A First-in-human Study to Evaluate the Safety, Tolerability and Pharmacokinetics, Pharmacodynamics and Preliminary Clinical Activity of BAY 3713372, a Novel 2nd Generation PRMT5 Inhibitor, in Participants With MTAP-deleted Solid Tumors.
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 450
- 试验地点
- 111
- 主要终点
- Dose Escalation (Master and Intervention Cohort 1): Number of participants with treatment-emergent adverse events (TEAEs)
研究概览
简要总结
The study treatment, BAY 3713372, is under development to treat MTAP (methylthioadenosine phosphorylase)-deleted solid tumors. It is thought to work by blocking the protein arginine N-methyltransferase 5 (PRMT5). This may kill the MTAP-deleted cancer cells while sparing the normal cells.
The main objective of this first-in-human study is to learn how safe BAY 3713372 is, how the body processes it, and how well it works in people with MTAP-deleted solid tumors.
For this, the researchers will study and analyze:
- the number of participants who have adverse events (AEs) after receiving different doses of BAY 3713372 and the AE's severity.
- the number of participants who experience dose-limiting toxicities (DLTs) after receiving different doses of BAY 3713372, the DLT's severity and how often they happened. A DLT is a pre-defined medical problem caused by a specific dose of a drug that is too severe to continue using that dose.
- the total amount of BAY 3713372 in participants' blood (also called AUC) over time after single and multiple doses.
- the highest level of BAY 3713372 in participants' blood (also called Cmax) after single and multiple doses.
Other than the main objective, researchers will also check for the number of participants who show a response to treatment and how long they live without the cancer getting worse.
The study participants will take part in one of the eight distinct groups or "intervention cohorts" of the study. The study will start with a dose escalation phase where distinct groups of participants will receive different doses of BAY 3713372 alone to find the dose that is deemed safe and works best for the participants. When this dose has been found, a larger number of participants will receive BAY 3713372 alone or with other treatments in a dose expansion phase.
Participants may take the study treatment as long as they benefit from the treatment without any severe medical problems.
Participants will visit the study site:
- at least twice before the treatment starts
- multiple times when they start taking the treatment
- once after 30 days of receiving the last dose and every 9 weeks after that until the cancer worsens, or the participant stops for any other reason
During the study, the doctors and their study team will:
- check participants' health by performing tests such as blood and urine tests, and checking heart health using an electrocardiogram
- check if the participants' cancer has grown and/or spread using computed tomography (CT) or magnetic resonance imaging (MRI) and, if needed, bone scan
- take tumor samples
The study doctors and their team will contact the participants every 3 months until 2 years after the last participant's last dose or the end of the study to learn about the participant's health.
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
- •Participant must be ≥ 18 years old of age, or the legal age of consent in the jurisdiction of the country in which the study takes place, at the time of signing the informed consent.
- •At least one measurable lesion that would qualify as target lesion by Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1).
- •Homozygous MTAP-deletion identified through molecular testing from a locally certified laboratory.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
排除标准
- •Previous additional cancer other than the one evaluated in this study within the past 2 years except for basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, superficial bladder tumors, localized prostate cancer or other tumors that in the opinion of the investigator, are considered cured or not immediately life-threatening, and will not interfere with the scientific goals of this study.
- •A marked prolongation of QT/QTc interval at screening (e.g., repeated demonstration of a QTc interval >450 ms). Participants with permanent pacemakers (i.e., a paced rhythm) may be eligible based on the investigator's clinical assessment and discretion.
- •Cardiac history comprising:
- •History of congestive heart failure Class >II according to the New York Heart Association Functional Classification.
- •Myocardial infarction less than 6 months before the start of study intervention.
- •Serious cardiac arrhythmias requiring treatment or any clinically important abnormalities in rhythm, conduction or morphology on resting ECG with the exception of atrial fibrillation which is well-controlled and requires only digoxin or beta blockers.
- •Unstable angina within 4 weeks before start of study intervention.
研究组 & 干预措施
Dose Escalation (Intervention Cohort 1)
For the escalation part, different dose levels of BAY 3713372 administered as monotherapy are planned.
干预措施: BAY 3713372 (Drug)
Backfill cohorts in Intervention Cohort 1 (Dose Escalation)
Backfill cohorts may be initiated concurrently with dose escalation cohorts to generate additional safety, pharmacokinetic, and pharmacodynamic data to facilitate the selection of the optimal doses for use in further development.
干预措施: BAY 3713372 (Drug)
Dose Expansion (Intervention Cohort 1)
Dose expansion with BAY 3713372 monotherapy in selected participants with MTAP-deleted solid tumors.
干预措施: BAY 3713372 (Drug)
Dose Expansion (Intervention Cohort 2)
Dose expansion with BAY 3713372 monotherapy in participants with MTAP-deleted non-small cell lung cancer (NSCLC).
干预措施: BAY 3713372 (Drug)
Dose Expansion (Intervention Cohort 5)
Dose expansion with BAY 3713372 monotherapy in participants with MTAP-deleted pancreatic ductal adenocarcinoma (PDAC).
干预措施: BAY 3713372 (Drug)
Dose Expansion (Intervention Cohort 3)
Dose expansion with BAY 3713372 in combination with other treatments in participants with MTAP-deleted NSCLC.
干预措施: BAY 3713372 (Drug)
Dose Expansion (Intervention Cohort 6)
Dose expansion with BAY 3713372 in combination with other treatments in participants with MTAP-deleted PDAC.
干预措施: BAY 3713372 (Drug)
Dose Expansion (Intervention Cohort 4)
Dose expansion with BAY 3713372 in combination with other treatments in participants with MTAP-deleted NSCLC.
干预措施: BAY 3713372 (Drug)
Window-of-opportunity trial in participants with MTAP-deleted GBM (Intervention Cohort 7)
A surgical window-of-opportunity trial of BAY 3713372 alone in participants with MTAP-deleted glioblastoma (GBM).
干预措施: BAY 3713372 (Drug)
结局指标
主要结局
Dose Escalation (Master and Intervention Cohort 1): Number of participants with treatment-emergent adverse events (TEAEs)
时间窗: From the first administration of study intervention up to 30 days after the last dose of study intervention
TEAEs will be graded according to NCI-CTCAE v.5.0 and will be reported using the latest version of MedDRA coding dictionary
Dose Escalation (Master and Intervention Cohort 1): Number of participants with treatment-emergent serious adverse events (TESAEs)
时间窗: From the first administration of study intervention up to 30 days after the last dose of study intervention
TESAEs will be graded according to NCI-CTCAE v.5.0 and will be reported using the latest version of MedDRA coding dictionary
Dose Escalation (Master and Intervention Cohort 1): Severity of treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs)
时间窗: From the first administration of study intervention up to 30 days after the last dose of study intervention
TEAEs and TESAEs will be graded according to NCI-CTCAE v.5.0 and will be reported using the latest version of MedDRA coding dictionary
Dose Escalation (Master and Intervention Cohort 1): Incidence of dose-limiting toxicities (DLTs)
时间窗: From the first dose of study intervention to the end of Cycle 1 (each cycle is 21 days)
DLTs per participants. DLTs will be graded according to NCI-CTCAE v.5.0
Dose Escalation (Master and Intervention Cohort 1): Number of participants with DLTs
时间窗: From the first dose of study intervention to the end of Cycle 1 (each cycle is 21 days)
Number of participants with at least one DLT
Dose Escalation (Master and Intervention Cohort 1): Maximum concentration (Cmax) of the respective dosing interval of BAY 3713372
时间窗: From the first dose of study intervention up to Cycle 2 Day 1 (each cycle is 21 days)
Dose Escalation (Master and Intervention Cohort 1): Area under the curve (AUC) of the respective dosing interval of BAY 3713372
时间窗: From the first dose of study intervention up to Cycle 2 Day 1 (each cycle is 21 days)
Dose Expansion (Master, Intervention Cohorts 1 - 6): Objective response rate (ORR)
时间窗: Approximately 1.5 years
Determined by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)
Dose Expansion (Intervention Cohorts 3, 4 and 6): Number of participants with DLTs
时间窗: From the first dose of study intervention to the end of Cycle 1 (each cycle is 21 days, except for Intervention Cohort 6, which has a cycle length of 28 days)
Number of participants with at least one DLT
Intervention Cohort 7: Tumor tissue SDMA levels
时间窗: From first dose through day of surgery (approximately 7 ± 2 days)
Change in symmetric dimethylarginine (SDMA) levels in brain tumor tissue collected at definitive surgery following neoadjuvant BAY 3713372 treatment, as a pharmacodynamic marker of PRMT5 inhibition
Dose Expansion (Master, Intervention Cohorts 1 - 6): Objective response rate (ORR)
时间窗: Approximately 1.5 years
Determined by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)
Dose Escalation (Master and Intervention Cohort 1): Number of participants with treatment-emergent adverse events (TEAEs)
时间窗: From the first administration of study intervention up to 30 days after the last dose of study intervention
TEAEs will be graded according to NCI-CTCAE v.5.0 and will be reported using the latest version of MedDRA coding dictionary
Dose Escalation (Master and Intervention Cohort 1): Number of participants with treatment-emergent serious adverse events (TESAEs)
时间窗: From the first administration of study intervention up to 30 days after the last dose of study intervention
TESAEs will be graded according to NCI-CTCAE v.5.0 and will be reported using the latest version of MedDRA coding dictionary
Dose Escalation (Master and Intervention Cohort 1): Severity of treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs)
时间窗: From the first administration of study intervention up to 30 days after the last dose of study intervention
TEAEs and TESAEs will be graded according to NCI-CTCAE v.5.0 and will be reported using the latest version of MedDRA coding dictionary
Dose Escalation (Master and Intervention Cohort 1): Incidence of dose-limiting toxicities (DLTs)
时间窗: From the first dose of study intervention to the end of Cycle 1 (each cycle is 21 days)
DLTs per participants. DLTs will be graded according to NCI-CTCAE v.5.0
Dose Escalation (Master and Intervention Cohort 1): Number of participants with DLTs
时间窗: From the first dose of study intervention to the end of Cycle 1 (each cycle is 21 days)
Number of participants with at least one DLT
Dose Escalation (Master and Intervention Cohort 1): Maximum concentration (Cmax) of the respective dosing interval of BAY 3713372
时间窗: From the first dose of study intervention up to Cycle 2 Day 1 (each cycle is 21 days)
Dose Escalation (Master and Intervention Cohort 1): Area under the curve (AUC) of the respective dosing interval of BAY 3713372
时间窗: From the first dose of study intervention up to Cycle 2 Day 1 (each cycle is 21 days)
Dose Expansion (Intervention Cohorts 3, 4 and 6): Number of participants with DLTs
时间窗: From the first dose of study intervention to the end of Cycle 1 (each cycle is 21 days, except for Intervention Cohort 6, which has a cycle length of 28 days)
Number of participants with at least one DLT
次要结局
- Dose Escalation (Master and Intervention Cohort 1): Objective response rate (ORR)(Approximately 1.5 years)
- Dose Escalation (Master and Intervention Cohort 1): Duration of response (DOR)(Approximately 3 years)
- Dose Escalation (Master and Intervention Cohort 1): Progression-free survival (PFS)(Approximately 3 years)
- Dose Escalation (Master and Intervention Cohort 1): Time to response (TTR)(Approximately 1.5 years)
- Dose Expansion (Master, Intervention Cohorts 1 - 6): Number of participants with treatment-emergent adverse events (TEAEs)(From the first administration of study intervention up to 30 days after the last dose of study intervention)
- Dose Expansion (Master, Intervention Cohorts 1 - 6): Progression-free survival (PFS)(Approximately 3 years)
- Dose Expansion (Master, Intervention Cohorts 1 - 6): Time to response (TTR)(Approximately 1.5 years)
- Dose Expansion (Master, Intervention Cohorts 1 - 4, and 6): Area under the curve (AUC) of the respective dosing interval of BAY 3713372(From the first dose of study intervention up to Cycle 2 Day 1 (each cycle is 21 days, except for Intervention Cohort 6, which has a cycle length of 28 days))
- Dose Escalation (Master and Intervention Cohort 1): Objective response rate (ORR)(Approximately 1.5 years)
- Dose Escalation (Master and Intervention Cohort 1): Duration of response (DOR)(Approximately 3 years)
- Dose Escalation (Master and Intervention Cohort 1): Progression-free survival (PFS)(Approximately 3 years)
- Dose Escalation (Master and Intervention Cohort 1): Time to response (TTR)(Approximately 1.5 years)
- Dose Expansion (Master, Intervention Cohorts 1 - 6): Number of participants with treatment-emergent adverse events (TEAEs)(From the first administration of study intervention up to 30 days after the last dose of study intervention)
- Dose Expansion (Master, Intervention Cohorts 1 - 6): Number of participants with treatment-emergent serious adverse events (TESAEs)(From the first administration of study intervention up to 30 days after the last dose of study intervention)
- Dose Expansion (Master, Intervention Cohorts 1 - 6): Severity of treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs)(From the first administration of study intervention up to 30 days after the last dose of study intervention)
- Dose Expansion (Master, Intervention Cohorts 1, 3, 4, and 6): Incidence of dose-limiting toxicities (DLTs)(From the first dose of study intervention to the end of Cycle 1 (each cycle is 21 days, except for Intervention Cohort 6, which has a cycle length of 28 days))
- Dose Expansion (Master, Intervention Cohorts 1 - 6): Duration of response (DOR)(Approximately 3 years)
- Dose Expansion (Master, Intervention Cohorts 1 - 6): Progression-free survival (PFS)(Approximately 3 years)
- Dose Expansion (Master, Intervention Cohorts 1 - 6): Time to response (TTR)(Approximately 1.5 years)
- Dose Expansion (Master, Intervention Cohorts 1 - 4, and 6): Maximum concentration (Cmax) of the respective dosing interval of BAY 3713372(From the first dose of study intervention up to Cycle 2 Day 1 (each cycle is 21 days, except for Intervention Cohort 6, which has a cycle length of 28 days))
- Dose Expansion (Master, Intervention Cohorts 1 - 4, and 6): Area under the curve (AUC) of the respective dosing interval of BAY 3713372(From the first dose of study intervention up to Cycle 2 Day 1 (each cycle is 21 days, except for Intervention Cohort 6, which has a cycle length of 28 days))