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

NCT03526185 | Terminated Early Phase 1 DMC FDA Drug

• 1 other identifier: 2000020477
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

Brief Summary

To determine the feasibility and safety of administering a regimen of TIL/IL-2, using a cell product manufactured in the Yale Advanced Cell Therapy Laboratories, in subjects with metastatic melanoma who are not responding or have progressed after receiving prior therapy with a PD-1/PD-L1 antagonist used alone or in combination with anti-CTLA-4. Additionally, a second cohort of patients with metastatic melanoma who are not responding or have progressed after receiving prior therapy with a PD-1/PD-L1 antagonist alone or in combination with anti-CTLA-4 will receive anti-PD-1 and anti-CTLA-4 therapy with Nivolumab and Ipilimumab.

Conditions

Metastatic Melanoma

Outcome Measures

Primary Outcomes (2)

• Adverse Events

  To determine the safety of administering a regimen of TIL/IL-2, incidence of drug-related adverse events (AEs) will be summarized across adverse event type in terms of frequency by event type.

  up to 12 months

• Serious Adverse Events

  To determine the safety of administering a regimen of TIL/IL-2, serious adverse events (SAEs) will be summarized across event type in terms of frequency by event type. SAE's will include events leading to discontinuation, deaths and clinical laboratory test abnormalities

  up to 12 months

Secondary Outcomes (1)

• Objective response rate to TIL

  up to 12 months

Other Outcomes (4)

• Assessment of Immune features of TIL: 4-1BB

  up to 12 months

• Assessment of Immune features of TIL: LAG-3

  up to 12 months

• Assessment of Immune features of TIL: TIM-3

  up to 12 months

Study Arms (2)

Cohort 1

EXPERIMENTAL

* 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).

Drug: Tumor Infiltrating Lymphocytes

Cohort 2

EXPERIMENTAL

* 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.

Drug: Tumor Infiltrating Lymphocytes; Drug: Nivolumab and Ipilimumab

Interventions

Tumor Infiltrating Lymphocytes DRUG

The regimen consists of treatment with cyclophosphamide and fludarabine,followed by infusion of up to 3x1011 lymphocytes (minimum of 1x109) expanded in vitro from subjects own resected tumor followed by the administration of aldesleukin (IL-2).

Also known as: Autologous TIL, Unselected TIL, Young TIL

Cohort 1; Cohort 2

Nivolumab and Ipilimumab DRUG

• 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.

Cohort 2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Yale University: lead

Study Sites (1)

Yale New Haven Hospital

New Haven, Connecticut, 06510, United States

Location

MeSH Terms

Conditions

Melanoma

Interventions

Nivolumab; Ipilimumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Medicine (Medical Oncology)

Model Details: 2 separate cohorts are included in the study design. These groups will not be directly compared.

Study Record Dates

• First Submitted: January 22, 2018
• First Posted: May 16, 2018
• Study Start: February 6, 2018
• Primary Completion: December 1, 2020
• Study Completion: December 1, 2020
• Last Updated: July 25, 2022

Record last verified: 2022-07

Locations

US (1)