receive standard of care avelumab IV over 1 hour every 2 weeks for 1 year or pembrolizumab IV over 30 minutes every 3 weeks for 1 year in the absence of disease progression or unacceptable toxicity. Patients with partial response or stable disease may then receive an additional cycle of FH-MCVA2TCR T-cells.

After completion of study treatment, patients are followed up periodically for up to 15 years.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 16 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Study of Autologous CD8+ and CD4+ Transgenic T Cells Expressing High Affinity MCPyV-Specific TCRs Combined With Avelumab and Class I MHC-Upregulation in Patients With Metastatic MCC Refractory to PD-1 Axis Blockade
Actual Study Start Date : July 3, 2019
Estimated Primary Completion Date : October 15, 2023
Estimated Study Completion Date : October 15, 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Avelumab

Arm Intervention/treatment
Experimental: Treatment (TCR-T cells, avelumab or pembrolizumab)

LYMPHODEPLETING CHEMOTHERAPY: Between 2-7 days prior to receiving FH-MCVA2TCR T-cells, patients receive fludarabine IV over 30 minutes and cyclophosphamide for 3 days.

Patients receive FH-MCVA2TCR T-cells IV over 60-120 minutes. Patients also receive standard of care avelumab IV over 1 hour every 2 weeks for 1 year or pembrolizumab IV over 30 minutes every 3 weeks for 1 year in the absence of disease progression or unacceptable toxicity. Patients with partial response or stable disease may then receive an additional cycle of FH-MCVA2TCR T-cells.

Biological: Autologous MCPyV-specific HLA-A02-restricted TCR-transduced CD4+ and CD8+ T-cells FH-MCVA2TCR
Given IV
Other Names:
  • Autologous CD8+ and CD4+ T-cells transduced with TCR A2-MCC1
  • FH-MCVA2TCR
  • , FH-MCVA2TCR Autologous CD8+ and CD4+ T-cells Transduced with TCR A2-MCC1

Drug: Avelumab
Given IV
Other Names:
  • 1537032-82-8
  • Bavencio
  • Immunoglobulin G1-lambda1
  • Anti-(Homo sapiens CD274 (Programmed Death Ligand 1, PDL1, pd-l1, B7 Homolog 1, B7H1))
  • Homo sapiens Monoclonal Antibody
  • MSB-0010718C
  • MSB0010718C

Biological: Pembrolizumab
Given IV
Other Names:
  • Anti-(Human Programmed Cell Death 1)
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Drug: Fludarabine
Given IV
Other Names:
  • 2-Fluoro-9-beta-arabinofuranosyladenine
  • 9-Beta-D-arabinofuranosyl-2-fluoroadenine
  • Fluradosa

Drug: Cyclophosphamide
Given IV
Other Names:
  • Cycloblastin
  • CTX
  • Cycloblastine
  • Cyclophosphamidum
  • Cytophosphane

Experimental: Treatment 2 (TCR-T cells, avelumab or pembrolizumab)

LYMPHODEPLETING CHEMOTHERAPY: Between 2-7 days prior to receiving FH-MCVA2TCR T-cells, patients receive fludarabine IV over 30 minutes and cyclophosphamide for 3 days.

Patients receive FH-MCVA2TCR T-cells IV over 60-120 minutes. Patients also receive standard of care avelumab IV over 1 hour every 2 weeks for 1 year or pembrolizumab IV over 30 minutes every 3 weeks for 1 year in the absence of disease progression or unacceptable toxicity. Patients with partial response or stable disease may then receive an additional cycle of FH-MCVA2TCR T-cells.

Biological: Autologous MCPyV-specific HLA-A02-restricted TCR-transduced CD4+ and CD8+ T-cells FH-MCVA2TCR
Given IV
Other Names:
  • Autologous CD8+ and CD4+ T-cells transduced with TCR A2-MCC1
  • FH-MCVA2TCR
  • , FH-MCVA2TCR Autologous CD8+ and CD4+ T-cells Transduced with TCR A2-MCC1

Drug: Avelumab
Given IV
Other Names:
  • 1537032-82-8
  • Bavencio
  • Immunoglobulin G1-lambda1
  • Anti-(Homo sapiens CD274 (Programmed Death Ligand 1, PDL1, pd-l1, B7 Homolog 1, B7H1))
  • Homo sapiens Monoclonal Antibody
  • MSB-0010718C
  • MSB0010718C

Biological: Pembrolizumab
Given IV
Other Names:
  • Anti-(Human Programmed Cell Death 1)
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Drug: Fludarabine
Given IV
Other Names:
  • 2-Fluoro-9-beta-arabinofuranosyladenine
  • 9-Beta-D-arabinofuranosyl-2-fluoroadenine
  • Fluradosa

Drug: Cyclophosphamide
Given IV
Other Names:
  • Cycloblastin
  • CTX
  • Cycloblastine
  • Cyclophosphamidum
  • Cytophosphane




Primary Outcome Measures :
  1. Incidence of adverse events grade 3 or higher determined to be possibly, probably or definitely secondary to any of the study treatments per Common Terminology Criteria for Adverse Events (CTCAE) v. 5.0 [ Time Frame: Up to 15 years ]
    Evidence of excessive toxicity will be an observed proportion of toxicities for which the associated lower 80% confidence limit exceeds 40%.

  2. Best overall response [ Time Frame: Up to 15 years ]
    Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 of complete or partial response. Irradiated and non-irradiated lesions will be separately tracked but response determined in totality.


Secondary Outcome Measures :
  1. Progression-free survival [ Time Frame: Up to 15 years ]
    Will be estimated using the method of Kaplan and Meier, with time zero the time of first T cell infusion.

  2. Overall survival [ Time Frame: Up to 15 years ]
    Will be estimated using the method of Kaplan and Meier, with time zero the time of first T cell infusion.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • EVALUATION: Metastatic or unresectable Merkel cell polyomavirus (MCPyV)-associated Merkel cell carcinoma (VP-MCC) that has progressed on or after prior treatment with a PD-1 axis immune checkpoint inhibitor.
  • EVALUATION: Individuals that may be consented to undergo evaluation to determine potential eligibility must have a history of metastatic or unresectable Merkel cell carcinoma (MCC) (as documented by medical record).
  • EVALUATION: Be capable of understanding and providing informed consent.
  • Participants must have metastatic or unresectable, histologically confirmed virus-positive MCC. Confirmation of diagnosis must be or have been performed by internal pathology review of initial or subsequent biopsy or other pathologic material at Fred Hutch/Seattle Cancer Care Alliance (SCCA).
  • Approximately 80% of MCCs are caused by Merkel cell polyomavirus (MCPyV) T Antigens and the treatment is expected to only be effective in this population. Merkel cell polyomavirus positivity may be established through one of two means: positive Merkel cell polyomavirus T antigen serology (preferred) or immunohistochemistry of a primary or metastatic MCC tumor lesion (if T antigen seronegative).
  • MCPyV T Antigen serology will be performed with the anti-Merkel cell panel (AMERK) assay run through the University of Washington Medical Center Laboratory Medicine Clinical Immunology Laboratory. Positivity will be defined as a Merkel oncoprotein antibody titer (MSCTT) of >= 75 standard titer units (STU) at any time point from initial diagnosis onward. Patients with negative T antigen serology but MCPyV positive tumor by other methodologies will be considered for additional MCPyV testing as clinically appropriate, as the T antigen serology assays are highly specific but incompletely sensitive for MCPyV status. In this case, immunohistochemistry of any tumor lesion will be performed with the CM2B4 Merkel cell polyomavirus T antigen antibody. Expression of MCPyV in at least 10% of tumor cells will be considered positive. CM2B4 staining performed at any point clinically and at any clinical laboratory may be accepted. However, if CM2B4 staining has not been previously performed by a clinical pathology laboratory as part of MCC diagnostic workup, it will be performed in a clinical diagnostic pathology laboratory at University of Washington (UW)/Fred Hutchinson Cancer Research Center (FHCRC)/SCCA as per standard staining protocols. Persons are not required to have both CM2B4 positivity and seropositivity; either will be acceptable confirmation of viral status and if one negative and the other positive the patient will remain eligible provided other criteria are met.
  • Patients must have been previously treated with at least one dose of a PD-1 axis inhibitor (e.g. PD-1 or PD-L1 inhibiting monoclonal antibody such as pembrolizumab, nivolumab, avelumab, atezolizumab, durvalumab), developed progression of their MCC tumor on or after treatment, and not developed grade 3 or higher toxicity. At least four weeks must have passed between the administration of the first dose of PD-1 axis inhibitor and determination of progression. If there is significant clinical concern for pseudoprogression (i.e. progression developed rapidly after checkpoint inhibitor therapy), biopsy must be performed to demonstrate true progression. Patients may have received 1 or more prior systemic regimens for MCC. There is no upper limit on prior regimens. Patients may have received prior anti-PD-1/anti-PD-L1 in the neoadjuvant or adjuvant setting.
  • Participants must be HLA-A*02:01 in order for infused transgenic T cells to recognize antigen-MHC complexes. HLA typing for HLA-A2 should be determined through molecular approaches at a clinical laboratory licensed for HLA testing.
  • Life expectancy must be anticipated to be > 3 months at trial entry.
  • Fewer than 0.5% of MCC occur in individuals aged 30 years or younger, thus the protocol includes only adult patients.
  • Capable of understanding and providing a written informed consent.
  • If fertile, willingness to comply with reproductive requirements.
  • Karnofsky performance status of >= 60%.
  • Should there be no tumor tissue that is accessible for biopsy, patients will still be considered for participation, at discretion of the investigator. Similarly, should an investigator determine that a biopsy cannot be performed safely for clinical reasons biopsies may be cancelled or retimed.
  • At least 3 weeks must have passed since any: immunotherapy (for example, T-cell infusions, immunomodulatory agents, interleukins, MCC vaccines, intravenous immunoglobulin, expanded polyclonal tumor infiltrating lymphocyte [TIL] or lymphokine-activated killer cell [LAK] therapy), natural killer (NK) therapy, small molecule or chemotherapy cancer treatment, other investigational agents or other systemic agents that target MCC. There is no washout period for radiation.
  • Serum creatinine < 2.5 or estimated glomerular filtration rate (eGFR) > 30.
  • Total bilirubin (tBili) < 3.0. Patients with suspected Gilbert syndrome may be included if Tbili > 3 but no other evidence of hepatic dysfunction.
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 5 x upper limit of normal (ULN).
  • =< grade 1 dyspnea.
  • Oxygen saturation (SaO2) >= 92% on ambient air.
  • If pulmonary function tests (PFTs) are performed based on the clinical judgment of the treating physician, patients with forced expiratory volume in one second (FEV1) >= 50% of predicted and diffusion capacity of the lung for carbon monoxide (DLCO) (corrected) of >= 40% of predicted will be eligible.
  • Patients 60 years of age or older are required to have left ventricular ejection fraction (LVEF) evaluation performed within 1 year prior to study treatment. LVEF may be established with echocardiogram or multigated acquisition (MUGA) scan, and must be >= 35%. Cardiac evaluation for other patients is at the discretion of the treating physician.
  • Absolute neutrophil count (ANC) > 1000 cells/mm^3.
  • Absolute lymphocyte count (ALC) > 200 cells/mm^3.
  • Hematocrit (HCT) > 30%.
  • Platelet count > 50K.

Exclusion Criteria:

  • Active autoimmune disease requiring immunosuppressive therapy is excluded unless discussed with the principal investigator (PI).
  • Kidney transplant will be considered on a case by case basis requiring discussion with PI. If kidney transplant, patient must have dialysis access, dialysis plan, supportive nephrologist, willingness to stop transplant immunosuppression, and express understanding that rejection is likely. Dialysis or costs related to transplant kidney will not be supported by the study. Participants having had any other solid organ transplants will be excluded, as will those with a history of allogeneic stem cell transplant.
  • Corticosteroid therapy at a dose equivalent of > 10 mg prednisone per day.
  • Concurrent use of other investigational agents or MCC directed therapies.
  • Any medical or psychological condition other than Merkel cell carcinoma that would significantly increase the risk of harm to a subject or interfere with the interpretation of trial endpoints.
  • Active uncontrolled infection. Human immunodeficiency virus (HIV) positive participants on highly active antiretroviral therapy (HAART) with a CD4 count > 500 cells/mm^3 are considered controlled, as are individuals with a history of hepatitis C who have successfully completed antiviral therapy with an undetectable viral load, and those with hepatitis B who have hepatitis well controlled on medication.
  • Uncontrolled concurrent illness. Participants may not have uncontrolled or concurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Untreated brain metastases. Participants with small asymptomatic brain metastases (< 1 cm) or those with brain metastases previously treated with surgery or radiotherapy will be considered for inclusion at discretion of principal investigator, so long as other eligibility criteria are met.
  • Grade 3 or higher immune related adverse event (iRAE) to any prior PD-1 axis blocking agent. iRAEs are persistent T cell mediated inflammatory syndromes caused by PD-1 or PD-L1 inhibitors including colitis, nephritis, pneumonitis, myositis, hepatitis, encephalitis.
  • Participants receiving treatment for prior immune-related adverse event (iRAE) are excluded, with exception of hormone supplementation or corticosteroid therapy at equivalent of up to 10 mg prednisone per day, unless otherwise approved by PI.
  • Study participants must not have significant active underlying neurologic disease, unless approved by PI. Mild neuropathy related to diabetes or prior chemotherapy is acceptable.
  • Other medical, social, or psychiatric factor that interferes with medical appropriateness and/or ability to comply with study, as determined by PI.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03747484


Contacts
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Contact: Joshua Veatch 206.667.5108 attacmcc@fredhutch.org

Locations
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United States, Washington
Fred Hutch/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Principal Investigator: Joshua Veatch         
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
National Cancer Institute (NCI)
bluebird bio
Investigators
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Principal Investigator: Joshua Veatch Fred Hutch/University of Washington Cancer Consortium
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Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT03747484    
Other Study ID Numbers: RG1003611
NCI-2018-02483 ( Registry Identifier: NCI / CTRP )
9845 ( Registry Identifier: FHCRC IRB )
ATTAC-MCC ( Other Identifier: Sponsor )
P30CA015704 ( U.S. NIH Grant/Contract )
P01CA225517 ( U.S. NIH Grant/Contract )
First Posted: November 20, 2018    Key Record Dates
Last Update Posted: July 28, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Fred Hutchinson Cancer Research Center:
Clinical Stage III Merkel Cell Carcinoma AJCC v8
Clinical Stage IV Merkel Cell Carcinoma AJCC v8
Pathologic Stage III Merkel Cell Carcinoma AJCC v8
Pathologic Stage IIIA Merkel Cell Carcinoma AJCC v8
Pathologic Stage IIIB Merkel Cell Carcinoma AJCC v8
Pathologic Stage IV Merkel Cell Carcinoma AJCC v8
Merkel cell carcinoma, metastatic
Merkel cell carcinoma, unresectable
Metastatic Merkel Cell Carcinoma
Unresectable Merkel Cell Carcinoma
Additional relevant MeSH terms:
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Vidarabine
Cyclophosphamide
Fludarabine
Fludarabine phosphate
Pembrolizumab
Antibodies, Monoclonal
Immunoglobulins
Immunoglobulin G
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites
Antineoplastic Agents, Immunological
Antiviral Agents
Anti-Infective Agents