A Phase 1 Open-Label Study of the Safety, Tolerability and Efficacy of KPT-9274, a Dual Inhibitor of PAK4 and NAMPT, in Patients With Advanced Solid Malignancies or Non-Hodgkin's Lymphoma
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 60
- 试验地点
- 8
- 主要终点
- Maximum Tolerated Dose (MTD) for KPT-9274
研究概览
简要总结
This study will evaluate the safety, tolerability, and efficacy of oral KPT-9274 for the treatment of patients with advanced solid malignancies or non-Hodgkin's lymphoma (NHL).
详细描述
This is a first-in-human, multi-center, open-label clinical study with separate Dose Escalation and Expansion Phases to assess preliminary safety, tolerability, and efficacy of KPT-9274, a dual inhibitor of PAK4 and NAMPT, in patients with advanced solid malignancies (including sarcoma, colon, lung, melanoma, etc.) or NHL for which all standard therapeutic options considered useful by the investigator have been exhausted.
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
- 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
- •Participants must meet all of the following inclusion criteria to be eligible to enroll in the Part C of this study.
- •Should have unresectable advanced, recurrent or metastatic melanoma and must have objective and measurable melanoma by RECIST 1.1 after disease progression on a prior anti-PD-1 or anti-PD-L1 therapy.
- •ECOG performance status of ≤
- •Life expectancy of ≥ 3 months.
- •Adequate hepatic function:
- •Total bilirubin < 1.5 times the ULN (except participants with Gilbert's syndrome [hereditary indirect hyperbilirubinemia] who must have a total bilirubin of ≤ 3 times ULN),
- •AST and ALT ≤ 2.5 times ULN (except participants with known liver involvement of their advanced solid malignancy who must have an AST and ALT ≤ 5.0 times ULN).
- •Adequate renal function:
- •Estimated creatinine clearance of ≥ 60 mL/min, calculated using the formula of Cockroft and Gault (140-Age) Mass (kg)/(72 creatinine mg/dL); multiply by 0.85 if female.
- •Adequate hematopoietic function:
- •Total WBC count ≥ 1500/mm³, ANC ≥ 1000/mm³, Hb ≥ 10.0 g/dL, platelet count ≥ 100,000/mm³
排除标准
- •Participants meeting any of the following exclusion criteria are not eligible to enroll in this study.
- •≤ 2 weeks since the last prior therapeutic regimen for melanoma. Palliative steroids for disease related symptoms < 7 days prior to C1D1, unless physiologic doses of steroids are used.
- •Have not recovered or stabilized (Gr 1 or to their baseline for non-hematologic toxicities, ≤ Gr 2 or to their baseline for hematologic toxicities) from toxicities related to their previous treatment except for alopecia.
- •Untreated CNS disease or leptomeningeal involvement are excluded. Participants without active brain or leptomeningeal metastases after prior treatment with local therapies are eligible provided that the treatment had been done ≥ 2 weeks prior to enrollment.
- •Active infection with completion of therapeutic antibiotics, antivirals, or antifungals within one week prior to C1D
- •Prophylactic antibiotics, antivirals or antifungals are permitted.
- •Significantly diseased or obstructed gastrointestinal tract or uncontrolled vomiting or diarrhea that could interfere with the absorption of KPT-
- •Active peptic ulcer disease or other active gastrointestinal bleeds.
- •Requiring treatment with corticosteroids at doses higher than substitute therapy (> 10 mg prednisone), are unstable with substitute hormonal therapy, or are deemed to be likely to re-occur by the treating physician when administered nivolumab.
研究组 & 干预措施
Part B: KPT-9274 80mg + Niacin 500mg
Participants received KPT-9274 80mg of oral tablet along with a starting dose of 500mg niacin ER orally three times a week every other day during each 28-day cycle.
干预措施: KPT-9274 (Drug)
Part A: KPT-9274 10mg
Participants received a 10 milligrams (mg) of oral tablets of KPT-9274 three times a week every other day during each 28 day cycle.
干预措施: KPT-9274 (Drug)
Part A: KPT-9274 20mg
Participants received a 20mg of oral tablets of KPT-9274 three times a week every other day during each 28 day cycle.
干预措施: KPT-9274 (Drug)
Part A: KPT-9274 30mg
Participants received a 30mg of oral tablets of KPT-9274 three times a week every other day during each 28 day cycle.
干预措施: KPT-9274 (Drug)
Part A: KPT-9274 40mg
Participants received a 40mg of oral tablets of KPT-9274 three times a week every other day during each 28 day cycle.
干预措施: KPT-9274 (Drug)
Part A: KPT-9274 40mg BIW
Participants received KPT-9274 40mg of oral tablet biweekly (BIW) during each 28-day cycle.
干预措施: KPT-9274 (Drug)
Part B: KPT-9274 30mg + Niacin 500mg
Participants received KPT-9274 30mg of oral tablet along with a starting dose of 500mg niacin extended release (ER) orally three times a week every other day during each 28-day cycle.
干预措施: KPT-9274 (Drug)
Part B: KPT-9274 30mg + Niacin 500mg
Participants received KPT-9274 30mg of oral tablet along with a starting dose of 500mg niacin extended release (ER) orally three times a week every other day during each 28-day cycle.
干预措施: Niacin ER (Drug)
Part B: KPT-9274 40mg + Niacin 500mg
Participants received KPT-9274 40mg of oral tablet along with a starting dose of 500mg niacin ER orally three times a week every other day during each 28-day cycle.
干预措施: KPT-9274 (Drug)
Part B: KPT-9274 40mg + Niacin 500mg
Participants received KPT-9274 40mg of oral tablet along with a starting dose of 500mg niacin ER orally three times a week every other day during each 28-day cycle.
干预措施: Niacin ER (Drug)
Part B: KPT-9274 60mg + Niacin 500mg
Participants received KPT-9274 60mg of oral tablet along with a starting dose of 500mg niacin ER orally three times a week every other day during each 28-day cycle.
干预措施: KPT-9274 (Drug)
Part B: KPT-9274 60mg + Niacin 500mg
Participants received KPT-9274 60mg of oral tablet along with a starting dose of 500mg niacin ER orally three times a week every other day during each 28-day cycle.
干预措施: Niacin ER (Drug)
Part B: KPT-9274 80mg + Niacin 500mg
Participants received KPT-9274 80mg of oral tablet along with a starting dose of 500mg niacin ER orally three times a week every other day during each 28-day cycle.
干预措施: Niacin ER (Drug)
Part B: KPT-9274 100mg + Niacin 500mg
Participants received KPT-9274 100mg of oral tablet along with a starting dose of 500mg niacin ER orally three times a week every other day during each 28-day cycle.
干预措施: KPT-9274 (Drug)
Part B: KPT-9274 100mg + Niacin 500mg
Participants received KPT-9274 100mg of oral tablet along with a starting dose of 500mg niacin ER orally three times a week every other day during each 28-day cycle.
干预措施: Niacin ER (Drug)
Part C: KPT-9274 20mg + Nivolumab 480mg
Participants received KPT-9274 20mg of oral tablet three times a week every other day during each 28-day cycle along with 480mg of nivolumab intravenous infusion on Day 1 of each cycle (once every 4-week cycle).
干预措施: KPT-9274 (Drug)
Part C: KPT-9274 20mg + Nivolumab 480mg
Participants received KPT-9274 20mg of oral tablet three times a week every other day during each 28-day cycle along with 480mg of nivolumab intravenous infusion on Day 1 of each cycle (once every 4-week cycle).
干预措施: Nivolumab (Drug)
Part C: KPT-9274 30mg + Nivolumab 480mg
Participants received KPT-9274 30mg of oral tablet three times a week every other day during each 28-day cycle along with 480mg of nivolumab intravenous infusion on Day 1 of each cycle (once every 4-week cycle).
干预措施: KPT-9274 (Drug)
Part C: KPT-9274 30mg + Nivolumab 480mg
Participants received KPT-9274 30mg of oral tablet three times a week every other day during each 28-day cycle along with 480mg of nivolumab intravenous infusion on Day 1 of each cycle (once every 4-week cycle).
干预措施: Nivolumab (Drug)
Part C: KPT-9274 40mg + Nivolumab 480mg
Participants received KPT-9274 40mg of oral tablet three times a week every other day during each 28-day cycle along with 480mg of nivolumab intravenous infusion on Day 1 of each cycle (once every 4-week cycle).
干预措施: KPT-9274 (Drug)
Part C: KPT-9274 40mg + Nivolumab 480mg
Participants received KPT-9274 40mg of oral tablet three times a week every other day during each 28-day cycle along with 480mg of nivolumab intravenous infusion on Day 1 of each cycle (once every 4-week cycle).
干预措施: Nivolumab (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD) for KPT-9274
时间窗: From start of study drug administration up to 44 weeks
The MTD was defined as the highest dose at which less than or equal to (\<=) 1 participant experienced a dose limiting toxicity (DLT) in Cycle 1. A DLT was defined as an adverse event (AE) or abnormal laboratory value occurring within the first 28 days of treatment of KPT-9274, excluding those clearly caused by underlying disease, disease progression, or external factors.
Number of Dose Limiting Toxicities (DLT) Experienced by Participants
时间窗: At Cycle 1 only (28-day cycle)
A DLT was defined as an AE or abnormal laboratory value occurring within the first 28 days of KPT-9274 treatment, excluding those clearly caused by underlying disease, disease progression, or extraneous causes, and meets any of the criteria for defining dose limiting toxicities.
Number of Participants With Adverse Event (AE) of Severity Grade >= 3 or 4, Serious AEs, and AEs Leading to Treatment Discontinuation
时间窗: From start of study drug administration up to 49 weeks
The AE severity was graded on a scale from 1 to 4 using the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.03; any events not specifically listed in the scale were defined as: Grade 1 is mild; Grade 2 is moderate; Grade 3 is severe or medically significant; Grade 4 is life-threatening. An SAE was any untoward medical occurrence that at any dose met one, more of the following criteria: results in death, life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent, significant disability/incapacity, a congenital abnormality/birth defect, an important medical event. The AE leading to treatment discontinuation in the study.
Percentage of Participants With Overall Response Rate (ORR)
时间窗: From date of randomization up to 44 weeks
The ORR was defined as percentage of participants who had a response of partial response (PR) or complete response (CR). The PR was achieved when a participant had at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. The CR was achieved in a participant when all target lesions disappeared. Any pathological lymph nodes (whether target or non target) must have reduction in the short axis to \<10 millimeter (mm).
Percentage of Participants With Disease Control Rate (DCR)
时间窗: From date of the first study treatment up to 44 weeks
The DCR was defined as percentage of participants who have a response of CR, PR, and stable disease (SD) \>= 16 weeks, DCR = CR + PR+ SD. The PR was achieved when a participant had at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. The CR was achieved in a participant when all target lesions disappeared. Any pathological lymph nodes (whether target or non-target) must have reduction in the short axis to \<10mm. The SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD).
Progression-free Survival (PFS)
时间窗: From the date of first study treatment until the first date of PD, or death due (up to 44 weeks)
The PFS was defined as the duration of time from date of the first study treatment until the first date that PD is objectively documented or death due to any cause. The PD is defined as at least a 20% increase in the sum of diameters of measured lesions taking as references the smallest sum of diameters recorded since the treatment started. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. Appearance of one or more new lesions will also constitute PD.
Overall Survival (OS)
时间窗: From date of the first study treatment until death (up to 44 weeks)
The OS was defined as the duration of time from date of the first study treatment until death from any cause.
Time to Progression (TTP)
时间窗: From date of the first study treatment until the first date of PD or death (up to 44 weeks)
The TTP was defined as the duration of time from date of the first study treatment until the first date that PD was objectively documented or death due to PD.
Duration of Response (DOR)
时间窗: Up to 44 weeks
The DOR was defined as the duration of time from the first meeting CR or PR measurement criteria (whichever occurs first) until the first date diseases progression.
次要结局
- Maximum Plasma Concentration (Cmax) in Participants Who Received KPT-9274(Cycle 1 and 2: Pre-dose, 3, 6, 8, 24, and 48 hours post-dose (each cycle =28 days))
- Time-to-peak Plasma Concentration (Tmax) in Participants Who Received KPT-9274(Cycle 1 and 2: Pre-dose, 3, 6, 8, 24, and 48 hours post-dose (each cycle =28 days))
- Terminal Half-life (T1/2) in Participants Who Received KPT-9274(Cycle 1 and 2: Pre-dose, 3, 6, 8, 24, and 48 hours post-dose (each cycle =28 days))
- Volume of Distribution (Vd/F) in Participants Who Received KPT-9274(Cycle 1 and 2: Pre-dose, 3, 6, 8, 24, and 48 hours post-dose (each cycle =28 days))
- Apparent Plasma Clearance (CL/F) in Participants Who Received KPT-9274(Cycle 1 and 2: Pre-dose, 3, 6, 8, 24, and 48 hours post-dose (each cycle =28 days))