A Multicenter Phase Ib/II Study to Evaluate the Safety, Efficacy and Pharmacokinetics of NBM-BMX in Patients With Metastatic Uveal Melanoma
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 36
- 试验地点
- 3
- 主要终点
- Phase Ib: Incidence of dose-limiting toxicities (DLTs)
研究概览
简要总结
This study is being done to find the best dose of an investigational drug called NBM-BMX for people with metastatic uveal melanoma, a type of eye cancer that has spread to other parts of the body.
The study will help doctors learn about the side effects of NBM-BMX, how the drug is processed in the body, and whether it may slow down or shrink tumors.
Participants will take NBM-BMX as a capsule by mouth twice daily on an empty stomach with at least six ounces (180 mL) of water. No food or drink (other than water) should be consumed for at least two hours after each dose.
Participants will visit the clinic about once every week or two for exams and blood tests while taking NBM-BMX. After stopping treatment, a follow-up visit will occur about 30 days later.
Treatment may continue as long as the cancer does not get worse and side effects remain manageable.
详细描述
NBM-BMX will be administered orally twice daily (BID) at approximately 12 ± 2-hour intervals for 28 consecutive days per cycle, beginning on Day 1 of Cycle 1. Patients will continue treatment until disease progression, intolerable toxicity likely attributable to NBM-BMX, or voluntary withdrawal from the study. If disease progression is equivocal and, in the investigator's judgment, the patient appears to be benefiting, treatment may continue with close monitoring and re-evaluation at the next scheduled tumor assessment.
The study drug will be provided in 100 mg dry powder hard gel capsules. All dosing will be performed on an outpatient basis. NBM-BMX must be taken on an empty stomach with at least six ounces (180 mL) of water.
Patients should not eat food for at least 1 hour before and 2 hours after each dose of NBM-BMX. Only water is permitted during this fasting window.
To minimize the risk of altered absorption, other oral medications should be taken at least 1 hour before or 2 hours after NBM-BMX administration, unless otherwise approved by the Investigator.
Due to the pH-dependent solubility of NBM-BMX, acid-reducing agents (such as PPIs or H2 blockers) may reduce drug absorption. Patients must avoid taking these agents during the study. Local antacids may be taken at least 2 hours before or after dosing if clinically indicated.
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
- •- Patients must meet the following criteria to be eligible for study entry:
- •Signed, written IRB-approved informed consent.
- •Men and women age ≥ 18 years
- •ECOG Performance status ≤ 2
- •Have measurable disease based on RECIST 1.1
- •Histologic or cytologic confirmation of metastatic uveal melanoma
- •Previous Therapy
- •Surgery: Previous surgery is permitted provided that a minimum of 28 days (4 weeks) has elapsed between any major surgery and date of registration, and that wound healing has occurred.
- •Cytotoxic Chemotherapy: There is no limit to the number of prior regimens received.
- •Other Systemic Therapy: There is no limit to the number of prior therapies received for metastatic uveal melanoma. Prior treatment with tebentafusp is required for HLA-A*02:01-positive patients unless unavailable or clinically inappropriate, as determined by the investigator. Prior HDAC inhibitor treatment is not permitted.
- •Patients must have recovered (to baseline or ≤ grade 1) from all reversible toxicity related to prior chemotherapy or systemic therapy and have adequate washout as follows:
- •Longest of one of the following:
- •Two weeks,
- •5 half-lives for investigational agents,
- •o For anti-cancer therapies with half-lives > 8 days, a washout period of at least 28 days will be acceptable,
- •Standard cycle length of standard therapies.
- •QTcF <= 480 msec
- •Adequate hematopoietic capacity, as defined by the following:
- •Hemoglobin ≥ 9.0 g/dL and not transfusion dependent
- •Platelets ≥ 100,000/mm3
- •Absolute neutrophil count ≥ 1,500 cells/mm3
- •Adequate hepatic function, as defined by the following:
- •AST and ALT ≤ 2.5 times upper limit of normal (ULN) or ≤ 5 times ULN if liver metastases are present
- •Total bilirubin ≤ 1.5 x ULN or within 3x the ULN for patients with Gilbert disease
- •Albumin ≥ 3.0 g/dL
- •Adequate renal function, as defined by the following:
- •- Renal: calculated creatinine clearance >45 mL/min for patients between 18 and 70 years old with abnormal, increased, creatinine levels (Cockcroft-Gault formula; Appendix F). For patients who are greater than 70 years old, investigator judgment may be used to assess the renal risk of study participation.
- •Women/men of childbearing potential must have agreed to use two effective contraceptive methods while on study and for 6 months after the last dose of NBM-BMX.
- •Willingness and ability to comply with the study scheduled visits, treatment plans, laboratory tests and other procedures.
排除标准
- •Patients who meet the following criteria will be excluded from study entry:
- •Pregnant or nursing women. NOTE: Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; or abstinence) prior to study entry and for the duration of study participation and for at least 6 months after the last dose of NBM-BMX. Should a man father a child, or a woman become pregnant or suspect she is pregnant while participating in this study, he or she should inform the treating physician immediately.
- •Concurrent non-protocol-specified anti-tumor therapy (e.g., chemotherapy, other targeted therapy, radiation therapy, or photodynamic therapy)
- •History of other malignancies within 3 years of Day 1, except for tumors with a negligible risk for metastasis or death, such as adequately treated squamous-cell carcinoma of the skin, ductal carcinoma in situ of the breast, or carcinoma in situ of the cervix.
- •Active or uncontrolled infections or with serious illnesses or medical conditions which would not permit the patient to be managed according to the protocol.
- •History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or that might affect interpretation of the results of the study or renders the patient at high risk from treatment complications.
- •Difficulty with swallowing oral medications.
- •Currently taking moderate and strong inhibitors (e.g., gemfibrozil) or inducers of CYP2C
- •A positive test for hepatitis B (HBsAg) and/or hepatitis C (anti-HCV antibody), unless the HBV DNA level and/or HCV RNA level is below the limit of detection.
- •Any of the following within 3 months of the first dose of NBM-BMX: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, congestive heart failure, or cerebrovascular accident including transient ischemic attack.
- •Current use or anticipated need for P-gp or BCRP inhibitors during the study period.
- •Use of proton pump inhibitors (PPIs), H2-receptor antagonists, or other systemic acid-reducing agents within 7 days prior to Cycle 1 Day 1 or planned use during the study treatment period, unless the patient can be switched to local antacids (e.g., calcium carbonate or aluminum hydroxide) taken at least 2 hours before or after NBM-BMX dosing.
- •Patients unable or unwilling to comply with this restriction should be excluded. Exceptions must be discussed with and approved by the Medical Monitor.
研究组 & 干预措施
In the present Phase Ib/II study, up to three dose levels are planned
NBM-BMX is a small molecule inhibitor of HDAC8 currently in Phase I testing that has demonstrated activity in a metastatic UM patient. Given the role of the HDAC8 pathway on development and growth of uveal melanoma and the initial clinical activity in the UM setting, there is a high probability that NBM-BMX would have efficacy in this disease
In the present Phase Ib/II study, up to four dose levels are planned:
- Dose Level 1: 200 mg daily (100 mg BID)
- Dose Level 2: 400 mg daily (200 mg BID)
- Dose Level 3: 600 mg daily (300 mg BID)
- Dose Level 4: 800 mg daily (400 mg BID) A total daily dose of 600 mg (300 mg BID) of the NBM-BMX dry powder formulation has been well tolerated in patients with advanced solid tumors. As three subjects have completed treatment at this dose level without evidence of DLTs, the 200 mg/day dose selected for this trial represents two full dose levels below the highest tolerated dose and is expected to be both safe and pharmacologically active.
干预措施: NBM-BMX Capsule are proprietary products developed by Novelwise Pharmaceutical Corporation (Novelwise) for treatment of patients suffering from cancers. (Drug)
结局指标
主要结局
Phase Ib: Incidence of dose-limiting toxicities (DLTs)
时间窗: Time Frame: Cycle 1 (up to 28 days)
Participants experiencing a DLT during Cycle 1 (28 days)
Phase Ib: Maximum Tolerated Dose (MTD)
时间窗: Cycle 1 (up to 28 days)
The highest dose level with ≤1 of 6 participants with a DLT, based on the incidence of DLTs at each dose level of NBM-BMX during Cycle 1 (28 days). MTD will inform the recommended Phase 2 dose (RP2D) of NBM-BMX
Phase II: Objective Response Rate (ORR)
时间窗: Assessed every 8-12 weeks from first dose; up to ~24 months
Proportion of patients with complete response (CR) + partial response (PR) determined per RECIST 1.1 while on NBM-BMX.
次要结局
- Phase Ib: Safety and Tolerability(From first dose through 30 days after last dose (up to ~25 months))
- Phase Ib: Objective Response Rate (ORR)(Assessed every 8 -12 weeks from first dose; up to ~24 months)
- Phase Ib. PK: Maximum plasma concentration (Cmax)(Cycle 1 Day 1: pre-dose to 12 hours post-dose)
- Phase Ib. PK: Time to Cmax (Tmax)(Cycle 1 Day 1: pre-dose to 12 hours post-dose)
- Phase Ib. PK: Area under the curve (AUC 0-12)(Cycle 1 Day 1: pre-dose to 12 hours post-dose)
- Phase Ib. PK: Apparent oral clearance (CL/F)(Cycle 1 Day 1)
- Phase Ib. PK: Elimination half-life (T½)(Cycle 1 Day 1)
- Phase Ib. PK: Apparent volume of distribution (Vd/F)(Cycle 1 Day 1)
- Phase II: 3-Month Progression-Free Survival (PFS) Rate(3 months from treatment initiation)
- Phase II: Overall Survival (OS)(Up to ~24 months)