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:

Not yet 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
  • NCT ID: NCT03747484

Conditions

  • Other Skin Disorders

Interventions

DrugSynonymsArms
Autologous T Cells modified to recognize Merkel Cell Polyomavirus (FH-MCVA2TCR)Treatment (autologous T-cells, avelumab, radiation therapy)
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 (autologous T-cells, avelumab, radiation therapy)

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

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

      Patients receive standard of care avelumab intravenously (IV) over 1 hour every 2 weeks for 1
      year and a single fraction of radiotherapy to one tumor lesion prior to T-cell infusion(s).
      Patients also receive FH-MCVA2TCR T-cells IV over 60-120 minutes 3-5 days after radiation
      therapy. 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 (autologous T-cells, avelumab, radiation therapy)ExperimentalPatients receive FH-MCVA2TCR T-cells IV over 60-120 minutes. Patients also receive standard of care avelumab IV every 2 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 T Cells modified to recognize Merkel Cell Polyomavirus (FH-MCVA2TCR)
  • Avelumab

Eligibility Criteria

        Inclusion Criteria:

        EVALUATION

          -  Adult patients with 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
             (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 Merkel cell carcinoma. Confirmation of diagnosis must be or have been
             performed by internal pathology review of initial or subsequent biopsy or other
             pathologic material at Fred Hutchinson Cancer Research Center (FHCRC)/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. MCPyV positivity may be
             established through immunohistochemistry of primary or metastatic MCC tumor lesion on
             a clinical or research basis, positive MCPyV T antigen serology at any point during
             the patients course, or presence of MCPyV deoxyribonucleic acid (DNA) or ribonucleic
             (RNA) in the tumor lesion by research or clinical sequencing. Patients with negative T
             antigen serology but MCPyV positive tumor by other methodologies will be considered
             MCPyV positive, as the T antigen serology assays are highly specific (high true
             positive rate) but incompletely sensitive for MCPyV status. T antigen expression may
             be established at any point prior to singing the treatment consent.

          -  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), 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 III 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.

          -  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
             (e.g. active infection, no safe approach), biopsies may be cancelled or retimed at the
             investigator's discretion.

          -  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 Merkel cell carcinoma. There is no washout period for
             radiation, so long as radiated lesion is not the lesion targeted for irradiation or
             Response Evaluation Criteria in Solid Tumors (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

          -  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.

          -  Human immunodeficiency virus (HIV) positive participants must be 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.

          -  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.

          -  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 III or higher immune-mediated toxicity 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.

          -  Any female patient who does not meet at least one of the following criteria will be
             considered to have reproductive potential:

               -  Post-menopausal for at least 12 consecutive months (i.e., no menses), or

               -  Undergone a sterilization procedure (hysterectomy, salpingectomy, or bilateral
                  oophorectomy; tubal ligation is not considered a sterilization procedure)

          -  Pregnancy test for females of reproductive potential must be negative within 14 days
             before leukapheresis.

          -  Female patients with reproductive potential who are not sexually abstinent and male
             patients who are sexually active with females of reproductive potential must agree to
             use a suitable method of contraception for the duration of the study.
      
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 III 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:Not yet 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
  • HLA-A*0201 Positive Cells Present
  • Merkel Cell Polyomavirus T Antigen Positive
  • 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

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