A PHASE 1 STUDY TO EVALUATE THE EFFECT OF HEPATIC IMPAIRMENT ON THE PHARMACOKINETICS AND SAFETY OF LORLATINIB IN ADVANCED CANCER PATIENTS
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- Pfizer
- 入组人数
- 1
- 试验地点
- 10
- 主要终点
- Area Under Plasma Lorlatinib Concentration-Time Curve From Time 0 to Dosing Interval of 24 Hours (AUC24) at Steady State On Cycle 2 Day 1
研究概览
简要总结
This is a phase 1 study in advanced cancer patients with varied hepatic functions to evaluate the potential effect of hepatic impairment on pharmacokinetics and safety of lorlatinib and provide dose recommendation for patients with hepatic impairment if possible.
详细描述
This will be a Phase 1, open label, multi center, multiple dose, non randomized, Phase 1 clinical trial of lorlatinib in advanced cancer patients with varying degrees of hepatic impairment and necessary age , weight , and gender matched prospect normal hepatic function patients. This study is intended to evaluate the potential effect of hepatic impairments on the PK and safety of lorlatinib after daily administration of lorlatinib and to provide dosing recommendation for patients with varied degree of hepatic impairment if possible.
Patients in the study will be assigned to different groups (A1, normal liver function, control for group B; A2, normal liver function, control for group C; B, mild hepatic impairment; C, moderate hepatic impairment; D, severe hepatic impairment) according to their liver function. The enrollment of approximately 76 advanced cancer patients is anticipated in this study in order to have 8 PK-evaluable patients in each of Groups A1, A2, B and C, and 6 PK-evaluable patients in Group D for final statistical analysis. Evaluable patients are those who complete the planned PK sample collection on Cycle 2 Day 1 and have no lorlatinib dose modification until completion of Cycle 2 Day 1 PK evaluation. Patients who are not evaluable for PK will be replaced. Each patient will be treated with repeated oral once daily doses of lorlatinib in 21-day cycles until disease progression, patient refusal, or unacceptable toxicity occurs. The dose schedule may be modified as necessary for individual patients according to tolerability.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 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 or cytologically confirmed solid malignancy or lymphoma that is metastatic or unresectable, and for which standard curative or palliative measures do not exist, or are no longer effective;
- •Biliary obstruction with a biliary drain or stent;
- •Neurologically stable gliomas and brain metastases;
- •ECOG performance status of 0, 1, or 2;
- •adequate bone marrow function;
- •adequate pancreatic function;
- •adequate renal function;
- •female patients with negative pregnancy test
排除标准
- •untreated esophageal varices; uncontrolled ascites;
- •episodes of hepatic encephalopathy within the last 4 weeks;
- •spinal cord compression; major surgery within 4 weeks prior to enrollment;
- •radiation therapy within 2 weeks prior to enrollment;
- •last anti-cancer treatment within 2 weeks prior to screening;
- •previous high-dose chemotherapy requiring stem cell rescue;
- •prior to irradiation to >25% of the bone marrow;
- •gastrointestinal abnormalities;
- •known prior or suspected hypersensitivity to lorlatinib or lorlatinib tablet;
- •clinically significant bacterial, fungal or viral infections for non-liver cancer patients;
- •clinically significant cardiovascular disease;
- •uncontrolled hypertension; acute pancreatitis with predisposing characteristics;
- •history of grade 3 or 4 interstitial fibrosis or interstitial lung disease;
- •active hemoelysis or evidence of biliary sepsis;
- •prior major gastrointestinal surgery;
- •concurrent use of known strong CYP3A inhibitors, inducers and P-gp substrates with a narrow therapeutic index;
- •concurrent use of CYP3A substrates with narrow therapeutic indices;
- •prior treatment with lorlatinib; active bleeding disorder
研究组 & 干预措施
Group A1 Normal hepatic function
continued daily administration of lorlatinib in patients with normal hepatic function
干预措施: lorlatinib (Drug)
Group A2 Normal hepatic function
continued daily administration of lorlatinib in patients with normal hepatic function
干预措施: lorlatinib (Drug)
Group B mild hepatic impairment
continued daily administration of lorlatinib in patients with mild hepatic impairment
干预措施: lorlatinib (Drug)
Group C moderate hepatic impairment
continued daily administration of lorlatinib in patients with moderate hepatic impairment
干预措施: lorlatinib (Drug)
Group D severe hepatic impairment
continued daily administration of lorlatinib in patients with severe hepatic impairment
干预措施: lorlatinib (Drug)
结局指标
主要结局
Area Under Plasma Lorlatinib Concentration-Time Curve From Time 0 to Dosing Interval of 24 Hours (AUC24) at Steady State On Cycle 2 Day 1
时间窗: Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
AUC24 was defined as area under the plasma concentration time profile during 1 dosing interval (24 hours).
Observed Maximal Plasma Concentration (Cmax) at Steady State on Cycle 2 Day 1
时间窗: Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.
Cmax was defined as maximum plasma concentration and was observed directly from data.
次要结局
- Duration of Response (DR)(Baseline up to approximately 1 year)
- The Time to Cmax (Tmax) of Lorlatinib After Single Dose on Cycle 1 Day 1(Cycle 1 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.)
- Observed Minimal Plasma Concentration (Cmin) at Steady State On Cycle 2 Day 1(Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.)
- Number Of Patients Experienced Treatment Emergent Adverse Event Assessed by Investigator(From Screening (within 28 days prior to Cycle 1 Day 1) through and including at least 28 days after after the last lorlatinib dose. The duration is approximately 42 days.)
- Objective Response Rate (ORR)(Baseline up to approximately 1 year)
- Lorlatinib Area Under Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) After Single Dose on Cycle 1 Day 1(Cycle 1 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.)
- Plasma Lorlatinib Tlast at Steady State On Cycle 2 Day 1(Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.)
- Apparent Clearance (CL/F) at Steady State On Cycle 2 Day 1(Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.)
- The Time of The Last Quantifiable Concentration (Tlast) of Lorlatinib After Single Dose on Cycle 1 Day 1(Cycle 1 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.)
- Plasma Lorlatinib Metabolite Tlast After Single Dose(Cycle 1 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.)
- Plasma Lorlatinib AUClast at Steady State On Cycle 2 Day 1(Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.)
- Plasma Lorlatinib Metabolite AUC24 at Steady State(Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.)
- Plasma Lorlatinib Metabolite Cmax After Single Dose(Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.)
- Metabolite Ratio of Lorlatinib Metabolite for Cmax (MRCmax) at Steady State on Cycle 2 Day 1(Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.)
- Plasma Lorlatinib Metabolite AUClast After Single Dose(Cycle 1 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.)
- Plasma Lorlatinib Metabolite AUClast at Steady State(Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.)
- Plasma Lorlatinib Metabolite Cmax at Steady State(Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.)
- Plasma Lorlatinib Metabolite Tlast at Steady State(Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.)
- Metabolite Ratio of Lorlatinib Metabolite for AUC24 (MRAUC24) at Steady State on Cycle 2 Day 1(Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.)
- Metabolite Ratio of Lorlatinib Metabolite for AUClast (MRAUClast) at Steady State on Cycle 1 Day 1(Cycle 1 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.)
- Metabolite Ratio of Lorlatinib Metabolite for AUClast (MRAUClast) at Steady State on Cycle 2 Day 1(Cycle 2 day 1 at times 0 (predose), 0.5, 1, 2, 4, 6, 10, and 24 hours post lorlatinib dose.)