A Pilot Study Using Short-Term Cultured Anti-Tumor Autologous Lymphocytes
Metastatic Melanoma

About this trial
This is an interventional treatment trial for Metastatic Melanoma
Eligibility Criteria
Inclusion Criteria:
For Cohorts 1 and 2:
- Metastatic melanoma;
- A metastatic lesion at least 1.5 cm in diameter that can be removed surgically
- Measurable or evaluable disease not including the resected lesion
- ECOG PS of 0 or 1 prior to cell harvest
- Assessment by the treating physician that ECOG performance status of no higher than 2 can be maintained at least for the period of cell generation, lymphoablation, cell infusion and IL-2 administration (for at least 6 weeks following cell harvest)
- Tumor refractory to or progressing following prior PD-1/PD-L1 therapy alone or in combination with an anti-CTLA-4 agent
- Ability to understand risks and benefits of the treatment and to give informed consent
Exclusion Criteria:
For Cohorts 1 and 2:
- Received prior cell transfer therapy that included non-myeloablative or ablative chemotherapy
- Any significant major organ dysfunction (see protocol)
- Residual toxicity > gr1 from immune checkpoint inhibitor other than persistent endocrinopathy on hormone replacement; all symptoms of prior colitis and enteritis must have resolved completely as assessed by history
- Any contraindication to neutropenia or thrombocytopenia for up to 2 weeks (no active major infection, no site of active, clinically significant bleeding)
- Concurrent major medical illnesses
- Any form of immunodeficiency
- Requirement for steroids > 10 mg prednisone daily or equivalent
- Severe hypersensitivity to any of the agents used in this study
- Contraindications for IL-2 administration
At the time of lymphoablation subjects must meet baseline eligibility criteria with the following additions and exceptions:
• Confirmation by lab that cell product can be ready for harvest and infusion within 7 days
For Cohort 2 only:
At the time of the start of anti-PD-1/anti-CTLA-4 therapy, subjects must meet baseline eligibility criteria with the following additions and exceptions:
- Patient cannot have a steroid requirement > 10 mg prednisone daily or equivalent
- Patients who have received prior PD-1/PD-L1 antagonist therapy and developed severe autoimmune disease precluding further immune checkpoint therapy
- Any organ dysfunction that makes the subject ineligible for anti-PD1 and anti-CTLA-4 treatment as deemed by the treating investigator
- ECOG PS of 0-2
- Hgb of at least 8.0 gm/dl (may be transfused to this level)
- Creatinine not greater than 2.5 mg/dl
- AST or ALT not > 5x ULN and total bilirubin not > 2.5 mg/dl
- No clinically significant change in major organ function compared to initial eligibility evaluation
- Prior to initiating the lymphoablation regimen, there can be no untreated brain lesion > 1.0 cm, and/or with significant evidence of hemorrhage. Subjects may begin lymphoablation no less than 1 full day after completing WBRT or stereotactic radiotherapy for brain lesions.
Sites / Locations
- Yale New Haven Hospital
Arms of the Study
Arm 1
Arm 2
Experimental
Experimental
Cohort 1
Cohort 2
Subjects will receive a non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide (60 mg/kg/day IV) on days -7 and -6 and fludarabine (25 mg/m2/day) on days -5 through -1. Prophylactic antibiotics will be administered as medically indicated until recovery of ANC to > 500 and recovery of ALC to > 400 On day 0 subjects will receive the infusion of autologous TIL and one hour later (but can be delayed up to 24 hours) will begin low-dose aldesleukin (IL-2) (72,000 IU/kg IV every 12 hours for up to 10 doses).
Subjects will receive a non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide (60 mg/kg/day IV) on days -7 and -6 and fludarabine (25 mg/m2/day) on days -5 through -1. Prophylactic antibiotics will be administered as medically indicated until recovery of ANC to > 500 and recovery of ALC to > 400 On day 0 subjects will receive the infusion of autologous TIL and one hour later (but can be delayed up to 24 hours) will begin low-dose aldesleukin (IL-2) (72,000 IU/kg IV every 12 hours for up to 10 doses). Within 1 week post discharge subjects will be treated with Nivolumab 1 mg/kg and Ipilimumab 3 mg/kg every 3 weeks for 4 doses. Following this, patients will receive Nivolumab 480 mg every 4 weeks. Adjuvant Nivolumab will continue until evidence of disease progression or inability to tolerate treatment.