This study is currently recruiting participants.
Number
001827-C
Sponsoring Institute
National Cancer Institute (NCI)
Recruitment Detail
Type: Participants currently recruited/enrolled Gender: Male & Female Min Age: 18 Years Max Age: 70 Years
Referral Letter Required
No
Population Exclusion(s)
Children;Pregnant Women;Neonates;Fetuses
Keywords
Immunotherapy; Cell Therapy; Checkpoint Inhibitor
Recruitment Keyword(s)
None
Condition(s)
Melanoma; Metastatic Melanoma; unresectable melanoma
Investigational Drug(s)
lifileucel pembrolizumab
Investigational Device(s)
Intervention(s)
Biological/Vaccine: Lifileucel Drug: Pembrolizumab Drug: Aldesleukin Drug: Fludarabine Drug: Cyclophosphamide
Supporting Site
National Cancer Institute
Melanoma is a type of skin cancer that can be difficult to treat. Researchers want to know if a drug that uses the body s own immune system to fight cancer (immunotherapy) can improve current treatments.
Objective:
To test a study drug (lifileucel), combined with an approved drug (pembrolizumab), in people with melanoma.
Eligibility:
People aged 18 to 70 years with melanoma that is untreated, cannot be removed with surgery, or has spread.
Design:
Participants will be screened. Tests will include imaging scans; blood and urine tests; and an eye exam. Any skin lesions may be photographed.
Half of study participants will be treated with lifileucel and pembrolizumab (Arm A); half will receive pembrolizumab only (Arm B).
Lifileucel is made with specialized white blood cells (T cells) removed from the participant s tumor. Those in Arm A will have surgery to remove tumor tissue for this purpose.
Pembrolizumab is given through a tube attached to a needle inserted into a vein. Participants in Arm B will receive this drug 2 times in 3 weeks and then once every 6 weeks.
Those in Arm A will get 2 doses of pembrolizumab over 3 weeks. Then they will enter the hospital for treatment with lifileucel. They will receive other drugs, both before and after the lifileucel, to help this treatment work better. They may remain in the hospital for a week or more. Then they will receive pembrolizumab once every 6 weeks.
All participants will have follow-up visits for up to 7 years.
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INCLUSION CRITERIA: Prospective approvals of protocol deviations to enrollment criteria, also known as protocol waivers or exemptions, are not permitted. Participants are eligible to be included in the study only if all of the following criteria apply: Age: -Participant is 18 to 70 years of age at the time of signing the informed consent form. Participants who are >70 years of age may be allowed to enroll after the investigator discusses with the medical monitor. Type of Participant and Disease Characteristics: -Participant has a histologically or pathologically confirmed diagnosis of Stage IIIC, IIID, or IV unresectable or metastatic melanoma. -In the investigator s assessment, the participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and an estimated life expectancy of > 6 months. -Participant is assessed as having at least one resectable lesion (or aggregate lesions) with an estimated minimum diameter of 1.5 cm for lifileucel generation. It is preferred that the tumor targeted for resection has not been previously irradiated. If it has, the irradiation must have occurred at least 3 months prior to tumor resection and the irradiated lesion(s) must have unequivocal radiographically demonstrated progression after radiation therapy. -Participant will have at least one measurable lesion, as defined by RECIST v1.1, at Baseline/cBaseline. Lesions in previously irradiated areas (or areas treated with local therapy) should not be selected as target lesions unless subsequent progression has been demonstrated in those lesions and the irradiation/local therapy was completed at least 3 months prior to randomization. -If the participant has pre-planned surgical procedure(s), the procedure will take place at least 14 days (for major operative procedures) prior to the tumor resection. Wound healing will have occurred, and all complications will have resolved at the time of tumor resection. -Participant has recovered from all prior anticancer treatment-related AEs to Grade <=1 (per Common Terminology Criteria for Adverse Events [CTCAE]), except for peripheral neuropathy, alopecia, vitiligo or medically controlled endocrine dysfunction (eg, thyroid or insulin replacement). Participants with stable Grade 2 toxicity from prior anticancer therapy must have been discussed with the medical monitor. Sex and Contraceptive/Barrier Requirements: -The participant agrees to abide by the following: a. Male Participants: Male participants are eligible to participate if they agree to the following during the study intervention period and for at least 12 months after the last dose of study intervention: --Refrain from donating sperm PLUS, either: ---Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent OR ---Must agree to use contraception as detailed below: Agree to use a male condom with female partner use of an additional highly effective contraceptive method with a failure rate of <1% per year. These participants should also be advised of the importance for a female partner of childbearing potential who is not currently pregnant to use a highly effective method of contraception as a condom may break or leak when having sexual intercourse b. Female Participants: A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies: --Is a woman of nonchildbearing potential (WONCBP) OR --Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency, during the study intervention period and for at least 12 months after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the potential for contraceptive method failure (eg, noncompliance, recently initiated) in relationship to the first dose of study intervention. --A WOCBP must have a negative serum or urine pregnancy test within 24 hours before the tumor resection. --Additional requirements for pregnancy testing during and after study intervention. --The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. Informed Consent/Protected Health Information: -Participant is capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol and the understanding that there are other FDA approved therapies for advanced melanoma and, if randomized to the lifileucel regimen, there may be a need for intensive supportive care measures. -Participant provided written authorization for use and disclosure of protected health information. Other Inclusion Criteria: -Participant has the following hematologic parameters: --ANC >=1000/mm^3 or >=1 x 10^9/L --Hemoglobin >=8.0 g/dL or >=4.96 mmol/L --Platelet count >=100,000/mm^3 or >=100 x 10^9/L -Participant has adequate organ function with the following laboratory values: --Serum ALT and AST <=3 x ULN; participants with liver metastasis may have ALT and AST <=5 x ULN --Total bilirubin <=2 mg/dL; participants with Gilbert s Syndrome may have total bilirubin <=3 mg/dL --Estimated CrCl >=40 mL/min using the Cockcroft-Gault formula. -Participant has an LVEF >45% and is NYHA Class 1. For participants >=60 years of age OR who have a history of clinically relevant cardiac disease, no irreversible wall movement abnormality is demonstrated on a cardiac stress test (or equivalent local standard stress test). Participants with an abnormal cardiac stress test may be considered for study participation if they have adequate ejection fraction and cardiology clearance with approval of the medical monitor. -A participant who meets any of the following criteria must, post-bronchodilator, achieve either a FEV1/FVC >70% or FEV1 >50%: --Has a history of cigarette smoking of >=20 pack-years --Ceased smoking within the past 2 years or continues to smoke --Has a history of COPD --Has any signs or symptoms of respiratory dysfunction --Has a history of pleural drainage within the past 3 months If the participant is unable to perform reliable spirometry due to abnormal upper airway anatomy (ie, tracheostomy), a 6-minute walk test may be used to assess pulmonary function. A participant who is able to walk a distance of at least 80% predicted for age and sex and does not demonstrate evidence of hypoxia (SpO2 <90%) at any point during the test is eligible for study participation. -Participant is willing to receive optimal supportive care, including intensive care, from enrollment until the first post treatment tumor assessment. Arm B optional crossover period only: Participants randomized to Arm B (pembrolizumab monotherapy) who subsequently have BIRC-verified initial disease progression will have the option to begin screening for participation in an optional crossover period to receive lifileucel monotherapy, but will be allowed to proceed only after BIRC verification of confirmed PD. Participants must meet the inclusion and exclusion criteria (except for Exclusion Criterion #3) for initial study participation, in addition to the following criteria. Participants may have a second tumor resection, if needed/applicable, especially when new lesions are available for resection. -Participant is capable of giving signed informed consent, which includes compliance with the crossover period requirements and restrictions listed in the ICF and in this protocol. -Participant provided written authorization for use and disclosure of protected health information. -Participant has BIRC-verified, confirmed, documented radiologic disease progression after at least 1 dose of pembrolizumab in Arm B during this study. -Participant has not received any new non-study anticancer therapy for unresectable or metastatic melanoma. EXCLUSION CRITERIA: Participants are excluded from the study if any of the following criteria apply: Medical Conditions: -Participant has melanoma of uveal/ocular origin. -Participant has symptomatic untreated brain metastases. Participants with brain metastases may be evaluated for study participation with the following considerations: --Participants with asymptomatic brain metastases who do not clinically require treatment may be considered for study participation. --A participant with historically treated brain metastases (ie, treatment was completed >28 days prior to consenting for study participation) may be considered for study participation if the participant is clinically stable for >=2 weeks, there are no new or worsening brain lesions via screening MRI, and the participant does not require ongoing corticosteroid treatment (>10 mg/day prednisone or equivalent). --If there are progressive or new brain metastases on the screening MRI, the participant should first receive treatment for them prior to restarting or continuing screening. A participant with recently treated brain metastases (ie, treatment of brain metastases was completed <=28 days prior to consenting for study participation) may be considered for study participation if the participant is asymptomatic, clinically stable for >=2 weeks, and does not require corticosteroids (>10 mg/day prednisone or equivalent) by the end of the screening period. Repeat brain imaging is not required after treatment; however, brain imaging is required at Baseline. -Participant received any of the following previous therapies: --Participant received more than 1 prior line of therapy --Participant received prior therapy for metastatic disease --Participants with a BRAF V600 mutation-positive tumor received prior adjuvant/neoadjuvant ICI therapy only Prior adjuvant/neoadjuvant therapy with BRAF +/- MEK inhibitor, PD-1 inhibitor, and/or CTLA-4 inhibitor is allowed if therapy was completed >=6 months prior to progression to unresectable or metastatic disease. -Participant has an active medical illness(es) that, in the opinion of the investigator, would pose increased risks for study participation, such as systemic infections; seizure disorders; coagulation disorders; or other active major medical illnesses of the cardiovascular, respiratory, or immune systems. -Participant has active uveitis that requires active treatment. Participants with a history of uveitis must have an eye examination performed by a trained eye specialist at Screening to rule out active uveitis that requires treatment. -Participant has any form of primary or acquired immunodeficiency (eg, SCID or AIDS). -Participant has a history of hypersensitivity to any component of the study intervention, including, but not limited to, any of the following: --NMA-LD (cyclophosphamide, mesna, and fludarabine) --Proleukin(R), aldesleukin, IL-2 --Antibiotics of the aminoglycoside group (ie, streptomycin, gentamicin). These participants may be eligible if current hypersensitivity has been excluded. --Any component of the lifileucel product formulation, including DMSO, HSA, IL-2, or dextran 40 --Pembrolizumab -Participant had another primary malignancy within the previous 3 years (except for those that do not require treatment or were curatively treated >1 year ago, and in the judgment of the investigator do not pose a significant risk of recurrence including, but not limited to, non-melanoma skin cancer, DCIS, LCIS, prostate cancer Gleason score <=6, or superficial bladder cancer). Prior/Concomitant Therapy: -Participant has a history of allogeneic cell or organ transplant. Autotransplant for lymphoma performed with curative intent >5 years ago with no further relapse is allowed. -Participant requires systemic steroid therapy >10 mg/day of prednisone or another steroid equivalent dose. Participants receiving steroids as replacement therapy for adrenocortical insufficiency at <=10 mg/day of prednisone or another steroid equivalent dose may be eligible. -Participant received or will receive a live or attenuated vaccination within 28 days prior to the start of the NMA-LD. Diagnostic Assessments: -Participant has evidence of any active viral, bacterial, or fungal infection requiring ongoing systemic treatment or that is identified during screening.
Prospective approvals of protocol deviations to enrollment criteria, also known as protocol waivers or exemptions, are not permitted.
Participants are eligible to be included in the study only if all of the following criteria apply:
Age:
-Participant is 18 to 70 years of age at the time of signing the informed consent form.
Participants who are >70 years of age may be allowed to enroll after the investigator discusses with the medical monitor.
Type of Participant and Disease Characteristics:
-Participant has a histologically or pathologically confirmed diagnosis of Stage IIIC, IIID, or IV unresectable or metastatic melanoma.
-In the investigator s assessment, the participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and an estimated life expectancy of > 6 months.
-Participant is assessed as having at least one resectable lesion (or aggregate lesions) with an estimated minimum diameter of 1.5 cm for lifileucel generation.
It is preferred that the tumor targeted for resection has not been previously irradiated. If it has, the irradiation must have occurred at least 3 months prior to tumor resection and the irradiated lesion(s) must have unequivocal radiographically demonstrated progression after radiation therapy.
-Participant will have at least one measurable lesion, as defined by RECIST v1.1, at Baseline/cBaseline.
Lesions in previously irradiated areas (or areas treated with local therapy) should not be selected as target lesions unless subsequent progression has been demonstrated in those lesions and the irradiation/local therapy was completed at least 3 months prior to randomization.
-If the participant has pre-planned surgical procedure(s), the procedure will take place at least 14 days (for major operative procedures) prior to the tumor resection. Wound healing will have occurred, and all complications will have resolved at the time of tumor resection.
-Participant has recovered from all prior anticancer treatment-related AEs to Grade <=1 (per Common Terminology Criteria for Adverse Events [CTCAE]), except for peripheral neuropathy, alopecia, vitiligo or medically controlled endocrine dysfunction (eg, thyroid or insulin replacement).
Participants with stable Grade 2 toxicity from prior anticancer therapy must have been discussed with the medical monitor.
Sex and Contraceptive/Barrier Requirements:
-The participant agrees to abide by the following:
a. Male Participants:
Male participants are eligible to participate if they agree to the following during the study intervention period and for at least 12 months after the last dose of study intervention:
--Refrain from donating sperm
PLUS, either:
---Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent
OR
---Must agree to use contraception as detailed below:
Agree to use a male condom with female partner use of an additional highly effective contraceptive method with a failure rate of <1% per year. These participants should also be advised of the importance for a female partner of childbearing potential who is not currently pregnant to use a highly effective method of contraception as a condom may break or leak when having sexual intercourse
b. Female Participants:
A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies:
--Is a woman of nonchildbearing potential (WONCBP)
--Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency, during the study intervention period and for at least 12 months after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the potential for contraceptive method failure (eg, noncompliance, recently initiated) in relationship to the first dose of study intervention.
--A WOCBP must have a negative serum or urine pregnancy test within 24 hours before the tumor resection.
--Additional requirements for pregnancy testing during and after study intervention.
--The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
Informed Consent/Protected Health Information:
-Participant is capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol and the understanding that there are other FDA approved therapies for advanced melanoma and, if randomized to the lifileucel regimen, there may be a need for intensive supportive care measures.
-Participant provided written authorization for use and disclosure of protected health information.
Other Inclusion Criteria:
-Participant has the following hematologic parameters:
--ANC >=1000/mm^3 or >=1 x 10^9/L
--Hemoglobin >=8.0 g/dL or >=4.96 mmol/L
--Platelet count >=100,000/mm^3 or >=100 x 10^9/L
-Participant has adequate organ function with the following laboratory values:
--Serum ALT and AST <=3 x ULN; participants with liver metastasis may have ALT and AST <=5 x ULN
--Total bilirubin <=2 mg/dL; participants with Gilbert s Syndrome may have total bilirubin <=3 mg/dL
--Estimated CrCl >=40 mL/min using the Cockcroft-Gault formula.
-Participant has an LVEF >45% and is NYHA Class 1. For participants >=60 years of age OR who have a history of clinically relevant cardiac disease, no irreversible wall movement abnormality is demonstrated on a cardiac stress test (or equivalent local standard stress test).
Participants with an abnormal cardiac stress test may be considered for study participation if they have adequate ejection fraction and cardiology clearance with approval of the medical monitor.
-A participant who meets any of the following criteria must, post-bronchodilator, achieve either a FEV1/FVC >70% or FEV1 >50%:
--Has a history of cigarette smoking of >=20 pack-years
--Ceased smoking within the past 2 years or continues to smoke
--Has a history of COPD
--Has any signs or symptoms of respiratory dysfunction
--Has a history of pleural drainage within the past 3 months
If the participant is unable to perform reliable spirometry due to abnormal upper airway anatomy (ie, tracheostomy), a 6-minute walk test may be used to assess pulmonary function. A participant who is able to walk a distance of at least 80% predicted for age and sex and does not demonstrate evidence of hypoxia (SpO2 <90%) at any point during the test is eligible for study participation.
-Participant is willing to receive optimal supportive care, including intensive care, from enrollment until the first post treatment tumor assessment.
Arm B optional crossover period only:
Participants randomized to Arm B (pembrolizumab monotherapy) who subsequently have BIRC-verified initial disease progression will have the option to begin screening for participation in an optional crossover period to receive lifileucel monotherapy, but will be allowed to proceed only after BIRC verification of confirmed PD. Participants must meet the inclusion and exclusion criteria (except for Exclusion Criterion #3) for initial study participation, in addition to the following criteria. Participants may have a second tumor resection, if needed/applicable, especially when new lesions are available for resection.
-Participant is capable of giving signed informed consent, which includes compliance with the crossover period requirements and restrictions listed in the ICF and in this protocol.
-Participant has BIRC-verified, confirmed, documented radiologic disease progression after at least 1 dose of pembrolizumab in Arm B during this study.
-Participant has not received any new non-study anticancer therapy for unresectable or metastatic melanoma.
EXCLUSION CRITERIA:
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
-Participant has melanoma of uveal/ocular origin.
-Participant has symptomatic untreated brain metastases. Participants with brain metastases may be evaluated for study participation with the following considerations:
--Participants with asymptomatic brain metastases who do not clinically require treatment may be considered for study participation.
--A participant with historically treated brain metastases (ie, treatment was completed >28 days prior to consenting for study participation) may be considered for study participation if the participant is clinically stable for >=2 weeks, there are no new or worsening brain lesions via screening MRI, and the participant does not require ongoing corticosteroid treatment (>10 mg/day prednisone or equivalent).
--If there are progressive or new brain metastases on the screening MRI, the participant should first receive treatment for them prior to restarting or continuing screening. A participant with recently treated brain metastases (ie, treatment of brain metastases was completed <=28 days prior to consenting for study participation) may be considered for study participation if the participant is asymptomatic, clinically stable for >=2 weeks, and does not require corticosteroids (>10 mg/day prednisone or equivalent) by the end of the screening period. Repeat brain imaging is not required after treatment; however, brain imaging is required at Baseline.
-Participant received any of the following previous therapies:
--Participant received more than 1 prior line of therapy
--Participant received prior therapy for metastatic disease
--Participants with a BRAF V600 mutation-positive tumor received prior adjuvant/neoadjuvant ICI therapy only
Prior adjuvant/neoadjuvant therapy with BRAF +/- MEK inhibitor, PD-1 inhibitor, and/or CTLA-4 inhibitor is allowed if therapy was completed >=6 months prior to progression to unresectable or metastatic disease.
-Participant has an active medical illness(es) that, in the opinion of the investigator, would pose increased risks for study participation, such as systemic infections; seizure disorders; coagulation disorders; or other active major medical illnesses of the cardiovascular, respiratory, or immune systems.
-Participant has active uveitis that requires active treatment.
Participants with a history of uveitis must have an eye examination performed by a trained eye specialist at Screening to rule out active uveitis that requires treatment.
-Participant has any form of primary or acquired immunodeficiency (eg, SCID or AIDS).
-Participant has a history of hypersensitivity to any component of the study intervention, including, but not limited to, any of the following:
--NMA-LD (cyclophosphamide, mesna, and fludarabine)
--Proleukin(R), aldesleukin, IL-2
--Antibiotics of the aminoglycoside group (ie, streptomycin, gentamicin). These participants may be eligible if current hypersensitivity has been excluded.
--Any component of the lifileucel product formulation, including DMSO, HSA, IL-2, or dextran 40
--Pembrolizumab
-Participant had another primary malignancy within the previous 3 years (except for those that do not require treatment or were curatively treated >1 year ago, and in the judgment of the investigator do not pose a significant risk of recurrence including, but not limited to, non-melanoma skin cancer, DCIS, LCIS, prostate cancer Gleason score <=6, or superficial bladder cancer).
Prior/Concomitant Therapy:
-Participant has a history of allogeneic cell or organ transplant.
Autotransplant for lymphoma performed with curative intent >5 years ago with no further relapse is allowed.
-Participant requires systemic steroid therapy >10 mg/day of prednisone or another steroid equivalent dose.
Participants receiving steroids as replacement therapy for adrenocortical insufficiency at <=10 mg/day of prednisone or another steroid equivalent dose may be eligible.
-Participant received or will receive a live or attenuated vaccination within 28 days prior to the start of the NMA-LD.
Diagnostic Assessments:
-Participant has evidence of any active viral, bacterial, or fungal infection requiring ongoing systemic treatment or that is identified during screening.
Principal Investigator
Referral Contact
For more information: