Phase I/Ib Trial of ATR Inhibitor BAY 1895344 in Combination With FOLFIRI in GI Malignancies With a Focus on Metastatic Colorectal and Gastric/Gastroesophageal Cancers
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 10
- 试验地点
- 17
- 主要终点
- Maximum tolerated dose (MTD) of elimusertib (BAY 1895344) in combination with irinotecan, fluorouracil, and leucovorin (FOLFIRI)
研究概览
简要总结
This phase I trial investigates the best dose, possible benefits and/or side effects of BAY 1895344 in combination with FOLFIRI in treating patients with stomach or intestinal cancer that that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced) or has spread from where it first started (primary site) to other places in the body (metastatic). BAY 1895344 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as irinotecan, fluorouracil, and leucovorin, (called FOLFIRI in short) work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving BAY 1895344 in combination with FOLFIRI may help shrink advanced or metastatic stomach and/or intestinal cancer.
详细描述
PRIMARY OBJECTIVE:
I. Determine the safety and maximum tolerated dose (MTD) of elimusertib (BAY 1895344) with leucovorin calcium, fluorouracil, and irinotecan hydrochloride (FOLFIRI).
SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity by overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).
II. Determine the response and clinical benefit rate (complete response + partial response + stable disease) of BAY 1895344 with FOLFIRI in colorectal and gastric/gastroesophageal cancers.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 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
- •For Dose Escalation: Patients must have histologically or cytologically confirmed advanced or metastatic gastrointestinal (GI) cancers with Response Evaluation Criteria in Solid Tumors 1.1 (RECIST1.1) measurable disease who have progressed on at least one prior treatment for metastatic disease and for whom FOLFIRI is considered a reasonable treatment option. Patients with mismatch repair deficiency should have progressed on immunotherapy
- •For Dose Expansion: Patients must have either:
- •Colorectal cancer who have previously progressed on irinotecan and tolerated an irinotecan dose equal to or greater than the recommended phase 2 dose (RP2D). If they have mismatch repair deficiency they should have progressed on immunotherapy OR
- •Gastroesophageal cancer who have progressed on at least one first-line therapy for metastatic disease. If they have mismatch repair deficiency they should have progressed on immunotherapy
- •For Dose Expansion: Patients be willing to undergo biopsies for research purposes only. The accessible tumor can be the primary or metastatic tumor site. Both research biopsies should be taken from the same tumor site
- •Patients must have progressive disease on at least first-line therapy for metastatic disease. Previous treatment with irinotecan is allowed
- •Age >= 18 years. Because no dosing or adverse event data are currently available on the use of BAY 1895344 in combination with FOLFIRI in patients <18 years of age, children are excluded from this study
- •Eastern Cooperative Oncology Group (ECOG) performance status =< 1
- •Leukocytes >= 3,000/mcL
- •Absolute neutrophil count >= 1,500/mcL
- •Platelets >= 100,000/mcL
- •Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)
- •Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN
- •Glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation
- •International normalization ratio (INR) =< 1.5 × ULN unless participant is receiving anticoagulant therapy, in which case prothrombin time (PT) or activated partial thromboplastin time (aPTT) should be within expected therapeutic range of anticoagulants. If patient has a new diagnosis of venous thromboembolism (VTE), then patient should be appropriately anticoagulated with low molecular weight heparin (LMWH) or direct acting oral anticoagulants (DOACs) and be clinically stable for at least 1 week post treatment onset
- •Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy, that does not interact with study therapy, with undetectable viral load within 6 months are eligible for this trial
- •For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy that does not interact with study therapy, if indicated
- •Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load and HCV therapy does not interact with study therapy
- •Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression
- •Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
- •Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
- •The effects of BAY 1895344 on the developing human fetus are unknown. For this reason and because DNA-damage response inhibitors agents as well as other therapeutic agents used in this trial, 5-FU and irinotecan, are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and for 6 months after completion of BAY 1895344 administration
- •Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of study treatment administration
- •Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally-authorized representative (LAR) and/or family member available will also be eligible
排除标准
- •Patients with a history of prior treatment with an ATR inhibitor
- •Patients with a history of other malignancy that could affect compliance with the protocol or interpretation of the results
- •Patients who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
- •Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia
- •Patients who are receiving any other investigational agents
- •History of hypersensitivity or allergic reactions attributed to compounds of similar chemical or biologic composition to BAY 1895344, 5-FU, leucovorin, or irinotecan. Patient eligibility can be discussed with the primary investigator (PI) if prior reactions do not seem to warrant excluding the patient
- •Patients receiving any medications that are substrates of CYP3A4 with a narrow therapeutic window or strong inhibitors/inducers of CYP3A4 are ineligible, if they cannot be transferred to alternative medication. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
- •Patients with uncontrolled intercurrent illness
- •Patients with psychiatric illness/social situations that would limit compliance with study requirements
- •Gastrointestinal pathology or history that adversely impact the ability to take or absorb oral medication
- •Pregnant women are excluded from this study because BAY 1895344 as a DNA-damage response inhibitor may have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with BAY 1895344 breastfeeding should be discontinued if the mother is treated with BAY 1895344 and for 4 months after end of treatment. These potential risks may also apply to other agents used in this study
- •Patients who were unable to tolerate prior irinotecan treatment are excluded from this study
- •Patients with a corrected QT (QTc) interval >= 470 msec are excluded from this study
研究组 & 干预措施
Treatment (elimusertib, FOLFIRI)
Patients receive elimusertib PO QD on days 2, 3, 16, and 17 and irinotecan hydrochloride IV over 90 minutes, fluorouracil IV over 46 hours, and leucovorin calcium IV on days 1 and 15. Cycles repeat every 28 day in the absence of disease progression or unacceptable toxicity. Patients undergo tumor biopsy during screening and on study and blood sample collection and imaging throughout the study.
干预措施: Biopsy Procedure (Procedure)
Treatment (elimusertib, FOLFIRI)
Patients receive elimusertib PO QD on days 2, 3, 16, and 17 and irinotecan hydrochloride IV over 90 minutes, fluorouracil IV over 46 hours, and leucovorin calcium IV on days 1 and 15. Cycles repeat every 28 day in the absence of disease progression or unacceptable toxicity. Patients undergo tumor biopsy during screening and on study and blood sample collection and imaging throughout the study.
干预措施: Diagnostic Imaging Testing (Procedure)
Treatment (elimusertib, FOLFIRI)
Patients receive elimusertib PO QD on days 2, 3, 16, and 17 and irinotecan hydrochloride IV over 90 minutes, fluorouracil IV over 46 hours, and leucovorin calcium IV on days 1 and 15. Cycles repeat every 28 day in the absence of disease progression or unacceptable toxicity. Patients undergo tumor biopsy during screening and on study and blood sample collection and imaging throughout the study.
干预措施: Leucovorin Calcium (Drug)
Treatment (elimusertib, FOLFIRI)
Patients receive elimusertib PO QD on days 2, 3, 16, and 17 and irinotecan hydrochloride IV over 90 minutes, fluorouracil IV over 46 hours, and leucovorin calcium IV on days 1 and 15. Cycles repeat every 28 day in the absence of disease progression or unacceptable toxicity. Patients undergo tumor biopsy during screening and on study and blood sample collection and imaging throughout the study.
干预措施: Biospecimen Collection (Procedure)
Treatment (elimusertib, FOLFIRI)
Patients receive elimusertib PO QD on days 2, 3, 16, and 17 and irinotecan hydrochloride IV over 90 minutes, fluorouracil IV over 46 hours, and leucovorin calcium IV on days 1 and 15. Cycles repeat every 28 day in the absence of disease progression or unacceptable toxicity. Patients undergo tumor biopsy during screening and on study and blood sample collection and imaging throughout the study.
干预措施: Fluorouracil (Drug)
Treatment (elimusertib, FOLFIRI)
Patients receive elimusertib PO QD on days 2, 3, 16, and 17 and irinotecan hydrochloride IV over 90 minutes, fluorouracil IV over 46 hours, and leucovorin calcium IV on days 1 and 15. Cycles repeat every 28 day in the absence of disease progression or unacceptable toxicity. Patients undergo tumor biopsy during screening and on study and blood sample collection and imaging throughout the study.
干预措施: Elimusertib (Drug)
Treatment (elimusertib, FOLFIRI)
Patients receive elimusertib PO QD on days 2, 3, 16, and 17 and irinotecan hydrochloride IV over 90 minutes, fluorouracil IV over 46 hours, and leucovorin calcium IV on days 1 and 15. Cycles repeat every 28 day in the absence of disease progression or unacceptable toxicity. Patients undergo tumor biopsy during screening and on study and blood sample collection and imaging throughout the study.
干预措施: Irinotecan Hydrochloride (Drug)
结局指标
主要结局
Maximum tolerated dose (MTD) of elimusertib (BAY 1895344) in combination with irinotecan, fluorouracil, and leucovorin (FOLFIRI)
时间窗: Up to 28 days
A BOIN - Bayesian Optimal intervals trial design will be used to determine the MTD.
Maximum Tolerated Dose (MTD) of Elimusertib (BAY 1895344) in Combination With Irinotecan, Fluorouracil, and Leucovorin (FOLFIRI)
时间窗: Up to 28 days
A BOIN - Bayesian Optimal intervals trial design will be used to determine the MTD.
Patients Who Experienced DLTs
时间窗: Up to 28 days
Percentage of Patients Who Experienced Dose Limiting Toxicities (DLTs) , per CTCAE v5.0
次要结局
- Overall response rate(Up to 1 year post treatment)
- Progression-free survival (PFS)(From start of treatment to time of progression or death, whichever occurs first, assessed up to 1 year)
- Overall survival (OS)(Up to 1 year post treatment)
- Peripheral blood mononuclear cell gammaH2AX and p-ATM signaling(Up to 1 year post treatment)
- Tumor multiplex immunofluorescence assay signaling(Up to 1 year post treatment)
- Area under curve (AUC) and concentration maximum (Cmax) of irinotecan and 5-FU(Up to 1 year post treatment)
- AUC and Cmax of BAY 1895344(Up to 1 year post treatment)
- ATM status(Up to 1 year post treatment)
- Cmax of Irinotecan (Lead in)(Up to 1 year post treatment)
- AUC of Irinotecan (Lead in)(Up to 1 year post treatment)
- AUC of 5FU (Lead-in)(Up to 1 year post treatment)
- Cmax of Irinotecan (Combination)(Up to 1 year post treatment)
- AUC of Irinotecan (Combination)(Up to 1 year post treatment)
- AUC of 5FU (Combination)(Up to 1 year post treatment)
- Cmax of BAY 1895344(Up to 1 year post treatment)
- AUC-6 of BAY 1895344(Up to 1 year post treatment)
- AUC of BAY 1895344(Up to 1 year post treatment)
- Overall Response Rate (ORR)(Up to 1 year post treatment)
- Clinical Benefit Rate (CBR)(Up to 1 year post treatment)
- Best Response(Up to 1 year post treatment)
- Progression-free Survival (PFS) - by Dose Level(Up to 24 months post treatment)
- 12-month Progression-free Survival (PFS) - by Dose Level(At 12 months)
- 24-month Progression-free Survival (PFS) - by Dose Level(At 24 months)
- Progression-free Survival (PFS) - Total Population(Up to 24 months post treatment)
- 12-month Progression-free Survival (PFS) - Total Population(At 12 months)
- 24-month Progression-free Survival (PFS) - Total Population(At 24 months)
- Overall Survival (OS) - by Dose Level(Up to 24 months post treatment)
- 12- Month Overall Survival (OS) - By Dose Level(At 12 months)
- 24-month Overall Survival (OS)(At 24 months)
- Overall Survival (OS) - Total Population(Up to 2 years post treatment)
- 12-month Overall Survival (OS) - Total Population(At 12 months)
- 24-month Overall Survival (OS) - Total Population(At 24 months)
- ATM Status(Up to 1 year post treatment)
- Peripheral Blood Mononuclear Cell gammaH2AX and p-ATM Signaling(Up to 1 year post treatment)
- Tumor Multiplex Immunofluorescence Assay Signaling(Up to 1 year post treatment)