A Phase II Trial of Tumour Infiltrating Lymphocyte Adoptive Cell Therapy in Patients With Immune Checkpoint Inhibitor Resistant Unresectable or Metastatic Melanoma

Phase 2Not Yet RecruitingNCT07651618

East Metropolitan Health Service, Australia10 enrolled

Overview

The goal of this study is to determine the activity of Perkileucel, a tumour infiltrating lymphocyte (TIL) adoptive cell transfer therapy (ACT), in patients with unresectable stage III or metastatic melanoma who have progressed on previous treatment with immune checkpoint inhibitors in the adjuvant or metastatic setting. Study details: All participants will receive the investigational treatment, Perkileucel. To create this therapy, participants need to undergo surgical excision of a melanoma lesion to harvest the TILs prior to treatment. Once the TILs have been manufactured, participants will be admitted to hospital to receive 5 days of chemotherapy to prepare their body (lymphodepletion) for the TIL-ACT. Treatment with TIL-ACT will then be given on Day 0 as a single intravenous infusion followed by up to 6 intravenous infusions of high-dose interleukin 2. Blood tests and other assessments will be performed regularly to monitor safety and response. The total duration of the study is 8 years. Safety will be assessed throughout the full duration of the study. Patients will be monitored for delayed adverse events. This study will show whether Perkileucel can help control melanoma that has not responded to other treatments and demonstrate feasibility of manufacture and delivery of this treatment in an Australian healthcare setting.

This is a single arm, open label phase II study to determine the activity of Perkileucel, a tumour infiltrating lymphocyte (TIL) adoptive cell transfer therapy (ACT), in patients with unresectable stage III or metastatic melanoma who have progressed on previous treatment with immune checkpoint inhibitors in the adjuvant or metastatic setting. Patients with sufficient and accessible tumour tissue measuring at least 1.5 cm will undergo surgical excision. Harvested tumour tissue will be cultured at CTTWA and TIL will be expanded within 5 weeks. Five days prior to infusion of TIL-ACT, patients will receive a nonmyeloablative lymphodepleting regimen with cyclophosphamide (60 mg/kg) once daily concurrently with fludarabine (25 mg/m\^2) IV once daily for 2 days followed by fludarabine (25mg/m\^2) once daily for 3 days. Patients will then receive a single dose of TIL-ACT of 1 × 10\^9 to 2 × 10\^11 TIL intravenously on Day 0. Patients will receive up to 6 doses of intravenous high-dose interleukin-2 (600 000 IU/kg IV) every 8-12 hours. The total inpatient stay from chemotherapy to recovery after IL-2 will be approximately 15 days. Blood tests and imaging assessments will be performed regularly to monitor safety and response. The total duration of the study is 8 years. Safety will be assessed throughout the full duration of the study. Patients will be monitored for delayed adverse events. The assessment of the activity of TIL ACT in patients unresectable or metastatic melanoma resistant to anti-PD1 will be performed using best objective response rate as per RECIST criteria 1.1.

Interventions

Tumour Infiltrating Lymphocytes Adoptive Cell TherapyBIOLOGICAL

TILs are autologous melanoma reactive cells, that are harvested from patient's own melanoma tissue. Patients will receive the TIL-ACT by a single intravenous infusion on Day 0 at of dose of 5 x 10\^9 to 2 x 10\^11 TILs.

Cyclophosphamide + Fludarabine Lymphodepletive ConditioningDRUG

Five days prior to infusion of TIL-ACT, patients will receive a lymphodepleting chemotherapy with cyclophosphamide (60 mg/kg) once daily concurrently with fludarabine (25 mg/m\^2) IV once daily for 2 days followed by fludarabine (25mg/m\^2) once daily for 3 days.

AldesleukinDRUG

Patients will receive up to 6 doses of intravenous aldesleukin (600 000 IU/kg IV) every 8-12 hours post the TIL-ACT infusion.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 70 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Adult patients = 18 years = 70 years of age. 2. ECOG 0-1 (Appendix A: Eastern Cooperative Oncology Group Performance Status Scale) with an estimated life expectancy of \> 6 months 3. Histologically confirmed unresectable or stage IV melanoma as per AJCC 8th edition. Unresectable melanoma is defined where the lesions are deemed to be unresectable by the treating surgeon. 4. Metastatic melanoma with at least 1 surgically accessible metastatic lesion (or aggregate lesions) with an estimated minimum diameter of = 1.5 cm 5. Measurable disease per RECIST 1.1 criteria (in addition to the resected lesion). 6. At least one anti-PD1 containing line of systemic therapy for unresectable or metastatic melanoma. Alternatively, one prior line of an adjuvant or neoadjuvant anti-PD1 containing regimen and all related adverse events have either returned to baseline or stabilized. Exclusion Criteria: 1. Life expectancy of less than 3 months. 2. Metastatic uveal melanoma. 3. Requirement for immunosuppressive doses of systemic corticosteroids (\>10 mg/day prednisone or equivalent) or other immunosuppressive drugs (e.g. mycophenolate, infliximab, or others) within the last 3 weeks prior to patient screening. Participants receiving steroids as replacement therapy for adrenocortical insufficiency at =10 mg/day of prednisone or another steroid equivalent dose are acceptable. 4. Participant has symptomatic untreated brain metastases. * A participant with historically treated brain metastases (ie, treatment was completed \>60 days prior to consenting for study participation) may be considered for study participation if the participant is clinically and radiologically stable for = 60 days * Participants with previously known asymptomatic brain metastases who do not clinically require treatment may be enrolled. 5. More than three melanoma brain metastases or evidence of leptomeningeal disease Other protocol defined exclusion criteria could apply.

Outcomes

Primary Outcomes

Assess the activity of TIL ACT in patients unresectable or metastatic melanoma resistant to anti-PD1 using objective response rate as per RECIST 1.1

Best objective response rate as per RECIST criteria 1.1

Time frame: From enrolment to 6 months, date of documented progression per RECIST criteria 1.1 or the date of subsequent anti-cancer therapy, whichever occurs first

Secondary Outcomes

Median Progression Free Survival

Median, calculated as the date between randomisation and the date of documented progression per RECIST 1.1 to month 12 post Perkileucel infusion

Time frame: From enrolment to 12 months post infusion of Perkileucel

Median Overall Survival

Median, calculated by the date from randomisation to 12 months post Perkileucel infusion, or date of death

Time frame: From enrolment to 12 months post infusion of Perkileucel

Median Progression Free Survival

Median, calculated as the date between randomisation and the date of documented progression per RECIST 1.1 to month 24 post Perkileucel infusion

Time frame: From enrolment to 24 months post Perkileucel infusion

Median Overall Survival

Median, calculated by the date from randomisation to 24 months post Perkileucel infusion, or date of death

Time frame: From enrolment to 24 months post Perkileucel infusion

Safety Analysis of Perkileucel

Safety analyses will be performed in all treated patients. Descriptive statistics of safety will be presented using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 6.0 by treatment group. All on-study AEs, treatment-related AEs, SAEs and treatment-related SAEs will be tabulated using worst grade per NCI CTCAE v6.0 criteria by system organ class and preferred term. On-study lab parameters including haematology, chemistry, liver function, and renal function will be summarised using worst grade NCI CTCAE v6.0 criteria.

Time frame: From enrolment to Day 100 post infusion of Perkileucel