临床试验/NCT02718066

NCT02718066已完成1 期

A Phase 1b/2 Study to Assess the Safety and Efficacy of HBI-8000 in Combination With Nivolumab in Subjects With Advanced Solid Tumors Including Melanoma, Renal Cell Carcinoma (RCC), and Non-Small Cell Lung Cancer (NSCLC)

HUYABIO International, LLC.6 个研究点分布在 1 个国家目标入组 96 人开始时间: 2016年8月18日最近更新: 2026年7月30日

适应症

干预措施

试验速览

阶段: 1 期
状态: 已完成
发起方
入组人数: 96
试验地点: 6
主要终点: Number of Patients Who Experienced at Least One DLT During the DLT Assessment Period for MTD Determination

研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

A Phase 1b/2 Study to Assess the Safety and Efficacy of HBI-8000 in Combination with Nivolumab in Patients with Advanced Solid Tumors Including Melanoma, Renal Cell Carcinoma (RCC), and Non-Small Cell Lung Cancer (NSCLC).

The primary objective of this study is:

-To evaluate the safety and tolerability of HBI-8000 when combined with a standard dose and regimen of nivolumab, and to evaluate frequency and severity of toxicities of this combination treatment

The secondary objectives of this study include:

To explore the efficacy of study treatment as measured by Objective Response Rate (ORR), Disease Control Rate (DCR), Clinical Benefit Rate (CBR), Duration of Response (DoR), Progression-Free Survival (PFS) in all subjects treated at RP2D
To obtain pharmacokinetics of twice weekly HBI-8000 when administered in combination with nivolumab administered once every two weeks (Phase 1b all sites)
To obtain pharmacokinetics of twice weekly HBI-8000 when administered in combination with nivolumab administered per package insert dose and administration (Phase 2 selected sites)
To characterize the effect of HBI-8000 on the electrocardiogram QT corrected (QTc) interval (Phase 1b only)

Exploratory:

To investigate the kinetics and extent of histone acetylation in peripheral blood mononuclear cells (PBMC) at the RP2D of HBI-8000 (Phase 2 only)
To explore potential biomarkers for disease response through sequential sampling of blood and/or tumor tissue in subjects consenting to correlative sub-studies at participating sites (Phase 2 only)

Dose Escalation (Phase 1b) will include up to 18 subjects, followed by Cohort Expansion (Phase 2) including up to 100 subjects (melanoma up to 60 subjects and NSCLC up to 40 subjects at MTD and/or RP2D.

详细描述

The primary objective of this study is:

-To evaluate the safety and tolerability of HBI-8000 when combined with a standard dose and regimen of nivolumab, to determine Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D) and to evaluate frequency and severity of toxicities of this combination treatment

The secondary objectives of this study include:

To explore the efficacy of study treatment as measured by Objective Response Rate (ORR), Disease Control Rate (DCR), Clinical Benefit Rate (CBR), Duration of Response (DoR), Progression-Free Survival (PFS) in all subjects treated at RP2D
To obtain pharmacokinetics of twice weekly HBI-8000 when administered in combination with nivolumab administered once every two weeks (Phase 1b all sites; Phase 2 selected sites)
To characterize the effect of HBI-8000 on the electrocardiogram QT corrected (QTc) interval (Phase 1b only)

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

•Subjects were entered in the study only if they met all of the following criteria:
•1. Adults at least 18 years of age.
•Eastern Cooperative Oncology Group (ECOG) performance status ≤
•Subjects with histopathologically or cytologically confirmed diagnosis of non uveal melanoma, RCC, or NSCLC, for whom the use of nivolumab was indicated. NSCLC subjects with EGFR or ALK genomic aberrations in tumor should have disease progression on FDA approved therapy for these aberrations prior to receiving nivolumab. (Phase 1b).
•Subjects with histopathologically or cytologically confirmed diagnosis of non uveal melanoma or NSCLC for whom the use of nivolumab is indicated (Phase 2 expansion). With Protocol Amendment 5, subjects with NSCLC were not eligible for enrollment.
•c, Non uveal melanoma and NSCLC subjects whose disease progressed after achieving stable disease (SD) for at least 3 months, with partial response (PR) or complete response (CR) as the best response that was documented by imaging studies on previous treatment with a PD L1 inhibitor with proven efficacy (Phase 2 expansion). With Protocol Amendment 5, subjects with NSCLC were not eligible for enrollment.
•4. Subject had at least one measurable target lesion as defined by Response Evaluation Criteria in Solid Tumors v1.1 (RECIST 1.1). Melanoma subjects participating in the optional correlative substudy had tumor tissue available from a metastatic or unresectable site for PD L1 and correlative biomarker analysis.
•5. All prior systemic therapy (chemotherapy, mutation targeting therapy, immune checkpoint therapy), or surgical or radiation treatment was completed at least 4 weeks before study drug* administration (2 weeks for palliative radiotherapy, 1 week for minor surgery), pending full recovery from therapy.
•6. The following laboratory results within 7 days prior to study drug* administration: Adequate hematopoietic, electrolyte, hepatic, and renal laboratory findings as defined below: white blood cells (WBC) ≥3000/μL, neutrophils ≥1500/μL, platelets ≥100x103/μL, hemoglobin ≥9.0 g/dL independent of transfusion, creatinine ≤1.5 mg/dL, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × upper limit of normal (ULN), alkaline phosphatase ≤2.5 x ULN (unless bone metastases present), bilirubin ≤1.5 × ULN (unless known Gilbert's disease, where value must be ≤3 × ULN), and serum albumin ≥3.0 g/dL.
•7. Life expectancy ≥12 weeks.
•A negative serum pregnancy test at baseline for women of childbearing potential.
•9. Were willing to abstain from heterosexual activity or practice physical barrier contraception prior to time of study entry to at least 5 months after the last day of treatment.
•10. Had the ability to understand and the willingness to sign a written informed consent document.

排除标准

•Subjects who fulfilled any of the following criteria at screening were not eligible for admission into the study:
•History of Grade 3 or above hypersensitivity reactions to other monoclonal antibodies.
•Subjects with a history of a cardiovascular illness including: congestive heart failure (New York Heart Association Grade III or IV); unstable angina or myocardial infarction within the previous 6 months; or symptomatic cardiac arrhythmia despite medical management. In addition, for Phase 1b only: QTc (Fridericia's correction) (QTcF) >450 ms in male, and >470 ms in female, congenital long QT syndrome.
•Uncontrolled hypertension, systolic blood pressure (SBP) >160 mmHg or diastolic blood pressure (DBP) >100 mmHg.
•Subjects with active brain metastasis; previously treated brain metastasis was allowed if it had been stable for 4 weeks or more and had not required steroids.
•Presence of leptomeningeal disease.
•History of hemorrhagic diarrhea, inflammatory bowel disease, active uncontrolled peptic ulcer disease, recurrent pleural effusion requiring repetitive palliative thoracentesis within 3 months prior to study entry (except for subjects with a pleurex port), or immune mediated toxicity leading to treatment discontinuation.
•Active, known, or suspected serious autoimmune disease, except for type I diabetes mellitus, hypothyroidism only requiring hormone replacement, and skin disorders (such as vitiligo, psoriasis, or alopecia).
•Active uncontrolled bacterial, viral, or fungal infection requiring systemic therapy.
•Known history of testing positive for human immunodeficiency virus (HIV), known acquired immunodeficiency syndrome (AIDS).
•Active hepatitis B (serum hepatitis B surface antigen [HBsAg] positive) or hepatitis C (hepatitis C virus [HCV] antibody test or serum HCV RNA positive) indicating acute or chronic infection.
•Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids were permitted.
•Use of other investigational agents (drugs not marketed for any indication) within 28 days or at least 5 half lives (whichever is shorter) before study drug administration.
•Pregnant or breast feeding women.
•Second malignancy unless in remission for 2 years, except for non melanomatous skin cancer, carcinoma in situ of the cervix treated with curative intent, or curatively treated prostate cancer with prostate specific antigen (PSA) <0.1 ng/mL.
•Underlying medical conditions that, in the Investigator's opinion, made the administration of study drug hazardous or obscure the interpretation of toxicity determination or adverse events.
•Unwilling or unable to comply with procedures required in this protocol.

研究组 & 干预措施

HBI-8000 in combination with nivolumab

Experimental

HBI-8000 dose escalation 20mg, 30mg, 40mg, orally, twice weekly; in combination with Nivolumab 240mg intravenous infusions every 2 weeks for Phase 1b and in accordance with the manufacturer package insert and institution's prescribing practice for Phase 2.

干预措施: HBI-8000 in combination with nivolumab (Drug)

结局指标

主要结局

Number of Patients Who Experienced at Least One DLT During the DLT Assessment Period for MTD Determination

时间窗: First 28 days

The dose escalation schema of HBI 8000 followed the conventional 3+3 design. The starting dose was HBI 8000 20 mg twice a week. Dose escalation to 30 mg or 40 mg was determined by observation of DLT. At each dose level, a minimum of 3 subjects evaluable for DLT were enrolled. If 0 of the initial 3, or no more than 1 in a total 6 subjects experienced DLT, escalation to the next higher dose was allowed.

次要结局

Objective Response Rate (ORR) in All Patients Treated at RP2D(From screening for baseline assessment to the date of CR or PR assessed, up to approximately 4 years and 7 months)
Disease Control Rate (DCR) in All Patients Treated at RP2D(From screening for baseline assessment to the date of best response (CR, PR, or SD) on study, up to approximately 4 years and 7 months)
Duration of Response (DoR) in All Patients Treated at RP2D(From the date of CR or PR until the date of PD, or until the date of death, up to approximately 4 years and 7 months)
Concentration Slope(0 (predose) up to 4 hours postdose on C1D1 and C2D1)
Progression-Free Survival (PFS) in All Patients Treated at RP2D(From the date of first dose of HBI-8000 until tumor progression by site reported RECIST 1.1, or clinical progression, or death, whichever occurs first, up to approximately 4 years and 7 months)
Pharmacokinetic - Cmax (Single Dosing)(From predose (0.5 hour prior to breakfast) to 7 hours postdose on Cycle 1 Day 1, at 24 hours on Cycle 1 Day 2 (no dose administered))
Pharmacokinetic - Cmax (Repeat Dosing)(From predose to 7 hours postdose on Cycle 2 Day 1)
Pharmacokinetic - AUC(0-7) (Single Dosing)(From predose (0.5 hour prior to breakfast) to 7 hours postdose on Cycle 1 Day 1)
Pharmacokinetic - AUC(0-7) (Repeat Dosing)(From predose to 7 hours postdose on Cycle 2 Day 1)
Pharmacokinetic - AUC(0-24)(From predose (0.5 hour prior to breakfast) on Cycle 1 Day 1 to 24 hours on Cycle 1 Day 2 (no dose administered))
Pharmacokinetic - Tmax (Single Dosing)(From predose (0.5 hour prior to breakfast) to 7 hours postdose on Cycle 1 Day 1, at 24 hours on Cycle 1 Day 2 (no dose administered))
Pharmacokinetic - Tmax (Repeat Dosing)(From predose to 24 hours postdose on Cycle 2 Day 1)
QTcF Values >450 Msec(0 (predose) up to 4 hours postdose on C1D1 and C2D1)
QTcF Increase > 30 Msec(0 (predose) up to 4 hours postdose on C1D1 and C2D1)

研究者

发起方

HUYABIO International, LLC.

申办方类型

Industry

责任方

Sponsor

研究点 (6)

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