A Phase I, Open-label, Uncontrolled, Multicenter, Dose-escalation Study of M3541 in Combination With Palliative Radiotherapy in Subjects With Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 15
- 试验地点
- 5
- 主要终点
- M3541 50 mg + 100 mg + 200 mg + RT: Number of Participants With Dose Limiting Toxicities (DLTs)
研究概览
简要总结
This dose-escalation study evaluated the safety, tolerability, pharmacokinetic (PK), pharmacodynamic, and explore antitumor activity of M3541 in combination with fractionated palliative radiotherapy (RT) in participants with solid tumors with malignant lesions in the thorax, abdominal cavity, head and neck region, or extremities likely to benefit from palliative RT.
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
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 have solid tumors with malignant lesions in the thorax, abdominal cavity, head and neck region, or extremities (any histology) likely to benefit from palliative radiotherapy; participants requiring palliative RT for lesions in the spine or lesions adjacent to the spinal cord are excluded from this study
- •Eastern Cooperative Oncology Group performance status (ECOG PS) =< 2
- •Life expectancy >= 3 months
- •Adequate hematologic, hepatic, and renal function
- •Agree to use highly effective contraception (that is, methods with a failure rate of less than 1 percent per year) if the participant is male or a female of childbearing potential (female partners of childbearing potential of male participants must also agree to use highly effective contraception)
- •Other protocol defined inclusion criteria could apply
排除标准
- •Use of other anticancer therapy within 15 days before the first dose of M3541 administration and should not be within the "at risk follow-up period" for that specific anticancer therapy. The use of any investigational agent is not allowed within 28 days before the first dose of M3541
- •Residual toxicity due to previous anticancer therapy with no return to baseline or =< Grade 1 (except alopecia) according to Common Terminology Criteria for Adverse Events (CTCAE) v4.03
- •Extensive prior RT on more than 30 percent of bone marrow reserves (by Investigator judgment), or prior bone marrow/stem cell transplantation within 5 years before study start
- •Prior RT to the same region that would be irradiated in this study
- •Participants at increased risk for radiation toxicities, such as known collagen vascular disease (example, scleroderma, Sjogren's disease, etc) or other inherited radiation hypersensitivity syndromes (example, Gorlin syndrome, Fanconi anemia, ataxia-telangiectasia, etc.)
- •Surgical intervention within 28 days prior to the first dose of M3541 administration
- •Known central nervous system metastases causing clinical symptoms or metastases that require therapeutic intervention. Participants with a history of treated central nervous system (CNS) metastases (by surgery or radiation therapy) are not eligible unless they have fully recovered from treatment, demonstrated no progression for at least 2 months, and do not require continued steroid therapy. Participants with CNS metastases incidentally detected during Screening that do not cause clinical symptoms and for which standard of care suggests no therapeutic intervention is indicated, should be discussed with the Sponsor Medical Responsible
- •Active difficulty swallowing, malabsorption or other chronic gastrointestinal disease or conditions (including pancreas deficiency requiring Creon therapy) that may hamper compliance and/or absorption of M3541
- •Participants currently receiving or unable to stop using medications or herbal supplements known to be potent inhibitors of cytochrome P450 (CYP) 3A and / or P-glycoprotein (P-gp) (CYP and / P-gp must stop at least 1 week before treatment with M3541) or potent inducers of CYP3A or P-gp (must stop at least 3 weeks before treatment with M3541) or drugs mainly metabolized by CYP3A with a narrow therapeutic index (must stop at least 1 day prior).
- •Other protocol defined exclusion criteria could apply
研究组 & 干预措施
M3541 50 mg + RT
Participants received 50 milligrams (mg) M3541 orally once per fraction day (FD) in combination with palliative radiotherapy (RT) administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10, for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays).
干预措施: M3541 (Drug)
M3541 50 mg + RT
Participants received 50 milligrams (mg) M3541 orally once per fraction day (FD) in combination with palliative radiotherapy (RT) administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10, for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays).
干预措施: Palliative Radiotherapy (RT) (Radiation)
M3541 100 mg + RT
Participants received 100 mg M3541 orally once per FD in combination with palliative RT administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10 for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays).
干预措施: M3541 (Drug)
M3541 100 mg + RT
Participants received 100 mg M3541 orally once per FD in combination with palliative RT administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10 for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays).
干预措施: Palliative Radiotherapy (RT) (Radiation)
M3541 200 mg + RT
Participants received 200 mg M3541 orally once per FD in combination with palliative RT administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10 for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays).
干预措施: M3541 (Drug)
M3541 200 mg + RT
Participants received 200 mg M3541 orally once per FD in combination with palliative RT administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10 for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays).
干预措施: Palliative Radiotherapy (RT) (Radiation)
M3541 300 mg + RT
Participants received 300 mg M3541 orally once per FD in combination with palliative RT administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10 for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays).
干预措施: M3541 (Drug)
M3541 300 mg + RT
Participants received 300 mg M3541 orally once per FD in combination with palliative RT administered in fraction of 30 Gray (Gy) given in 10 fractions of 3 Gy/FD on FD 1 to FD 10 for 2 consecutive calendar weeks (ie, Monday through Friday, with the intervening Saturday and Sunday as M3541 / RT holidays).
干预措施: Palliative Radiotherapy (RT) (Radiation)
结局指标
主要结局
M3541 50 mg + 100 mg + 200 mg + RT: Number of Participants With Dose Limiting Toxicities (DLTs)
时间窗: Baseline up to 5 weeks (including 2 weeks of treatment and 3 weeks of follow-up period)
DLT is classified per the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and defined as any of the following events occurring after first dose of study intervention and judged not to be related to underlying disease or any previous or concomitant medication. Grade (Gr) \>=3 non-hematologic toxicity with exception of Nausea, vomiting and diarrhea lasting =\<3 days in once per FD; Worsening of preexisting tumor pain associated with tumor lesions for which participant was irradiated in context of this study; Evidence of treatment-related hepatocellular injury for \>3 days in the once per FD; Any occurrence of Hy's law; Gr 4 neutropenia lasting for \>5 days, Gr 4 thrombocytopenia or Gr 4 anemia that was unexplained by underlying disease; Any toxicity related to study treatment that caused participant to interrupt treatment for not to be able to be treated within 24 hours of the scheduled treatment time.
M3541 300 mg + RT: Number of Participants With Dose Limiting Toxicities (DLTs)
时间窗: Baseline up to 4 weeks (including 2 weeks of treatment and 2 weeks of the follow-up period)
DLT is classified per the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and defined as any of the following events occurring after first dose of study intervention and judged not to be related to underlying disease or any previous or concomitant medication. Grade (Gr) \>=3 non-hematologic toxicity with exception of Nausea, vomiting and diarrhea lasting =\<3 days in once per FD; Worsening of preexisting tumor pain associated with tumor lesions for which participant was irradiated in context of this study; Evidence of treatment-related hepatocellular injury for \>3 days in the once per FD; Any occurrence of Hy's law; Gr 4 neutropenia lasting for \>5 days, Gr 4 thrombocytopenia or Gr 4 anemia that was unexplained by underlying disease; Any toxicity related to study treatment that caused participant to interrupt treatment for not to be able to be treated within 24 hours of the scheduled treatment time.
次要结局
- Dose Normalized Area Under Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]/Dose) of M3541(Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10)
- Oral Clearance (CL/F) of M3541(Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10)
- Accumulation Ratio for Maximum Observed Plasma Concentration (Racc[Cmax])(Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10)
- Number of Participants With Abnormalities in Vital Signs(Baseline up to 379 days)
- Number of Participants With Abnormalities in Physical Examination Reported as Adverse Events (AEs)(Baseline up to 379 days)
- Apparent Terminal Half-Life (t1/2) of M3541(Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10)
- Area Under Plasma Concentration-Time Curve From Time Zero to the Last Quantifiable Sampling Time Point (AUC[0-last]) of M3541(Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10)
- Dose Normalized Area Under the Concentration-Time Curve From Time Zero to the Last Quantifiable Sampling Time Point (AUC[0-last]/Dose) of M3541(Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10)
- Number of Participants With Abnormal Change From Baseline in Electrocardiogram (ECG)(Baseline up to 15 days)
- Progression-Free Survival (PFS) Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator(From first dose of study drug to disease progression or death from any cause, assessed up to 964 days)
- Maximum Observed Plasma Concentration (Cmax) of M3541(Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10)
- Number of Participants With Grade 3 or Higher Laboratory Abnormalities Based on National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE)(Baseline up to Day 44)
- Number of Participants With Best Overall Response (BOR) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1(Time from randomization to 964 days)
- Dose Normalized Maximum Observed Plasma Concentration (Cmax/Dose) of M3541(Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10)
- Time to Reach Maximum Observed Plasma Concentration (Tmax) of M3541(Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10)
- Area Under the Concentration-Time Curve From Time Zero to 6 Hour Postdose (AUC[0-6h]) of M3541(Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10)
- Area Under Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC[0-inf]) of M3541(Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10)
- Oral Clearance at Steady-State (CLss/F) of M3541(Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10)
- Apparent Volume of Distribution During Terminal Phase (Vz/F) of M3541(Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10)
- Average Plasma Concentration (Cavg) of M3541(Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10)
- Number of Participants With Treatment Emergent Adverse Events (TEAEs), Grade >=3 Adverse Events (AEs), Serious TEAEs and Deaths According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 4.03 (CTCAE V4.03)(Baseline up to 749 days)
- Apparent Volume of Distribution at Steady-State (Vss/F) of M3541(Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10)
- Accumulation Ratio for Area Under Plasma Concentration-Time Curve From Time Zero to 6 Hour (Racc[AUC0-6]) of M3541(Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10)
- Pre-dose Plasma Concentration (Ctrough) of M3541(Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10)
- Minimum Observed Plasma Concentration (Cmin) of M3541(Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, 6 hours post-dose on Fraction Day 1; Pre-dose, 2.25 hours post-dose on Fraction Day 2, 5, 6 and 7; Pre-dose, 0.5, 1, 1.5, 2.25, 3, 4, and 6 hours post-dose on Fraction Day 10)