Inclusion Criteria:
1. Participants must be 18 years or older.
2. Participants must be willing and able to provide informed consent.
3. Participants must have HLA A*02:01.
4. Participants must have histologically documented locally advanced, unrespectable, 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, participants with cutaneous, mucosal, or unknown primary
melanoma will be enrolled. Participants with uveal melanoma may be eligible for
future enrollment into distinct cohorts during the dose confirmation phase.
Participants should have received standard-of-care (SOC) therapy per standard
clinical practice guidelines. Participants must not have had exposure to more than 3
prior lines of anti-PD-1 antibody-containing therapeutic regimens administered in
the metastatic setting.
5. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance
status of 0 or 1.
6. Life expectancy 3 months.
7. Participants who received one or more prior systemic therapy are allowed for
enrollment. 8. A female participant 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 in during the study treatment period
and for 6 months post PRAME-TCR-NK cell infusion. Female participants who become
pregnant or suspect pregnancy must immediately notify their doctor.
Female participants who become pregnant will be taken off the study.
9. Male participants must agree to follow the contraceptive guidelines during the study
treatment period and for 6 months post PRAME-TCR-NK cell infusion. Male participants
who father a child or suspect that they have fathered a child must immediately
notify their doctor.
10. 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 [£]-hCG])
pregnancy test will be required.
11. Participants must have measurable disease per the Response Evaluation Criteria in
Solid Tumors (RECIST).
12. Participants must have adequate organ function as defined below within 10 days
before the start of lymphodepleting chemotherapy:
13. Left ventricular ejection fraction >50%.
14. Adequate respiratory reserve defined as dyspnea Grade 0 or 1 and baseline oxygen
saturation >92% in room air.
15. Willing to undergo mandatory blood collection and biopsies as required by the study.
16. Participants must agree not to receive a live vaccine for at least 24 months
post-infusion.
17. 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:
1. 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.
2. Has received systemic anticancer therapy within 2 weeks or 5 half-lives, whichever
is shorter, before the start of lymphodepleting chemotherapy. For participants
treated with monoclonal antibodies, at least 3 weeks must have elapsed before the
start of lymphodepleting chemotherapy. Participants 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.
3. Participants must have recovered from all AEs due to previous therapies to . Grade 1
or baseline. Participants 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 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
participant received major surgery, they must have recovered adequately from the
toxicity and/or complications from the intervention before the start of
lymphodepleting chemotherapy.
4. Has received prior radiotherapy within 2 weeks of the start of lymphodepleting
chemotherapy. Participants 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-CNS disease.
5. 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 are live attenuated vaccines and are not allowed.
6. Has a diagnosis of immunodeficiency or receiving chronic systemic steroid therapy
(in doses exceeding10 mg daily of prednisone equivalent).
7. 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 participants 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.
8. 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.
9. 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) is allowed.
10. Need for systemic immunosuppressive therapy or other physiological replacement of
corticosteroids.
11. Interstitial lung disease that is symptomatic or may interfere with the detection or
management of suspected drug-related pulmonary toxicity.
12. Active infection (e.g., COVID-19, influenza, severe acute respiratory syndrome
[SARS], recent sepsis). For participants recovered from infections, lymphodepletion
may start after full recovery.
13. Known human immunodeficiency virus (HIV) infection, active or chronic hepatitis B or
hepatitis C virus infection.
14. History or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the study, interfere with the participants
participation for the full duration of the study, or is not in the best interest of
the participants to participate, in the opinion of the treating investigator.
15. Known psychiatric or substance abuse disorders that would interfere with cooperation
with the requirements of the study.
16. Has had an allogeneic tissue/solid organ transplant.
17. 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.
18. Prolongation of corrected QT interval using Fridericia's formula to >480
milliseconds.
19. Participants with bleeding or thrombotic disorders or at risk for severe hemorrhage.
Participants with a known history of deep vein thrombosis/pulmonary embolism who are
on appropriate anti-coagulation treatment are eligible.
20. Participants with LDH > 2.5-fold ULN. The evaluation should be conducted at
screening.
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