A Phase I Clinical Trial of Carfilzomib in Combination With Sotorasib in Patients With KRASG12C Mutated Advanced Non-Small Cell Lung Cancer
概览
- 阶段
- 1 期
- 干预措施
- Biopsy
- 疾病 / 适应症
- Advanced Lung Non-Small Cell Carcinoma
- 发起方
- City of Hope Medical Center
- 入组人数
- 15
- 试验地点
- 4
- 主要终点
- Incidence of dose limiting toxicities
- 状态
- 招募中
- 最后更新
- 29天前
概览
简要总结
This phase I trial tests the safety, side effects, and best dose of carfilzomib in combination with sotorasib in treating patients with KRAS G12C-mutated non-small cell lung cancer (NSCLC) that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced) or that has spread from where it first started (primary site) to other places in the body (metastatic). Carfilzomib is a drug that binds to and inhibits the activity of the protein complex that is responsible for degrading other damaged or unneeded proteins. The inhibition of this protein by carfilzomib can then cause tumor growth inhibition and cell death. Sotorasib is a drug that binds to and inhibits the activity of the KRAS G12C mutant. This may inhibit growth in KRAS G12C-expressing tumor cells. Combining carfilzomib and sotorasib may be a safe and effective treatment option for patients with KRAS G12C-mutated advanced or metastatic NSCLC.
详细描述
PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of the combination of carfilzomib and sotorasib in KRAS G12C mutated NSCLC following progression on KRAS inhibitor. II. Describe the safety of the combination of carfilzomib and sotorasib in KRAS G12C mutated NSCLC following progression on KRAS inhibitor. SECONDARY OBJECTIVES: I. Describe clinical responses at all dose levels, including the recommended dose level using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. II. Describe other efficacy endpoints, including progression-free survival (PFS), duration of response (DOR), and overall survival (OS) at the recommended dose level. EXPLORATORY OBJECTIVES: I. Evaluate the pharmacokinetics of the combination of carfilzomib and sotorasib. II. Explore biomarkers of response and resistance through tumor biopsies and circulating tumor deoxyribonucleic acid (ctDNA). OUTLINE: This is a dose-escalation study of carfilzomib in combination with (fixed-dose) sotorasib. Patients receive carfilzomib intravenously (IV) over 30 minutes on days 1, 2, 8, 9, 15, and 16 of each cycle and sotorasib orally (PO) once daily (QD) on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo echocardiography (ECHO) at screening and undergo computed tomography (CT) or magnetic resonance imaging (MRI) and collection of blood samples at screening and on study. Patients may undergo optional biopsies on study. After completion of study treatment, patients are followed up at 30 days.
研究者
入排标准
入选标准
- •Documented informed consent of the participant and/or legally authorized representative
- •Age: ≥ 18 years
- •Eastern Cooperative Oncology Group (ECOG) ≤ 2
- •Histologically confirmed NSCLC that is metastatic or advanced. The tumor must exhibit evidence of KRASG12C mutation which is determined by either a Clinical Laboratory Improvement Act (CLIA) certified ctDNA assay or by a CLIA certified tumor tissue assay
- •Measurable disease by RECIST v1.1
- •Failed prior KRAS inhibitor
- •Fully recovered from the acute toxic effects (except alopecia) from prior anti-cancer therapy
- •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
- •Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate central nervous system (CNS) specific treatment is not required and is unlikely to be required during the first cycle of therapy
- •Absolute neutrophil count (ANC) ≥ 1,500/mm\^3 (performed within 14 days prior to day 1 of protocol therapy)
排除标准
- •Chemotherapy or immunotherapy within 21 days prior to day 1 of protocol therapy
- •Radiation therapy within 14 days prior to day 1 of protocol therapy
- •KRAS inhibitor within 14 days prior to day 1 of protocol therapy
- •Investigational therapy within 28 days prior to day 1 of protocol therapy (or 5 half-lives, use whichever is shorter)
- •Inability to previously tolerate (240 mg, QD) sotorasib
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
- •Clinically significant uncontrolled illness
- •Evidence of chronic hepatitis B virus (HBV) infection and HBV viral load detectable
- •Evidence of untreated chronic hepatitis C virus (HCV) infection. Patients with HCV infection currently on treatment are eligible if they have an undetectable HCV viral load
- •Active infection requiring antibiotics (not to be completed by day 1 of protocol therapy)
研究组 & 干预措施
Treatment (carfilzomib, sotorasib)
Patients receive carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16 of each cycle and sotorasib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO at screening and undergo CT or MRI and collection of blood samples at screening and on study. Patients may undergo optional biopsies on study.
干预措施: Biopsy
Treatment (carfilzomib, sotorasib)
Patients receive carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16 of each cycle and sotorasib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO at screening and undergo CT or MRI and collection of blood samples at screening and on study. Patients may undergo optional biopsies on study.
干预措施: Biospecimen Collection
Treatment (carfilzomib, sotorasib)
Patients receive carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16 of each cycle and sotorasib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO at screening and undergo CT or MRI and collection of blood samples at screening and on study. Patients may undergo optional biopsies on study.
干预措施: Computed Tomography
Treatment (carfilzomib, sotorasib)
Patients receive carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16 of each cycle and sotorasib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO at screening and undergo CT or MRI and collection of blood samples at screening and on study. Patients may undergo optional biopsies on study.
干预措施: Echocardiography
Treatment (carfilzomib, sotorasib)
Patients receive carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16 of each cycle and sotorasib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO at screening and undergo CT or MRI and collection of blood samples at screening and on study. Patients may undergo optional biopsies on study.
干预措施: Magnetic Resonance Imaging
Treatment (carfilzomib, sotorasib)
Patients receive carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16 of each cycle and sotorasib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO at screening and undergo CT or MRI and collection of blood samples at screening and on study. Patients may undergo optional biopsies on study.
干预措施: Carfilzomib
Treatment (carfilzomib, sotorasib)
Patients receive carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16 of each cycle and sotorasib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO at screening and undergo CT or MRI and collection of blood samples at screening and on study. Patients may undergo optional biopsies on study.
干预措施: Sotorasib
结局指标
主要结局
Incidence of dose limiting toxicities
时间窗: During cycle 1 (each cycle is 28 days)
The incidence of dose-limiting toxicities during cycle 1 will be used to determine the maximum tolerated dose and the recommended phase II dose of the comibination of carfilzomib and sotorasib. Will be described and graded at all dose levels using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0.
Incidence of grade 3 and 4 treatment-related toxicities
时间窗: Up to 30 days after completion of study treatment
Grade 3 and 4 adverse events will be described and graded at all dose levels using the NCI CTCAE v5.0.
次要结局
- Objective response rate(From the start of treatment until disease progression/recurrence, assessed up to 30 days after completion of study treatment)
- Duration of response(From treatment response to progression or death, assessed up to 30 days after completion of study treatment)
- Progression-free survival(From day 1 of treatment until the criteria for disease progression is met or until death, assessed up to 30 days after completion of study treatment)
- Overall survival(From the date of study enrollment to the date of death, assessed up to 30 days after completion of study treatment)