A Phase I/II Trial of Lurbinectedin With Berzosertib, an ATR Kinase Inhibitor in Small Cell Cancers and High Grade Neuroendocrine Cancers
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 37
- 试验地点
- 1
- 主要终点
- MTD
研究概览
简要总结
Background:
Small cell lung cancer (SCLC) and high-grade neuroendocrine cancers (HGNEC) are aggressive neuroendocrine cancers. At first, SCLC and HGNEC respond to chemotherapy. But then they relapse quickly and become resistant to treatment. Researchers want to see if a combination of drugs can help.
Objective:
To see if the combination of lurbinectedin and berzosertib may be effective to shrink SCLC and HGNEC tumors, and to find the best dose of the combination.
Eligibility:
Adults ages 18 and older with a solid tumor, SCLC, or HGNEC.
Design:
Participants will get lurbinectedin by intravenous (IV) catheter on Day 1 of each cycle (1 cycle = 21 days). They will get berzosertib by IV on Days 1 and 2 of each cycle.
Participants will continue to receive treatment as long as they are benefiting from treatment.
Participants will have physical exams and blood tests. Their symptoms, medicines, and ability to perform their normal activities will be reviewed.
Participants will have electrocardiograms to test heart function. Sticky pads will be placed on their chest, arms, and legs.
Participants will give blood and hair samples for research. They may have optional tumor biopsies.
Participants will have computed tomography (CT) scans to see if the treatment is effective.
Participants will have a follow-up visit 1 month after treatment ends. Then they will be followed by email or phone for the rest of their life.
详细描述
Background:
Small cell lung cancer (SCLC) and high-grade neuroendocrine cancers (HGNEC) are aggressive neuroendocrine cancers with poor prognosis. Although responsive to chemotherapy initially, both tumor types relapse quickly and become refractory to treatment within a few months.
Replication stress is an SCLC hallmark, driven by oncogenes that drive rapid and unscheduled proliferation (TP53 and RB1 inactivation, MYC amplification, etc.). HGNECs share similarities in morphology, biologic behavior with SCLC. Treatment paradigms have largely paralleled those established for SCLC.
ATR is the master regulator of replication stress response. Upon activation, the ATR CHK1 signaling leads to cell cycle arrest and promotes replication fork stabilization and restart.
ATR inhibition generates replication stress and disables cell cycle checkpoints to ultimately cause mitotic catastrophe and cell death. Many genotoxic agents currently used in cancer therapy are also potent inducers of replication stress.
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
- •INCLUSION CRITERIA:
- •Both Phase I and Phase II:
- •>= 18 years of age.
- •ECOG performance status <= 2
- •Measurable disease, per RECIST 1.
- •Individuals with evaluable, but not measurable disease will be eligible for Phase I.
- •Adequate organ functions
- •Hemoglobin >= 9.0 g/dL
- •Absolute neutrophil count >= 1.5x10^9/L
- •Platelets >= 100x10^9/L
- •Total Bilirubin <= 2.0 mg/dL
- •Transaminases <= 2 x ULN or if liver metastases were present, <= 3 x ULN
- •Creatinine <= 1.5 mg/dL or creatinine clearance by Cockcroft-Gault formula >= 60 mL/min
- •Ability to understand and the willingness to sign a written informed consent document.
- •Individuals of child-bearing potential (IOCBP) and individuals able to father a child must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, during study participation and for 6 months after the last dose of berzosertib/lurbinectedin for IOCBP and for 4 months after lurbinectedin or 3 months after berzosertib for individuals able to father children.
- •Histologically confirmed advanced solid cancers will be eligible.
- •At least one prior chemotherapy
- •- Histological confirmation of SCLC or HGNEC. Although NCI confirmation of pathology is not required prior to starting treatment, every effort will be made to obtain outside pathology to be reviewed by an NCI pathologist.
排除标准
- •Individuals with tumor amenable to potentially curative therapy.
- •Currently receiving any other investigational agents.
- •Received chemotherapy, or undergone major surgery within the prior 2 weeks and radiotherapy within the last 24 hours.
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to (study agent) or other agents used in study.
- •Symptomatic brain metastases will be excluded from trial secondary to poor prognosis. However, individuals who have had treatment for their brain metastasis and whose brain disease is stable without steroid therapy for 1 week or on physiologic doses of steroids may be enrolled.
- •Requirement for any medications or substances that are strong inhibitors or inducers of CYP3A during the course of the study are ineligible.
- •Evidence of severe or uncontrolled systemic disease, or any concurrent condition, which could compromise participation in the study, including, but not limited to, active or uncontrolled infection, immune deficiencies, Hepatitis B, Hepatitis C, uncontrolled diabetes, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmia, stroke/cerebrovascular accident within the past 6 months, or psychiatric illness/social situations which would jeopardize compliance with the protocol.
- •HIV-positive on or off combination antiretroviral therapy are ineligible.
- •Pregnant individuals are excluded from this study.
研究组 & 干预措施
1/ Phase I
Dose escalation of Berzosertib + lurbinectedin
干预措施: Lurbinectedin (Drug)
1/ Phase I
Dose escalation of Berzosertib + lurbinectedin
干预措施: Berzosertib (Drug)
2/ Phase II
Berzosertib + lurbinectedin at MTD
干预措施: Lurbinectedin (Drug)
2/ Phase II
Berzosertib + lurbinectedin at MTD
干预措施: Berzosertib (Drug)
结局指标
主要结局
MTD
时间窗: Phase I
Maximum tolerated dose (MTD) of lurbinectedin in combination with berzosertib.
Clinical response rate
时间窗: Phase II
\- Fraction of participants who experience a PR or CR in each cohort reported along with a 95% confidence interval. - Overall response rate for both cohorts combined, along with a 95% confidence interval.
次要结局
- Safety and tolerability(Phase I)
- Pharmacodynamic markers of response(Phase I)
- Pharmacokinetic profile of Berzosertib and Lurbinectedin(Phase I)
- Progression-free survival (PFS)(Phase II)
- Overall survival (OS)(Phase II)
- Duration of response(Phase II)
- Safety and tolerability of the MTD(Phase II)