An Open-label, Multi-center Phase I/Ib Dose Finding and Expansion Study of HRO761 as Single Agent and in Combinations in Patients With Microsatellite Instability-High or Mismatch Repair Deficient Advanced Solid Tumors.
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 123
- 试验地点
- 34
- 主要终点
- Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs)
研究概览
简要总结
The main purpose of the study is to evaluate the safety and tolerability of HRO761 and identify the recommended dose(s), i.e., the optimal safe and active dose of HRO761 alone or in combination with pembrolizumab or irinotecan that can be given to patients who have cancers with specific molecular alterations called MSIhi (Microsatellite Instability-high) or dMMR (Mismatch Repair Deficient) that might work best to treat these specific cancer types and to understand how well HRO761 is able to treat those cancers.
详细描述
The new drug being tested in the study, HRO761, is an oral drug that acts on a protein called Werner (WRN), which may contribute to cancer growth. By acting on WRN, HRO761 may be able to stop the growth of the cancer.
This is the first time HRO761 is given to patients and the first time HRO761 is used in combination with pembrolizumab or irinotecan.
Pembrolizumab and irinotecan are drugs approved in several countries and used as standard treatment for certain types of cancer (e.g., colon cancer and small cell lung cancer).
This research study will consist of various treatment arms to investigate HRO761 as single agent and in the combinations.
For HRO761 single agent, the research will be done in two parts. The first part is called "dose escalation" and the second part is called "dose optimization". In the dose escalation part, different groups of people will be given different doses of HRO761 to understand how the body reacts to different doses of the drug and how well the drug acts against the cancer. During the dose optimization part, the selected doses will be tested in more patients until a recommended dose(s) is found.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
盲法说明
This is an open label study. Treatment will be open to patients, Investigator staff, persons performing the assessments and the Sponsor clinical trial team.
For the dose escalation and dose expansion, no randomization will be performed. For the dose optimization (HRO761 single agent arm only), patients will be equally randomized to the two selected HRO761 single agent treatment dose levels.
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with advanced unresectable or metastatic MSIhi or MMR deficient (dMMR) solid tumors who have progressed after or are intolerant to prior standard therapy.
- •Arm A and C: Patients must have progressed on the most recent therapy for advanced disease including one prior line of immune checkpoint inhibitor therapy.
- •Arm B: Patients should have received prior chemotherapy or targeted therapy, and patients should have received prior immune checkpoint inhibitor or should be expected to benefit from immune checkpoint inhibitor therapy.
- •Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1
- •Measurable disease as determined by RECIST version 1.1
- •• All patients (Arm A, B and C) will have available archival tumor tissue obtained prior to study treatment initiation, to allow retrospective MSIhi/dMMR status confirmation. A newly obtained biopsy will only be collected at screening if there is no archival tumor tissue available and if safe and medically feasible according to treating institution's guidelines. Exceptions may be considered after documented discussion with Novartis.
排除标准
- •Impaired cardiac function or clinically significant cardiac disease
- •Clinically significant eye impairment
- •Patients with a primary Central Nervous System (CNS) tumor or tumor metastatic to the CNS
- •Human Immunodeficiency Virus (HIV) infection
- •Active Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) or Tuberculosis infection. Patients whose disease is controlled under antiviral therapy should not be excluded.
- •History of severe hypersensitivity reactions to any ingredient of study drug(s)
- •Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drugs (e.g., severe ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection), except for prior gastrectomy.
- •Other protocol-defined inclusion/exclusion criteria may apply
研究组 & 干预措施
A: HRO761 single agent
phase Ib (Dose finding (Escalation and Optimization) and expansion)
干预措施: HRO761 (Drug)
B: HRO761 + pembrolizumab
phase Ib (Dose escalation and expansion)
干预措施: HRO761 (Drug)
B: HRO761 + pembrolizumab
phase Ib (Dose escalation and expansion)
干预措施: pembrolizumab (Biological)
C: HRO761 + irinotecan
phase Ib (Dose escalation and expansion)
干预措施: HRO761 (Drug)
C: HRO761 + irinotecan
phase Ib (Dose escalation and expansion)
干预措施: irinotecan (Drug)
结局指标
主要结局
Incidence and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs)
时间窗: at month 36
Month 36 is assumed to be study end. Incidence and severity of AEs and SAEs by treatment group, including changes in vital signs, electrocardiograms (ECGs) and laboratory results qualifying and reported as AEs.
Frequency of dose reductions as a measure of tolerability
时间窗: at month 36
Month 36 is assumed to be study end Number of dose reductions by treatment group/arm as a measure of tolerability.
Incidence of dose limiting toxicities (DLTs) of treatment (Escalation only)
时间窗: at Day 28
A DLT is defined as an adverse event or abnormal laboratory value that is not primarily related to disease, disease progression, intercurrent illness/injury, or concomitant medications that occurs within the first 28 days of study treatment and meets a defined criteria.
Frequency of dose interuptions as a measure of tolerability
时间窗: at month 36
Month 36 is assumed to be study end Number of dose interruptions by treatment group/arm as a measure of tolerability.
Frequency of dose discontinuations as a measure of tolerability
时间窗: at month 36
Month 36 is assumed to be study end Number of dose discontinuations by treatment group/arm as a measure of tolerability.
次要结局
- Overall Response Rate (ORR) per RECIST v1.1(at month 36)
- Disease Control Rate (DCR) per RECIST v1.1(at month 36)
- Progression Free Survival (PFS) per RECIST v1.1(at month 36)
- Duration of Response (DOR) per RECIST v1.1(at month 36)
- PK parameter (Tmax) of HRO761(at month 12)
- PK parameter (Cmax) of HRO761(at month 12)
- PK parameter (AUC) of HRO761(at month 12)
- Plasma concentrations of HRO761(at Day 1, Day 8, Day 29, Day 57, Day 85, Day 113, Day 141, Day 225, and Day 309)