PRAME-TCR-NK Cells for the Treatment of Patients with Locally Advanced, Unresectable, or Metastatic Recurrent and/or Refractory Melanoma, PRAMETIME-Mel Trial

Inclusion Criteria

• Patients must be 18 years or older
• Patients must be willing and able to provide informed consent
• Patients must have human leukocyte antigen (HLA) A*02:01
• Patients must have histologically documented locally advanced, unresectable, or metastatic melanoma that is relapsed and/or refractory to immune checkpoint inhibitor (ICI) therapy including either anti-PD-1 either with or without anti-CTLA-4 blocking antibody and/or anti-LAG-3 antibody. During dose escalation, patients with cutaneous, mucosal, or unknown primary melanoma will be enrolled. Patients with uveal melanoma may be eligible for future enrollment into distinct cohorts during the dose confirmation phase. Patients should have received standard-of-care (SOC) therapy per standard clinical practice guidelines. Patients must not have had exposure to more than 3 prior lines of anti-PD-1 antibody-containing therapeutic regimens administered in the metastatic setting
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Life expectancy > 3 months
• Patients who received one or more prior systemic therapy are allowed for enrollment
• A female patient is eligible to participate if at least one of the following conditions applies: * Not a woman of childbearing potential (WOCBP) OR * A WOCBP who agrees to follow the contraceptive guidelines during the study treatment period and for 6 months post PRAME-TCR-NK cell infusion * Female patients who become pregnant or suspect pregnancy must immediately notify their doctor * Female patients who become pregnant will be taken off the study
• Male patients must agree to follow the contraceptive guidelines during the study treatment period and for 6 months post PRAME-TCR-NK cell infusion. Male patients who father a child or suspect that they have fathered a child must immediately notify their doctor
• WOCBP must have a negative urine pregnancy test within 72 hours before the start of lymphodepleting chemotherapy. If a WOCBP has a urine pregnancy test that cannot be confirmed as negative, a serum (beta-human chorionic gonadotropin [β-hCG]) pregnancy test will be required
• Patients must have measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1
• Absolute neutrophil count (ANC) ≥ 1500/uL (within 10 days before the start of lymphodepleting chemotherapy)
• Platelets ≥ 100,000/uL (within 10 days before the start of lymphodepleting chemotherapy)
• Hemoglobin ≥ 9.0 g/dL (within 10 days before the start of lymphodepleting chemotherapy) * Criteria must be met without erythropoietin dependency and without packed red blood cell transfusion within the last 2 weeks of the screening test. Patients may be on a stable dose of erythropoietin (≥ approximately 3 months)
• Creatinine ≤ 1.5 x upper limit of normal (ULN) OR creatinine clearance (CrCl) by Cockcroft-Gault formula ≥ 45 mL/min for patients with creatinine > 1.5 x ULN (within 10 days before the start of lymphodepleting chemotherapy) * Serum creatinine and CrCl should be interpreted and calculated per institutional standard
• Total bilirubin ≤1.5 x ULN OR direct bilirubin ≤ ULN for patients with total bilirubin levels > 1.5 x ULN except for patients with Gilbert’s disease (within 10 days before the start of lymphodepleting chemotherapy)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver metastases) (within 10 days before the start of lymphodepleting chemotherapy)
• Prothrombin time (PT)/international normalized ratio (INR)/activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless patient is receiving anticoagulant therapy as long as PT or aPTT is within the therapeutic range of intended use of anticoagulants (within 10 days before the start of lymphodepleting chemotherapy)
• Left ventricular ejection fraction > 50%
• Adequate respiratory reserve defined as dyspnea grade 0 or 1 and baseline oxygen saturation > 92% in room air
• Willing to undergo mandatory blood collection and biopsies as required by the study
• Patients must agree not to receive a live vaccine for at least 24 months post-infusion
• Willing to sign consent for long-term follow-up on protocol PA17-0483 which will be signed at the same time with the clinical trial enrollment consent form

Exclusion Criteria

• Pregnant, breastfeeding, or expecting to conceive within the projected duration of the study, starting with the screening visit through 6 months post PRAME-TCR-NK cell infusion
• Has received systemic anticancer therapy within 2 weeks or 5 half-lives, whichever is shorter, before the start of lymphodepleting chemotherapy. For patients treated with monoclonal antibodies, at least 3 weeks must have elapsed before the start of lymphodepleting chemotherapy. Patients who have entered the follow-up phase of an investigational study may participate as long as it has been 3 weeks after the last dose of the previous investigational agent
• Patients must have recovered from all adverse events (AEs) due to previous therapies to ≤ grade 1 or baseline. Patients with ≤ grade 2 neuropathy, alopecia, or other non-relevant AEs may be deemed eligible at the discretion of the principal investigator (PI)/co-PIs. If a patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention before the start of lymphodepleting chemotherapy
• Has received prior radiotherapy within 2 weeks of the start of lymphodepleting chemotherapy. Patients must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-central nervous system (CNS) disease
• Has received a live vaccine within 6 weeks prior to PRAME-TCR-NK infusion. Examples of live vaccines include but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin, and typhoid vaccine. Seasonal influenza and COVID-19 vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed
• Has a diagnosis of immunodeficiency or receiving chronic systemic steroid therapy (in doses exceeding 10 mg daily of prednisone equivalent)
• History of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years. The time requirement does not apply to patients who underwent successful definitive resection of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, or other in situ cancers
• Known active CNS metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate if they completed radiation therapy, are clinically stable, and without the requirement of steroid treatment for at least 2 weeks prior to study enrollment
• Active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with the use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is allowed
• Need for systemic immunosuppressive therapy or other physiological replacement of corticosteroids
• Interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity
• Active infection (e.g., COVID-19, influenza, severe acute respiratory syndrome [SARS], recent sepsis). For patients recovered from infections, lymphodepletion may start after full recovery
• Known human immunodeficiency virus (HIV) infection, active or chronic hepatitis B or hepatitis C virus infection
• History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient’s participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating investigator
• Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study
• Has had an allogeneic tissue/solid organ transplant
• Clinically significant cardiovascular disease within 12 months before the start of lymphodepleting chemotherapy, including New York Heart Association class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebrovascular event, or cardiac arrhythmia associated with hemodynamic instability. NOTE: A medically controlled arrhythmia would be permitted
• Prolongation of corrected QT interval using Fridericia’s formula to > 480 milliseconds
• Patients with bleeding or thrombotic disorders or at risk for severe hemorrhage. Patients with a known history of deep vein thrombosis/pulmonary embolism who are on appropriate anti-coagulation treatment are eligible
• Patients with lactate dehydrogenase (LDH) > 2.5-fold ULN. The evaluation should be conducted at screening