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

Summary

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.

Conditions

• Metastatic Solid Tumors
• Treatment-Refractory Cancers

Interventions

DRUG

rhIL-15

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.

DRUG

Ipilimumab

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.

DRUG

Nivolumab

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.

PROCEDURE

Tumor biopsies

Triplet C Pre-study and Cycle 1, Week 6.

DIAGNOSTIC_TEST

EKG

Pre-study

DIAGNOSTIC_TEST

ECHO

Pre-study

DIAGNOSTIC_TEST

CT Scan

Restaging every cycle (every 6 weeks) ± 1 week during cycles 1-4 and every 2 cycles (every 12 weeks) ± 1 week thereafter.

Sponsors & Collaborators

• National Cancer Institute (NCI)

  lead NIH

Principal Investigators

• Jibran Ahmed, M.D. · National Cancer Institute (NCI)

Study Design

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Max Age

120 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2018-02-05

Primary Completion

2024-11-27

Completion

2025-05-08

FDA Drug

Yes

Countries

• United States

Study Locations