Recombinant Interleukin-15 in Combination With Checkpoint Inhibitors Nivolumab and Ipilimumab in People With Refractory Cancers

Part of paid clinical trials in Bethesda, Maryland.

Sponsor
National Cancer Institute (NCI)
Study ID
NCT03388632
Phase
PHASE1
Status
Completed

Conditions

  • Metastatic Solid Tumors
  • Treatment-Refractory Cancers

Eligibility Criteria

Sex
ALL
Age
18 Years - 120 Years
Healthy Volunteers
Not accepted

Interventions

  • rhIL-15 — DRUG
    Recombinant human interleukin 15 (IL-15) is a stimulatory cytokine that activates the immune system, inducing proliferation of T lymphocytes and naturel killer (NK) cells. Administration of recombinant human IL-15 (rhIL-15) has been shown to result in a dramatic increase of circulating cytotoxic T lymphocyte (CD8+T) cells and NK cells; these changes in immune cell populations suggest potential for anti-tumor activity.
  • Ipilimumab — DRUG
    Ipilimumab is a fully human monoclonal antibody against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), a receptor present on the surface of activated T cells that functions as an immune checkpoint. Immune checkpoints pathways typically act to downregulate T cell activity and are co-opted by tumors to allow the malignant cells to evade the immune response. Blocking the engagement of CTLA-4 with ipilimumab allows infiltrating T cells to mount an anti-tumor response. Ipilimumab is approved by the Food and Drug Administration (FDA) for the treatment of certain patients with melanoma and has shown clinical activity in other tumor types as well.
  • Nivolumab — DRUG
    Nivolumab is a humanized monoclonal antibody against programmed death 1 (PD-1), a receptor present on the surface of activated T cells that functions as an immune checkpoint. One of the ligands for PD-1, programmed death-ligand 1 (PD-L1), is commonly expressed by tumor cells. Similar to inhibition of the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathway by ipilimumab, blocking of PD-1/PD-L1 signaling by nivolumab allows infiltrating T cells to mount an immune response against the tumor. Nivolumab is approved as a single agent for several cancer types, as well as for the treatment of advanced melanoma in combination with ipilimumab.
  • Tumor biopsies — PROCEDURE
    Triplet C Pre-study and Cycle 1, Week 6.
  • EKG — DIAGNOSTIC_TEST
    Pre-study
  • ECHO — DIAGNOSTIC_TEST
    Pre-study
  • CT Scan — DIAGNOSTIC_TEST
    Restaging every cycle (every 6 weeks) ± 1 week during cycles 1-4 and every 2 cycles (every 12 weeks) ± 1 week thereafter.

Study Details

Background: The drug Interleukin-15 (IL-15) activates the immune system. The drugs nivolumab and ipilimumab unblock immune cells. The drugs together may allow immune cells to recognize and attack cancer cells, causing tumors to shrink. Objective: To test the effects and maximum dose of IL-15, nivolumab, and ipilimumab. Eligibility: People ages 18 and older who have cancer that does not respond to treatment Design: Participants will be screened with: * Medical history * Physical exam * Heart, blood, and urine tests * Scans Tumor biopsy: A small needle removes a tumor sample. Participants will be in 1 of 3 treatment groups: * IL-15 with nivolumab * IL-15 with ipilimumab * IL-15 with nivolumab and ipilimumab Participants will take the drugs in four 6-week cycles. IL-15 is injected under the skin. The other two drugs are injected into an arm vein over 60-90 minutes. Participants may need to stay at the hospital 2-3 hours after the first dose of any drug to watch for side effects. Each cycle will include: * Weekly blood and urine tests * 16 IL-15 injections * 1 ipilimumab injection if applicable * 3 nivolumab injections if applicable * Blood tests weekly during cycles 1 and 2 * Urine tests weekly during cycles 1 and 2 * Scans and a tumor biopsy on day 42 After cycle 4, participants will stop taking IL-15. They will continue the other drugs until they can no longer tolerate the side effects, or their cancer gets worse. Those cycles will include: * 1 ipilimumab injection if applicable * 3 nivolumab injections if applicable * Scans every other cycle After participants stop treatment, their doctor will monitor their side effects for 4 months or until they go away.

Key Dates

Start date
Feb 5, 2018
Status verified
Dec 2025
Primary completion
Nov 27, 2024
Completion
May 8, 2025

Study Design

Enrollment
31 participants (actual)
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT

Arms

  • Experimental: Lead-in Doublet A
    Lead-in doublet for initial safety evaluation: Recombinant interleukin-15 (rhIL-15) given subcutaneous (SC) days 1-8 and 22- 29 + nivolumab (anti-programmed cell death protein 1 (PD1) given intravenous (IV) on days 8, (IL-15 doses are limited to first 4 cycles only).
  • Experimental: Lead-in Doublet B
    Lead-in doublet for initial safety evaluation: Recombinant interleukin-15 (rhIL-15) given subcutaneous (SC) days 1-8 and 22- 29 + ipilimumab (anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) given intravenous (IV) on day 8, (IL-15 doses are limited to first 4 cycles only).
  • Experimental: Triplet C
    Dose escalation of the triplet combination: Recombinant human interleukin-15 (rhIL-15) given subcutaneous (SC) days 1-8 and 22- 29 + nivolumab (anti-programmed cell death protein 1 (PD1) given intravenous (IV) on days 8 + ipilimumab (anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) given intravenous (IV) on day 8, IL-15 will initially be given at 0.5 µg/kg/day (dose level 1, DL1). If the safety profile is acceptable at DL1, the dose of IL-15 will be increased to 1.0 µg/kg/day (DL2) in subsequent patients, then to 2.0 µg/kg/day (DL3) if the safety profile of DL2 is acceptable. (IL-15 doses are limited to first 4 cycles only).

Primary Outcome Measure

Maximum Tolerated Dose (MTD) at Which Dose-Limiting Toxicities (DLT) Occurred With rhIL-15 Administered in Combination With Fixed Doses of Nivolumab and Ipilimumab [ Time Frame: Cycle 1 (42 days) ]

Locations (1)

FacilityCityStateZIPSite coordinators
National Institutes of Health Clinical CenterBethesdaMaryland20892-

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National Institutes of Health Clinical Center· Bethesda, MD

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