Phase Ia/Ib and Potential Phase IIa Study of the Safety and Pharmacokinetics of NOX66 Both as a Monotherapy and in Combination With Carboplatin in Patients With Refractory Solid Tumours
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 19
- 试验地点
- 4
- 主要终点
- Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Treatment Emergent Adverse Events (SAEs) Related to NOX66.
研究概览
简要总结
The study evaluates the safety and activity of NOX66 in patients with refractory solid tumors that are non responsive to standard therapies.
This is a two part with a potential third part, open-label, multicenter, dose escalation study of NOX66 as monotherapy and in combination with carboplatin.
详细描述
Idronoxil is a synthetic small molecule that pre-clinical studies have identified as a strong candidate for development as a chemo-sensitising drug.
Human studies using idronoxil administered in oral and intravenous dosage forms have shown that the drug is highly susceptible to Phase 2 metabolism, resulting in loss of bio-activity.
NOX66 is idronoxil in a new dosage formulation developed specifically to protect the drug from Phase 2 metabolism and thereby ensure retention of the majority of administered drug in a bio-active form.
The main purpose of the current study is to confirm the safety of the new dosage formula both as a monotherapy and in combination with carboplatin, given that it is anticipated that the drug will be present in the body in a bio-active form at considerably higher levels than previously achieved.
A secondary objective is to observe if NOX66 is able to restore response to carboplatin in tumours considered unresponsive to this chemotherapy, and moreover to provide a meaningful clinical benefit in combination with a lower-than-normal dosage of carboplatin.
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
- Single (Outcomes Assessor)
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
- •Provision of informed consent
- •Male or female ≥18 years of age
- •Histologic or cytologic confirmed locally advanced or metastatic cancer that has no standard therapeutic alternatives.
- •ECOG Performance status 0-1
- •A minimum life expectancy of 12 weeks
- •Adequate bone marrow, hepatic and renal function as evidenced by:
- •Absolute neutrophil count (ANC) > 1.5 x 109/L
- •Platelet count > 100 x 109/L
- •Hemoglobin > 9.0 g/dL
- •Serum bilirubin < 1.5 x ULN
- •AST/ALT (SGOT/SGPT) 2.5 x ULN for the reference laboratory or < 5 x ULN in the presence of liver metastases
- •Serum creatinine 1.5 x ULN
- •Female patients who are known to be capable of conception should have a negative serum pregnancy test (beta-human chorionic gonadotropin (β-hCG)) within 1 week of starting the study
- •All potentially fertile patients will agree to use an effective form of contraception during the study and for 90 days following the last dose of NOX66 (an effective form of contraception is defined as an oral contraceptive or a double barrier method
- •At least 4 weeks must have elapsed prior to commencement of NOX66 treatment since prior chemotherapy, investigational drug or biologic therapy and any toxicity associated with these treatments has recovered to ≤ NCI-CTCAE Grade 1
- •At least 21 days must have elapsed prior to Day 1 Cycle 1 since radiotherapy (limited palliative radiation is allowed > 2 weeks), immunotherapy or following major surgery and any surgical incision should be completely healed
排除标准
- •Patients who are pregnant or breastfeeding.
- •Uncontrolled infection or systemic disease.
- •Clinically significant cardiac disease not well controlled with medication (e.g. congestive heart failure, symptomatic coronary artery disease, angina, and cardiac arrhythmias) or myocardial infarction within the last 12 months.
- •Patients with QTc of > 470 msec on screening ECG. (If a patient has QTc interval >470 msec on screening ECG, the screening ECG may be repeated twice (at least 24 hours apart). The average QTc from the 3 screening ECGs must be <470 msec in order for the patient to be eligible for the study.
- •Any major surgery, radiotherapy, or immunotherapy within the last 21 days (limited palliative radiation is allowed > 2 weeks).
- •Chemotherapy regimens with delayed toxicity within the last 4 weeks. Chemotherapy regimens given continuously or on a weekly basis with limited potential or delayed toxicity within the last 2 weeks.
- •No concurrent systemic chemotherapy or biologic therapy is allowed.
- •Known human immunodeficiency virus (HIV) or Hepatitis B or C (active, previously treated or both).
- •History of solid organ transplantation.
- •Psychiatric disorder or social or geographic situation that would preclude study participation.
- •Known unsuitability for treatment with carboplatin including renal disease where there is impaired glomerular filtration rate (GFR).
研究组 & 干预措施
1a NOX66
NOX66 administered daily for 14 day in a 21-day treatment cycle. NOX66 treatment given to two cohorts of patients as 1 of 2 dose regimens:
Regimen 1: 400 mg; Regimen 2: 800 mg (idronoxil)
干预措施: NOX66 (Drug)
1b NOX66 and Carboplatin (combined)
NOX66 administered on Days 1-7 and carboplatin IV infusion on Day 2 of each 28-day treatment cycle up to 6 cycles.
NOX66 at the same dosage received in the Run-In Arm combined with 2 carboplatin doses starting with low dose carboplatin AUC = 4 for treatment cycles 1-3 followed by higher dose carboplatin AUC = 6 for treatment cycles 4-6.
干预措施: NOX66 (Drug)
1b NOX66 and Carboplatin (combined)
NOX66 administered on Days 1-7 and carboplatin IV infusion on Day 2 of each 28-day treatment cycle up to 6 cycles.
NOX66 at the same dosage received in the Run-In Arm combined with 2 carboplatin doses starting with low dose carboplatin AUC = 4 for treatment cycles 1-3 followed by higher dose carboplatin AUC = 6 for treatment cycles 4-6.
干预措施: Carboplatin (Drug)
2a NOX66 and Carboplatin
This arm triggered by observed meaningful clinical responses from the 1b Combination Arm in particular disease indications.
Treatment NOX66 + carboplatin administered over 6 cycles each of 28-days at observed clinical response dosage. A maximum of 2 cohorts, each comprising patients with specific tumour type.
干预措施: NOX66 (Drug)
2a NOX66 and Carboplatin
This arm triggered by observed meaningful clinical responses from the 1b Combination Arm in particular disease indications.
Treatment NOX66 + carboplatin administered over 6 cycles each of 28-days at observed clinical response dosage. A maximum of 2 cohorts, each comprising patients with specific tumour type.
干预措施: Carboplatin (Drug)
结局指标
主要结局
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Treatment Emergent Adverse Events (SAEs) Related to NOX66.
时间窗: From enrollment through 30 days after the last cycle of therapy (8 months)
An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Treatment-emergent are events between first dose of study drug that were absent before treatment or that worsened relative to pre-treatment state. Treatment-related are events which had causal relationship to study drug as assessed by the Investigator and were suspected to be reasonably related to the study drug.
Number of Participants Who Experience Dose Limiting Toxicity (DLT) During NOX66 Monotherapy and During NOX66 Combination With Carboplatin
时间窗: Up to 1 month for NOX66 monotherapy from enrollment and up to 7 months from start of NOX66 combination therapy
Dose limiting toxicity during monotherapy and combination therapy defined as any Grade 3 or more toxicity (by National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI CTCAE version 4.03\]) (related to therapy) excluding Grade 3 or more neutropenia lasting greater than 5 days or thrombocytopenia associate with bleeding or Grade 4 thrombocytopenia.
次要结局
- Objective Response Rate (ORR) at Cycle 3 and at Cycle 6 of Combination Therapy(Radiological evaluation at baseline and at 3 months and at 6 months)
- Overall Clinical Response Rate at Cycle 3 and at Cycle 6 of Combination Therapy(Radiological evaluation at baseline and at 3 months and at 6 months)