Ignite Creation Date:
2025-12-24 @ 9:32 PM
Ignite Modification Date:
2026-01-10 @ 2:23 PM
Study NCT ID:
NCT03388632
Status:
COMPLETED
Last Update Posted:
2025-12-18
First Post:
2017-12-30
Is Gene Therapy:
True
Has Adverse Events:
True
Brief Title:
Recombinant Interleukin-15 in Combination With Checkpoint Inhibitors Nivolumab and Ipilimumab in People With Refractory Cancers
Sponsor:
National Cancer Institute (NCI)
Organization:
Study Overview
Official Title:
Phase I Study of Recombinant Interleukin 15 in Combination With Checkpoint Inhibitors Nivolumab and Ipilimumab in Subjects With Refractory Cancers
Status:
COMPLETED
Status Verified Date:
2025-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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.
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.
Detailed Description:
BACKGROUND:
* Interleukin-15 (IL-15) is a stimulatory cytokine that activates the immune system, inducing proliferation of T lymphocytes and natural killer (NK) cells. Administration of recombinant human IL-15 (rhIL-15) has been shown to result in a dramatic increase of circulating cytotoxic T lymphocytes (CD8+T cells) and NK cells; these changes in immune cell populations suggest potential for anti-tumor activity.
* Immune checkpoint inhibitors, including nivolumab (anti-programmed cell death protein 1 (PD-1) and ipilimumab (anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), block the engagement of specific T-cell signaling pathways by tumor cells. These regulatory pathways typically act to downregulate T cell activity and are co-opted by tumors to allow the malignant cells to evade the immune response.
* The combination of rhIL-15 with two checkpoint inhibitor therapies has potential to lead to enhanced immune activation, resulting in anti-tumor T cell responses that are effective in refractory cancers.
PRIMARY OBJECTIVE:
\- Determine the safety, toxicity profile, dose-limiting toxicity (DLT) and maximum tolerated doses (MTD) of subcutaneous administration of rhIL-15 given in combination with the anti- CTLA-4 antibody ipilimumab and the anti-PD-1 antibody nivolumab in patients with metastatic or treatment-refractory cancers.
EXPLORATORY OBJECTIVE:
* Assess the clinical activity of rhIL-15, ipilimumab, and nivolumab combination therapy as characterized by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and immune RECIST (iRECIST) response rate of patients treated in this trial.
* Investigate the biological effects of this combination on circulating T cell subsets and on PD-1/programmed death-ligand 1 (PD-L1) expression and immune cell activation in tumor tissue.
ELIGIBILITY:
\- Patients greater than or equal to 18 years of age with histologically confirmed solid tumor malignancy that is metastatic or treatment-refractory cancers.
STUDY DESIGN:
* The first 4-6 patients enrolling in the study will be placed into lead-in doublets with a combination of rhIL-15 and either nivolumab OR ipilimumab; once toxicity is cleared in both doublets (i.e., 2 patients enrolled on each doublet remain free of DLTs for 6 weeks) and a safety analysis is reviewed and approved by the Institutional Review Board (IRB), new patients will be enrolled directly onto the triple agent combination.
* For the first four 42-day cycles on the triplet, patients will receive subcutaneous (SC) rhIL-15 on days 1-8 and 22-29, intravenous (IV) nivolumab on days 8, 22, and 36, and IV ipilimumab on day 8. Cycles 5 and onwards will not include treatment with rhIL-15.
* Patients will be encouraged to report any and all adverse events, given the high likelihood of toxicities with the triplet combination therapy.
* Blood for pharmacodynamic (PD) endpoints will be collected throughout the study and tumor biopsies will be collected pretreatment and on cycle 1, day 42 (C1D42) (optional during the doublets and triplet escalation phase, mandatory during the triplet expansion phase)
* Interleukin-15 (IL-15) is a stimulatory cytokine that activates the immune system, inducing proliferation of T lymphocytes and natural killer (NK) cells. Administration of recombinant human IL-15 (rhIL-15) has been shown to result in a dramatic increase of circulating cytotoxic T lymphocytes (CD8+T cells) and NK cells; these changes in immune cell populations suggest potential for anti-tumor activity.
* Immune checkpoint inhibitors, including nivolumab (anti-programmed cell death protein 1 (PD-1) and ipilimumab (anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), block the engagement of specific T-cell signaling pathways by tumor cells. These regulatory pathways typically act to downregulate T cell activity and are co-opted by tumors to allow the malignant cells to evade the immune response.
* The combination of rhIL-15 with two checkpoint inhibitor therapies has potential to lead to enhanced immune activation, resulting in anti-tumor T cell responses that are effective in refractory cancers.
PRIMARY OBJECTIVE:
\- Determine the safety, toxicity profile, dose-limiting toxicity (DLT) and maximum tolerated doses (MTD) of subcutaneous administration of rhIL-15 given in combination with the anti- CTLA-4 antibody ipilimumab and the anti-PD-1 antibody nivolumab in patients with metastatic or treatment-refractory cancers.
EXPLORATORY OBJECTIVE:
* Assess the clinical activity of rhIL-15, ipilimumab, and nivolumab combination therapy as characterized by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and immune RECIST (iRECIST) response rate of patients treated in this trial.
* Investigate the biological effects of this combination on circulating T cell subsets and on PD-1/programmed death-ligand 1 (PD-L1) expression and immune cell activation in tumor tissue.
ELIGIBILITY:
\- Patients greater than or equal to 18 years of age with histologically confirmed solid tumor malignancy that is metastatic or treatment-refractory cancers.
STUDY DESIGN:
* The first 4-6 patients enrolling in the study will be placed into lead-in doublets with a combination of rhIL-15 and either nivolumab OR ipilimumab; once toxicity is cleared in both doublets (i.e., 2 patients enrolled on each doublet remain free of DLTs for 6 weeks) and a safety analysis is reviewed and approved by the Institutional Review Board (IRB), new patients will be enrolled directly onto the triple agent combination.
* For the first four 42-day cycles on the triplet, patients will receive subcutaneous (SC) rhIL-15 on days 1-8 and 22-29, intravenous (IV) nivolumab on days 8, 22, and 36, and IV ipilimumab on day 8. Cycles 5 and onwards will not include treatment with rhIL-15.
* Patients will be encouraged to report any and all adverse events, given the high likelihood of toxicities with the triplet combination therapy.
* Blood for pharmacodynamic (PD) endpoints will be collected throughout the study and tumor biopsies will be collected pretreatment and on cycle 1, day 42 (C1D42) (optional during the doublets and triplet escalation phase, mandatory during the triplet expansion phase)
Study Oversight
Has Oversight DMC:
False
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
Secondary ID Infos
| Secondary ID | Type | Domain | Link | View |
|---|---|---|---|---|
| 18-C-0033 | None | None | View |