Phase I Study of Recombinant Interleukin 15 in Combination With Checkpoint Inhibitors Nivolumab and Ipilimumab in Subjects With Refractory Cancers
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 31
- 试验地点
- 1
- 主要终点
- Maximum Tolerated Dose (MTD) at Which Dose-Limiting Toxicities (DLT) Occurred With rhIL-15 Administered in Combination With Fixed Doses of Nivolumab and Ipilimumab
研究概览
简要总结
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.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 120 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
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).
干预措施: rhIL-15 (Drug)
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).
干预措施: Nivolumab (Drug)
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).
干预措施: EKG (Diagnostic Test)
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).
干预措施: ECHO (Diagnostic Test)
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).
干预措施: CT Scan (Diagnostic Test)
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).
干预措施: rhIL-15 (Drug)
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).
干预措施: Ipilimumab (Drug)
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).
干预措施: EKG (Diagnostic Test)
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).
干预措施: ECHO (Diagnostic Test)
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).
干预措施: CT Scan (Diagnostic Test)
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).
干预措施: rhIL-15 (Drug)
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).
干预措施: Ipilimumab (Drug)
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).
干预措施: Nivolumab (Drug)
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).
干预措施: Tumor biopsies (Procedure)
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).
干预措施: EKG (Diagnostic Test)
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).
干预措施: ECHO (Diagnostic Test)
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).
干预措施: CT Scan (Diagnostic Test)
结局指标
主要结局
Maximum Tolerated Dose (MTD) at Which Dose-Limiting Toxicities (DLT) Occurred With rhIL-15 Administered in Combination With Fixed Doses of Nivolumab and Ipilimumab
时间窗: Cycle 1 (42 days)
Here is the maximum tolerated dose (MTD) (i.e., highest dose) of rhIL-15 administered in combination with fixed doses of nivolumab and ipilimumab at which dose-limiting toxicities occurred in ≤1 of 6 participants during cycle 1, dose escalation in participants receiving the triplet combination. A DLT is defined as an adverse event that is felt to be related (possibly, probably, or definitely) to administration of study drugs, and meets prespecified criteria, including any condition requiring long-term treatment with corticosteroids or permanent discontinuation of one of the agents.
Number of Dose-limiting Toxicities (DLT) Possibly, Probably, or Definitely Related to Study Drugs
时间窗: Cycle 1 (42 days)
A DLT is defined as an adverse event (AE) that is felt to be related (possibly, probably, or definitely) to administration of study drugs, and meets prespecified criteria, including any condition requiring long-term treatment with corticosteroids or permanent discontinuation of one of the agents.
Number of Participants Experiencing Dose-Limiting Toxicities (DLT)
时间窗: Cycle 1 (42 days)
Here is the number of participants experiencing dose-limiting toxicities (DLT). A DLT is defined as an adverse event that is felt to be related (possibly, probably, or definitely) to administration of study drugs, and meets prespecified criteria, including any condition requiring long-term treatment with corticosteroids or permanent discontinuation of one of the agents.
次要结局
- Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)(Adverse Events were monitored/assessed from the first study intervention through 30 days after the study agent (s) was/were administered up to approximately 23 months.)
研究者
Jibran Ahmed
Principal Investigator
National Cancer Institute (NCI)