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

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.

• Tumour Infiltrating Lymphocytes Adoptive Cell Therapy (Biological): 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 Conditioning (Drug), also known as Flu-Cy: 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.
• Aldesleukin (Drug), also known as Interleukin-2: Patients will receive up to 6 doses of intravenous aldesleukin (600 000 IU/kg IV) every 8-12 hours post the TIL-ACT infusion.

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 [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]: Best objective response rate as per RECIST criteria 1.1

Secondary outcomes

• Median Progression Free Survival [From enrolment to 12 months post infusion of Perkileucel]: Median, calculated as the date between randomisation and the date of documented progression per RECIST 1.1 to month 12 post Perkileucel infusion
• Median Overall Survival [From enrolment to 12 months post infusion of Perkileucel]: Median, calculated by the date from randomisation to 12 months post Perkileucel infusion, or date of death
• Median Progression Free Survival [From enrolment to 24 months post Perkileucel infusion]: Median, calculated as the date between randomisation and the date of documented progression per RECIST 1.1 to month 24 post Perkileucel infusion
• Median Overall Survival [From enrolment to 24 months post Perkileucel infusion]: Median, calculated by the date from randomisation to 24 months post Perkileucel infusion, or date of death
• Safety Analysis of Perkileucel [From enrolment to Day 100 post infusion 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.

Sex: All, ages: 18 Years to 70 Years

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.

• Peter Lau, MBBS, Study chair, Harry Perkins Institute for Medical Research
• Ben Carnley, MBBS, Principal investigator, Royal Perth Hospital