A Phase 1/2, Open-label, Multicenter, Dose Escalation and Dose Expansion Study of NKTR-262 in Combination With Bempegaldesleukin (NKTR-214) With or Without Nivolumab in Patients With Locally Advanced or Metastatic Solid Tumor Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 64
- 试验地点
- 14
- 主要终点
- Number of Participants Experiencing Dose-Limiting Toxicities (DLTS)
研究概览
简要总结
Patients received intratumoral (IT) injections of NKTR-262 in 3-week cycles for up to 3 cycles; bempegaldesleukin with or without nivolumab was administered every 3 weeks (q3w), and treatment continued until unacceptable toxicity, death, or disease progression per RECIST 1.1. Based on Phase 1 results of the study, the decision was made not to start the Phase 2 part of the study and the study was terminated.
详细描述
Cancer treatments that couple pharmacological activation of tumor antigen presentation with activation and expansion of CD8+ T and natural killer (NK) cells in the tumor environment have the potential to induce an effective anti-tumor immune response in patients. NKTR-262 is a small molecule agonist of toll-like receptors (TLRs) 7/8 designed to be retained in the tumor micro-environment in order to activate antigen-presenting cells (APC), such as dendritic cells, to create new antigen-specific cytotoxic T cells. As a CD122-biased agonist, bempegaldesleukin monotherapy increases newly proliferative CD8+ T cells in tumors. NKTR-262 plus bempegaldesleukin is expected to increase expansion of antigen-specific CD8+ T cells. In preclinical studies, a single IT injection of NKTR-262 plus IV bempegaldesleukin resulted in complete abscopal effects in tumor models. Preliminary clinical data show bempegaldesleukin plus nivolumab enhances immune-stimulatory responses. The REVEAL trial will assess safety and anti-tumor activity of NKTR-262 with bempegaldesleukin +/- nivolumab for the treatment of selected cancers.
- Melanoma (1st-line and relapsed/refractory)
- Merkel Cell Carcinoma (2nd-line and relapsed/refractory)
- Triple Negative Breast Cancer (1st- and 2nd-line and relapsed/refractory)
- Renal Cell Carcinoma (1st-line and relapsed/refractory)
- Colorectal Cancer (2nd-line and relapsed/refractory; MSI non-high)
- Colorectal Cancer (2nd 3rd-line+, I-O therapy naive; relapsed/refractory; MSI high)
- Head and Neck Squamous Cell Carcinoma (2nd-line and relapsed/refractory)
- Sarcoma (2nd-line and relapsed/refractory)
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically confirmed diagnosis of a locally advanced (not amenable to curative therapy such as surgical resection) metastatic cancer of the following histologies: melanoma (MEL), Merkel cell carcinoma (MCC), triple-negative breast cancer (TNBC), renal cell carcinoma (RCC), colorectal cancer, head and neck squamous cell carcinoma (HNSCC), or sarcoma.
- •Life expectancy > 12 weeks as determined by the Investigator.
- •Eastern Cooperative Oncology Group (ECOG) performance status 0 or
- •Measurable disease per RECIST 1.
- •Patients enrolled in Cohorts 1-10, Cohort A, Cohort B and Phase 2 Doublet must be refractory to all therapies known to confer clinical benefit to their disease.
- •Fresh tumor tissue available for cellular characterization and programmed cell death protein 1 (PD-L1) status.
- •Injected lesions (up to two) must be between 20 mm and 90 mm in diameter for IT injection; lesions must be accessible for baseline and on-treatment biopsies. Any liver lesion targeted for injection must not exceed 50 mm at the time of injection.
- •Demonstrated adequate organ function within 14 days of Cycle 1 Day 1 (C1D1).
排除标准
- •Use of an investigational agent or an investigational device within 21 days before administration of first dose of study drug(s).
- •Patients treated with prior interleukin-2 (IL-2).
- •Patients who have been previously treated with a toll-like receptor (TLR) agonist (excluding topical agents) and patients who have received experimental cancer vaccines.
- •Patients who have received systemic interferon (IFN)α within the previous 6 months prior to enrollment to the study.
- •Other active malignancy, except non-melanomic skin cancer
- •Evidence of clinically significant interstitial lung disease or active, noninfectious pneumonitis.
- •Prior surgery or radiotherapy within 14 days of initiating study drug(s). Patients must have recovered from all radiation-related toxicities, not required corticosteroids and have not had radiation pneumonitis.
- •Prolonged Fridericia's corrected QT interval (QTcF) > 450 ms for men and > 470 ms for women at Screening.
- •History of unstable or deteriorating cardiac disease within the previous 6 months prior to screening including but not limited to the following:
- •Unstable angina or myocardial infarction.
- •Congestive heart failure (NYHA Class III or IV).
- •Uncontrolled clinically significant arrhythmias.
- •Patients with a history of any retinal disorders (e.g., retinal detachment, diabetic retinopathy, retinal hemorrhage, macular degeneration).
- •Uveal melanoma will be excluded
- •Patients with tumor that invade the superior vena cava or other major blood vessels.
- •Additional general and tumor specific inclusion and exclusion criteria will apply.
研究组 & 干预措施
NKTR-262 + bempegaldesleukin or + bempegaldesleukin with nivolumab
Phase 1: NKTR-262 in escalating doses, combined with bempegaldesleukin. The goal of this dose escalation part of the study is to establish a recommended Phase 1b dose for NKTR-262 + bempegaldesleukin with nivolumab, followed by a dose-confirmation cohort.
干预措施: NKTR-262 (Drug)
NKTR-262 + bempegaldesleukin or + bempegaldesleukin with nivolumab
Phase 1: NKTR-262 in escalating doses, combined with bempegaldesleukin. The goal of this dose escalation part of the study is to establish a recommended Phase 1b dose for NKTR-262 + bempegaldesleukin with nivolumab, followed by a dose-confirmation cohort.
干预措施: bempegaldesleukin (Drug)
NKTR-262 + bempegaldesleukin or + bempegaldesleukin with nivolumab
Phase 1: NKTR-262 in escalating doses, combined with bempegaldesleukin. The goal of this dose escalation part of the study is to establish a recommended Phase 1b dose for NKTR-262 + bempegaldesleukin with nivolumab, followed by a dose-confirmation cohort.
干预措施: nivolumab (Drug)
结局指标
主要结局
Number of Participants Experiencing Dose-Limiting Toxicities (DLTS)
时间窗: The DLT window is 21 days following NKTR-262 single agent administration (Cycle 1) and an additional 9 days when combined with bempeg for staggered dosing administration (Cohorts 1 and 2), or 7 days for the same day administration (Cohort 3 and higher).
DLTs were assessed in Cohort 1 through Cohort 9, which had dose levels of NKTR-262 as 0.03mg, 0.06mg, 0.06mg, 0.12mg, 0.24mg, 0.48mg, 0.96mg, 1.92mg, and 3.84mg in combination with bempegaldesleukin (bempeg). There was only 1 DLT that occurred in one of the Cohort 9 patients. Therefore, the maximum tolerated dose (MTD) of NKTR 262 was not reached.
Objective Response Rate (ORR) Per RECIST 1.1 in Cohort A and Cohort B at Recommended Phase 2 Dose (RP2D)
时间窗: From Cycle 1 Day 1 to 100 days after the last dose of study drug or the date for new anti-cancer therapy, whichever is earlier.
Objective Response Rate (ORR) per RECIST 1.1 in Cohort A and Cohort B at Recommended Phase 2 Dose (RP2D). ORR is defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 and as assessed by Blinded Independent Central Review (BICR).
次要结局
未报告次要终点