Clinical Trials /

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

NCT03747484

Description:

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.

Related Conditions:
  • Merkel Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: RG1003611
  • SECONDARY ID: NCI-2018-02483
  • SECONDARY ID: 9845
  • SECONDARY ID: ATTAC-MCC
  • SECONDARY ID: P30CA015704
  • SECONDARY ID: P01CA225517
  • NCT ID: NCT03747484

Conditions

  • Other Skin

Interventions

DrugSynonymsArms
Autologous MCPyV-specific HLA-A02-restricted TCR-transduced CD4+ and CD8+ T-cells FH-MCVA2TCRAutologous CD8+ and CD4+ T-cells transduced with TCR A2-MCC1, FH-MCVA2TCR, , FH-MCVA2TCR Autologous CD8+ and CD4+ T-cells Transduced with TCR A2-MCC1Treatment (TCR-T cells, avelumab or pembrolizumab, radiation)
Avelumab1537032-82-8, 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, MSB0010718CTreatment (TCR-T cells, avelumab or pembrolizumab, radiation)
PembrolizumabAnti-(Human Programmed Cell Death 1), Keytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (TCR-T cells, avelumab or pembrolizumab, radiation)

Purpose

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.

Detailed Description

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

      Patients receive FH-MCVA2TCR T-cells intravenously (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 and a single fraction of radiotherapy to one tumor
      lesion 3-5 days prior to T-cell infusion(s). Patients with partial response or stable disease
      may then receive an additional course of FH-MCVA2TCR T-cells.

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

Trial Arms

NameTypeDescriptionInterventions
Treatment (TCR-T cells, avelumab or pembrolizumab, radiation)ExperimentalPatients receive FH-MCVA2TCR T-cells intravenously (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 and a single fraction of radiotherapy to one tumor lesion 3-5 days prior to T-cell infusion(s). Patients with partial response or stable disease may then receive an additional course of FH-MCVA2TCR T-cells.
  • Autologous MCPyV-specific HLA-A02-restricted TCR-transduced CD4+ and CD8+ T-cells FH-MCVA2TCR
  • Avelumab
  • Pembrolizumab
Treatment 2(TCR-T cells, avelumab or pembrolizumab, radiation)ExperimentalPatients receive FH-MCVA2TCR T-cells intravenously (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 and a single fraction of radiotherapy to one tumor lesion 3-5 days prior to T-cell infusion(s). Patients with partial response or stable disease may then receive an additional course of FH-MCVA2TCR T-cells.
  • Autologous MCPyV-specific HLA-A02-restricted TCR-transduced CD4+ and CD8+ T-cells FH-MCVA2TCR
  • Avelumab
  • Pembrolizumab

Eligibility 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.

          -  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).

          -  Be capable of understanding and providing informed consent.

          -  TREATMENT PHASE:

          -  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 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.

          -  Measurable disease by RECIST 1.1, with at least two tumor lesions

             * Participants must have measurable disease, defined as at least one target lesion
             that can be measured in at least one dimension (longest diameter to be recorded) as >=
             10 mm, unless lymph node in which case short axis must be >= 15 mm. For patients with
             bone-only metastases, bony lesions can only be selected as a target lesion if they
             have a measurable soft-tissue component. If a patient has only one measurable target
             lesion, they must have a second MCC lesion (bone lesion, smaller lesion, etc.) that is
             amenable to HLA upregulation (with single fraction radiation), in order to allow for
             efficacy assessments; this second lesion does not need to be measurable. Baseline
             imaging (for example computed tomography [CT] chest/abdomen/pelvis and imaging of the
             affected extremity as appropriate), and brain imaging (magnetic resonance imaging
             [MRI] or CT scan) must be obtained within 45 days of prior to start of first planned
             FH-MCVA2TCR infusion. Positron emission tomography (PET) CT or MRI can be substituted
             for CTs as appropriate.

          -  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-major 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 Merkel cell carcinomas 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, so long as
             radiated lesion is not the lesion targeted for irradiation or RECIST measurements on
             the protocol.

          -  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:

          -  TREATMENT:

          -  Pregnancy or lactation: Participants of childbearing potential must have a negative
             serum pregnancy test within the 2 weeks preceding FH-MCVA2TCR infusion. Childbearing
             potential is defined as women who have not been surgically sterilized and who are not
             post-menopausal (free of menses for at least 1 year).

          -  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.

          -  Chronic lymphocytic leukemia (CLL) or other active hematologic malignancy.

          -  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.

          -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description:Evidence of excessive toxicity will be an observed proportion of toxicities for which the associated lower 80% confidence limit exceeds 40%.

Secondary Outcome Measures

Measure:Progression-free survival
Time Frame:Up to 15 years
Safety Issue:
Description:Will be estimated using the method of Kaplan and Meier, with time zero the time of first T cell infusion.
Measure:Overall survival
Time Frame:Up to 15 years
Safety Issue:
Description:Will be estimated using the method of Kaplan and Meier, with time zero the time of first T cell infusion.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Fred Hutchinson Cancer Research Center

Trial Keywords

  • 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

Last Updated

December 30, 2019