NCT07824960尚未招募1 期
Neoadjuvant Avutometinib/Defactinib and mFOLFIRINOX Combination Therapy in Pancreatic Adenocarcinoma: A Phase IB/II Safety and Efficacy Study
适应症
干预措施
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 31
- 试验地点
- 1
- 主要终点
- Dose limiting toxicities (DLTs) - Part A
研究概览
简要总结
The goal of this study is to find out if taking two oral study drugs (avutometinib and defactinib) are safe for patients with pancreatic ductal adenocarcinoma (PDAC). Researchers also want to see if the drugs can slow down tumor growth and shrink tumors for possible surgery. These drugs are approved by the FDA to treat a certain kind of ovarian cancer. This study has two parts:
- Part A is for patients whose cancer has spread to other parts of the body.
- Part B is for patients whose cancer has not spread, but who cannot have surgery.
Participants will take both drugs as told by their doctor with their regular cancer medicine. Participants will also give blood samples throughout the study. These samples will help researchers learn about how participants respond to treatment and about their pancreatic cancer.
详细描述
Participants in part A will take the study drugs in 28-day cycles for up to 6 cycles with their chemotherapy. Participants whose cancer is not getting worse (known as disease control) may continue the study drugs in combination with maintenance chemotherapy until their disease worsens or negative side effects are noted.
Participants in part B will take the study drugs in 28-day cycles for up to 6 cycles with their chemotherapy. After cycle 4 and cycle 6, participants will have their disease re-assessed with consideration for surgery. Participants whose cancer is not getting worse (disease control) but are ineligible for surgery may continue the study drugs in combination with maintenance chemotherapy until their disease worsens or negative side effects are noted.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 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
- •Provision of signed and dated informed consent form.
- •Individuals ≥ 18 years of age.
- •Stated willingness to comply with all study procedures and availability for the duration of the study.
- •Ability to take oral medication and be willing to adhere to the study intervention regimen.
- •Ability to receive mFOLFIRINOX.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-
- •Adenocarcinoma of the pancreas, confirmed by histology or cytology.
- •Part A: Metastatic pancreatic cancer
- •Part B: Borderline resectable or locally advanced PDAC not eligible for primary surgical resection per institutional standards and following a multidisciplinary discussion at local tumor board
- •No prior systemic or localized treatment for PDAC.
- •Radiographically measurable disease of at least one site by computed tomography (CT) or magnetic resonance (MR) imaging, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.
- •Individuals must have adequate organ function defined by the following laboratory parameters:
- •Absolute neutrophil count (ANC): ≥ 1500/mm3 Platelets: ≥100,000/mm3 Hemoglobin: ≥9 g/dL Serum Creatinine: ≤ 1.5 x ULN or creatinine clearance rate of ≥ 50 mL/min as calculated by the Cockcroft-Gault formula Bilirubin: ≤ 1.5 x ULN (except in patients with Gilbert's disease, where bilirubin to 3x ULN is allowed).
- •AST and ALT: ≤ 2.5 x ULN or ≤ 5 x ULN for patients with liver metastasis INR: ≤ 1.5 x ULN in the absence of anticoagulation or therapeutic levels in the presence of anticoagulation Creatine phosphokinase (CPK): ≤ 2.5 x ULN
- •Baseline corrected QT interval (QTc) interval ≤ 480 millisecond (ms) (CTCAE v5.0, Grade 0-1) using Fridericia's QT correction formula.
- •Patients with a left bundle branch block (LBBB) > 480 ms will need their QTc calculated by Bazett (QTc = QT(measured) - 0.5 × QRS(LBBB)).
排除标准
- •Patients with pancreatic neuroendocrine tumors (PNET), islet cell tumors, mucinous cystic, acinar or squamous (≥ 50%) histology are excluded.
- •Prior treatment for pancreatic ductal adenocarcinoma.
- •Presence of distant metastases (Part B only).
- •Presence of symptomatic ascites or the need for paracentesis within 2 weeks prior to registration.
- •Major surgery within 4 weeks (excluding placement of vascular access) of registration.
- •Patients with a prior or concurrent malignancy within past 5 years whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen. Examples of malignancies that may be permitted include non-melanoma skin cancer, localized prostate cancer treated with curative intent or under active surveillance, localized thyroid cancer (papillary or follicular), non-muscle invasive low-grade bladder cancer, resected gastrointestinal stromal tumor, stage I testicular cancer post orchiectomy, WHO (World Health Organization) grade 1 meningioma.
- •Prior treatment with either inhibitors of the RAS/MAPK pathway [e.g., MEK inhibitors] or inhibitors of FAK within the last 6 months.
- •Patients on treatment with warfarin within 5 days of registration. Patients on warfarin for deep vein thrombosis or pulmonary embolism can be converted to low-molecular-weight heparin or direct oral anticoagulants (DOACs).
- •Participants requiring medications or supplements with potential for drug-drug interactions, specifically strong CYP3A4 or CYP2C9 inhibitors or inducers (Table 7). Participants must be off these medications for 7 days prior to the first dose of study intervention(s). These substances should also be avoided during the course of therapy.
- •Patients with known UGT1A1 deficiency based on genetic analysis of the UGT1A1 gene.
- •Receipt of live vaccines (not limited to the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG) within 30 days of registration. Seasonal influenza vaccines for injection are generally killed virus vaccines and are permitted. However, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not permitted.
- •Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy.
- •Active Human Immunodeficiency Virus (HIV) infection, unless patient is on effective anti-retroviral therapy and was shown to have a negative viral load within 6 months of registration.
- •Active Hepatitis B Virus (HBV) or Hepatitis C (HCV) infection, unless patient is on antiviral therapy and was shown to have a negative viral load test within 6 months of registration.
- •Active skin disorder that requires current systemic therapy.
- •Concurrent ocular disorders:
- •Patients with history of glaucoma or history of retinal vein occlusion (RVO).
- •Patients with history of retinal pathology or evidence of visible retinal pathology that is considered a risk factor for RVO.
- •Patients with active or chronic, visually significant corneal disorders, other active ocular conditions requiring ongoing therapy that prevent adequate monitoring of drug-induced keratopathy. Examples of visually significant corneal disorders include corneal degeneration, active or recurrent keratitis, and other forms of serious ocular surface inflammatory conditions. Visually significant corneal disorders do NOT include dry eyes, blepharitis, and uncomplicated corneal erosions.
- •Patients with history of interstitial lung disease (ILD) or pulmonary fibrosis.
- •Patients with history of severe obstructive pulmonary disease on long-term, home oxygen.
- •Patients with congestive heart failure III/ IV cardiac disease (New York Heart Association [NYHA]), myocardial infarction within the last 6 months, unstable arrhythmias or unstable angina.
- •Patients receiving immunosuppressive or myelosuppressive medications that, in the opinion of the investigator, would increase the risk of serious neutropenic complications. Subjects receiving replacement therapy of ≤10 mg of prednisone (or the equivalent hydrocortisone dose) per day are eligible.
- •History of prior allogeneic stem cell or solid organ transplantation.
- •Patients with impaired gastrointestinal absorption due to gastrectomy or active inflammatory bowel disease.
- •Patients with pre-existing peripheral neuropathy of CTCAE Grade ≥2 (severe symptoms limiting self-care ADL (activity of daily living)).
- •Patients with a history of allergy or known hypersensitivity to any of the study treatments or any of their excipients as outlined in the respective package insert.
- •Individuals with reproductive potential who do not agree to use highly effective method of contraceptive as described in Lifestyle Considerations (sections 5.4.2 and 5.4.3).
- •Patients who are pregnant or breastfeeding.
- •Treatment with another investigational drug during the study participation.
- •Any other medical condition, related to the underlying disease (e.g., cardiac, gastrointestinal, pulmonary, psychiatric, neurological) that in the opinion of the investigator would place the patient at unacceptably high risk for toxicity.
研究组 & 干预措施
Neoadjuvant avutometinib + defactinib with standard of care chemotherapy
Experimental
Avutometinib and defactinib will be taken for 3 weeks, followed by a 1-week rest period in each 4 week cycle.
干预措施: Avutometinib (VS-6766) + Defactinib (VS-6063) (Drug)
结局指标
主要结局
Dose limiting toxicities (DLTs) - Part A
时间窗: 1 cycle (28 days)
For each participant, we will determine DLTs during first cycle of neoadjuvant therapy
Objective response (OR) - Part B
时间窗: through 6 cycles (each cycle is 28 days)
PR (partial response) or CR (complete response) per RECIST criteria
次要结局
- TRAEs (Treatment-related adverse events)(Up to 30 days after completion of study treatment (average of 6 months))
- (Part B only): Surgical resection rate(after all participants complete up to 6 cycles (each cycle is 28 days))
- EFS (event free-survival)(through study completion (an average of a year))
研究者
Matthew Reilley
Associate Professor; Principal Investigator
University of Virginia
研究点 (1)
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