Complete title: ATTAC-MCC: 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
|Research Study Number||9845|
|Principal Investigator||Joshua Veatch|
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.
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.
Other eligibility criteria may apply.
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.
Other exclusion criteria may apply.
|Research Study Number||9845|
|Contact||Seattle Cancer Care Alliance Intake Office|
|Telephone||800-804-8824 / 206-606-1024|
Keywords: Carcinoma, Merkel Cell; Skin Diseases
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