DINOMITE (Decreasing Hypoxia With Mitochondrial Inhibition in Locally Advanced Rectal Cancer): Phase 1 Trial of Papaverine in Combination With Radiation
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 36
- 试验地点
- 1
- 主要终点
- Acute dose limiting toxicity (DLT)
研究概览
简要总结
This phase I trial studies the side effects and best dose of papaverine (PPV) when given together with radiation therapy (RT) and tests how well it works in treating patients with rectal cancer that has spread to nearby tissue or lymph nodes (locally advanced). PPV is an enzyme inhibitor, and it may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. RT uses high energy x-rays, particles, or radioactive seeds to kill tumor cells and shrink tumors. Giving PPV with RT may be safe, tolerable, and/or effective in treating patients with locally advanced rectal cancer.
详细描述
PRIMARY OBJECTIVES:
I. Determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of papaverine (PPV) in combination with radiation therapy (RT) for locally advanced rectal cancer (LARC).
II. Describe the safety and tolerability of PPV in combination with standard of care (SOC) RT for LARC.
SECONDARY OBJECTIVES:
I. Determine the clinical complete response rate (cCR), and local-regional control rate of PPV in combination with RT for LARC.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 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
- •Documented informed consent of the participant and/or legally authorized representative
- •Willingness to participate in all correlative studies: fMRI, and tissue collection of tumor and normal rectum (ribonucleic acid [RNA]/deoxyribonucleic acid [DNA]/protein), blood (plasma/peripheral blood mononuclear cell [PBMC]) draws and stool collection
- •Age: ≥ 18 years
- •Eastern Cooperative Oncology Group (ECOG) ≤ 2
- •Histologically confirmed rectal adenocarcinoma
- •Patient wants to pursue an organ preservation/non-operative management (NOM) approach after completion of total neoadjuvant therapy (TNT)
- •Locally advanced rectal cancer (T3-4 or node+, M0)
- •Tumor is microsatellite stable (MSS) (defined as not microsatellite instability-high [MSI-H] or mismatch repair deficient [dMMR])
- •Absolute neutrophil count (ANC) ≥ 1,500/mm^3 (within 30 days of start). NOTE: Growth factor is not permitted within 14 days of ANC assessment unless cytopenia is secondary to disease involvement
- •Platelets ≥ 100,000/mm^3 (within 30 days of start). NOTE: Platelet transfusions are not permitted within 14 days of platelet assessment unless cytopenia is secondary to disease involvement
- •Hemoglobin ≥ 9g/dL (within 30 days of start). NOTE: Red blood cell transfusions are not permitted within 14 days of hemoglobin assessment unless cytopenia is secondary to disease involvement
- •Total bilirubin ≤ 1.5 X upper limit of normal (ULN) (within 30 days of start)
- •Aspartate aminotransferase (AST) =< 2.5 x ULN (within 30 days of start)
- •Alanine aminotransferase (ALT) =< 2.5 x ULN (within 30 days of start)
- •Creatinine clearance of ≥ 50 mL/min per 24 hour urine test or the Cockcroft-Gault formula (within 30 days of start)
- •For patients with known infections only: seropositive for HIV, hepatitis C virus (HCV) or hepatitis B virus (HBV), nucleic acid quantitation must be performed. Viral load must be undetectable. HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial (within 28 days of start)
- •Women of childbearing potential (WOCBP): negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required (within 30 days of start)
- •Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 4 months after the last dose of protocol therapy
- •Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)
排除标准
- •Chemotherapy, biological therapy, immunotherapy within 14 days or five half-lives (whichever is shorter) prior to day 1 of protocol therapy
- •Prior pelvic irradiation resulting in overlapping fields
- •Use of levodopa in the last 30 days
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
- •Unable to undergo MRI and endoscopic procedures
- •History of complete atrioventricular block, hepatic dysfunction (e.g. cirrhosis), or priapism
- •Other active malignancy. 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
- •Females only: Pregnant or breastfeeding
- •Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
- •Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)
研究组 & 干预措施
Cohort 1 (RT, CC)
Patients undergo RT QD on days 1-5 (Monday-Friday) of week 1. Starting at week 5, patients receive SOC CC with either mFOLFOX6 or CAPOX for 3-4 months in the absence of disease progression or unacceptable toxicity. As early as four weeks following completion of CC, patients with persistent disease (non-cCR) or disease recurrence in the rectum during disease evaluation may undergo ToME. Additionally, patients undergo one fMRI on study as well as CT, MRI, endoscopy, and blood and tissue sample collection throughout the trial.
干预措施: Biospecimen Collection (Procedure)
Cohort 1 (RT, CC)
Patients undergo RT QD on days 1-5 (Monday-Friday) of week 1. Starting at week 5, patients receive SOC CC with either mFOLFOX6 or CAPOX for 3-4 months in the absence of disease progression or unacceptable toxicity. As early as four weeks following completion of CC, patients with persistent disease (non-cCR) or disease recurrence in the rectum during disease evaluation may undergo ToME. Additionally, patients undergo one fMRI on study as well as CT, MRI, endoscopy, and blood and tissue sample collection throughout the trial.
干预措施: Computed Tomography (Procedure)
Cohort 1 (RT, CC)
Patients undergo RT QD on days 1-5 (Monday-Friday) of week 1. Starting at week 5, patients receive SOC CC with either mFOLFOX6 or CAPOX for 3-4 months in the absence of disease progression or unacceptable toxicity. As early as four weeks following completion of CC, patients with persistent disease (non-cCR) or disease recurrence in the rectum during disease evaluation may undergo ToME. Additionally, patients undergo one fMRI on study as well as CT, MRI, endoscopy, and blood and tissue sample collection throughout the trial.
干预措施: Consolidation Therapy (Drug)
Cohort 1 (RT, CC)
Patients undergo RT QD on days 1-5 (Monday-Friday) of week 1. Starting at week 5, patients receive SOC CC with either mFOLFOX6 or CAPOX for 3-4 months in the absence of disease progression or unacceptable toxicity. As early as four weeks following completion of CC, patients with persistent disease (non-cCR) or disease recurrence in the rectum during disease evaluation may undergo ToME. Additionally, patients undergo one fMRI on study as well as CT, MRI, endoscopy, and blood and tissue sample collection throughout the trial.
干预措施: Functional Magnetic Resonance Imaging (Procedure)
Cohort 1 (RT, CC)
Patients undergo RT QD on days 1-5 (Monday-Friday) of week 1. Starting at week 5, patients receive SOC CC with either mFOLFOX6 or CAPOX for 3-4 months in the absence of disease progression or unacceptable toxicity. As early as four weeks following completion of CC, patients with persistent disease (non-cCR) or disease recurrence in the rectum during disease evaluation may undergo ToME. Additionally, patients undergo one fMRI on study as well as CT, MRI, endoscopy, and blood and tissue sample collection throughout the trial.
干预措施: Gastrointestinal Endoscopy (Procedure)
Cohort 1 (RT, CC)
Patients undergo RT QD on days 1-5 (Monday-Friday) of week 1. Starting at week 5, patients receive SOC CC with either mFOLFOX6 or CAPOX for 3-4 months in the absence of disease progression or unacceptable toxicity. As early as four weeks following completion of CC, patients with persistent disease (non-cCR) or disease recurrence in the rectum during disease evaluation may undergo ToME. Additionally, patients undergo one fMRI on study as well as CT, MRI, endoscopy, and blood and tissue sample collection throughout the trial.
干预措施: Magnetic Resonance Imaging (Procedure)
Cohort 1 (RT, CC)
Patients undergo RT QD on days 1-5 (Monday-Friday) of week 1. Starting at week 5, patients receive SOC CC with either mFOLFOX6 or CAPOX for 3-4 months in the absence of disease progression or unacceptable toxicity. As early as four weeks following completion of CC, patients with persistent disease (non-cCR) or disease recurrence in the rectum during disease evaluation may undergo ToME. Additionally, patients undergo one fMRI on study as well as CT, MRI, endoscopy, and blood and tissue sample collection throughout the trial.
干预措施: Radiation Therapy (Radiation)
Cohort 1 (RT, CC)
Patients undergo RT QD on days 1-5 (Monday-Friday) of week 1. Starting at week 5, patients receive SOC CC with either mFOLFOX6 or CAPOX for 3-4 months in the absence of disease progression or unacceptable toxicity. As early as four weeks following completion of CC, patients with persistent disease (non-cCR) or disease recurrence in the rectum during disease evaluation may undergo ToME. Additionally, patients undergo one fMRI on study as well as CT, MRI, endoscopy, and blood and tissue sample collection throughout the trial.
干预措施: Total Mesorectal Excision (Procedure)
Cohort 2 (PPV, RT, CC)
Patients receive PPV IV over 15-30 minutes on day -3 of week 0 and days 1-5 of week 1. Patients also undergo RT QD on days 1-5 (Monday-Friday) of week 1, 1-2 hours after PPV. Starting at week 5, patients receive SOC CC with either mFOLFOX6 or CAPOX for 3-4 months in the absence of disease progression or unacceptable toxicity. As early as four weeks following completion of CC, patients with persistent disease (non-cCR) or disease recurrence in the rectum during disease evaluation may undergo ToME. Additionally, patients undergo two fMRI on study as well as CT, MRI, endoscopy, and blood and tissue sample collection throughout the trial.
干预措施: Biospecimen Collection (Procedure)
Cohort 2 (PPV, RT, CC)
Patients receive PPV IV over 15-30 minutes on day -3 of week 0 and days 1-5 of week 1. Patients also undergo RT QD on days 1-5 (Monday-Friday) of week 1, 1-2 hours after PPV. Starting at week 5, patients receive SOC CC with either mFOLFOX6 or CAPOX for 3-4 months in the absence of disease progression or unacceptable toxicity. As early as four weeks following completion of CC, patients with persistent disease (non-cCR) or disease recurrence in the rectum during disease evaluation may undergo ToME. Additionally, patients undergo two fMRI on study as well as CT, MRI, endoscopy, and blood and tissue sample collection throughout the trial.
干预措施: Computed Tomography (Procedure)
Cohort 2 (PPV, RT, CC)
Patients receive PPV IV over 15-30 minutes on day -3 of week 0 and days 1-5 of week 1. Patients also undergo RT QD on days 1-5 (Monday-Friday) of week 1, 1-2 hours after PPV. Starting at week 5, patients receive SOC CC with either mFOLFOX6 or CAPOX for 3-4 months in the absence of disease progression or unacceptable toxicity. As early as four weeks following completion of CC, patients with persistent disease (non-cCR) or disease recurrence in the rectum during disease evaluation may undergo ToME. Additionally, patients undergo two fMRI on study as well as CT, MRI, endoscopy, and blood and tissue sample collection throughout the trial.
干预措施: Consolidation Therapy (Drug)
Cohort 2 (PPV, RT, CC)
Patients receive PPV IV over 15-30 minutes on day -3 of week 0 and days 1-5 of week 1. Patients also undergo RT QD on days 1-5 (Monday-Friday) of week 1, 1-2 hours after PPV. Starting at week 5, patients receive SOC CC with either mFOLFOX6 or CAPOX for 3-4 months in the absence of disease progression or unacceptable toxicity. As early as four weeks following completion of CC, patients with persistent disease (non-cCR) or disease recurrence in the rectum during disease evaluation may undergo ToME. Additionally, patients undergo two fMRI on study as well as CT, MRI, endoscopy, and blood and tissue sample collection throughout the trial.
干预措施: Functional Magnetic Resonance Imaging (Procedure)
Cohort 2 (PPV, RT, CC)
Patients receive PPV IV over 15-30 minutes on day -3 of week 0 and days 1-5 of week 1. Patients also undergo RT QD on days 1-5 (Monday-Friday) of week 1, 1-2 hours after PPV. Starting at week 5, patients receive SOC CC with either mFOLFOX6 or CAPOX for 3-4 months in the absence of disease progression or unacceptable toxicity. As early as four weeks following completion of CC, patients with persistent disease (non-cCR) or disease recurrence in the rectum during disease evaluation may undergo ToME. Additionally, patients undergo two fMRI on study as well as CT, MRI, endoscopy, and blood and tissue sample collection throughout the trial.
干预措施: Gastrointestinal Endoscopy (Procedure)
Cohort 2 (PPV, RT, CC)
Patients receive PPV IV over 15-30 minutes on day -3 of week 0 and days 1-5 of week 1. Patients also undergo RT QD on days 1-5 (Monday-Friday) of week 1, 1-2 hours after PPV. Starting at week 5, patients receive SOC CC with either mFOLFOX6 or CAPOX for 3-4 months in the absence of disease progression or unacceptable toxicity. As early as four weeks following completion of CC, patients with persistent disease (non-cCR) or disease recurrence in the rectum during disease evaluation may undergo ToME. Additionally, patients undergo two fMRI on study as well as CT, MRI, endoscopy, and blood and tissue sample collection throughout the trial.
干预措施: Magnetic Resonance Imaging (Procedure)
Cohort 2 (PPV, RT, CC)
Patients receive PPV IV over 15-30 minutes on day -3 of week 0 and days 1-5 of week 1. Patients also undergo RT QD on days 1-5 (Monday-Friday) of week 1, 1-2 hours after PPV. Starting at week 5, patients receive SOC CC with either mFOLFOX6 or CAPOX for 3-4 months in the absence of disease progression or unacceptable toxicity. As early as four weeks following completion of CC, patients with persistent disease (non-cCR) or disease recurrence in the rectum during disease evaluation may undergo ToME. Additionally, patients undergo two fMRI on study as well as CT, MRI, endoscopy, and blood and tissue sample collection throughout the trial.
干预措施: Radiation Therapy (Radiation)
Cohort 2 (PPV, RT, CC)
Patients receive PPV IV over 15-30 minutes on day -3 of week 0 and days 1-5 of week 1. Patients also undergo RT QD on days 1-5 (Monday-Friday) of week 1, 1-2 hours after PPV. Starting at week 5, patients receive SOC CC with either mFOLFOX6 or CAPOX for 3-4 months in the absence of disease progression or unacceptable toxicity. As early as four weeks following completion of CC, patients with persistent disease (non-cCR) or disease recurrence in the rectum during disease evaluation may undergo ToME. Additionally, patients undergo two fMRI on study as well as CT, MRI, endoscopy, and blood and tissue sample collection throughout the trial.
干预措施: Total Mesorectal Excision (Procedure)
Cohort 2 (PPV, RT, CC)
Patients receive PPV IV over 15-30 minutes on day -3 of week 0 and days 1-5 of week 1. Patients also undergo RT QD on days 1-5 (Monday-Friday) of week 1, 1-2 hours after PPV. Starting at week 5, patients receive SOC CC with either mFOLFOX6 or CAPOX for 3-4 months in the absence of disease progression or unacceptable toxicity. As early as four weeks following completion of CC, patients with persistent disease (non-cCR) or disease recurrence in the rectum during disease evaluation may undergo ToME. Additionally, patients undergo two fMRI on study as well as CT, MRI, endoscopy, and blood and tissue sample collection throughout the trial.
干预措施: Papaverine (Drug)
结局指标
主要结局
Acute dose limiting toxicity (DLT)
时间窗: From time of single-agent papaverine (PPV) week 0 treatment to start of consolidation chemotherapy (CC), assessed up to 4 weeks
As assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. A defined adverse event considered to be possibly, probably, or definitely related to study treatment (radiation therapy or PPV). Will employ the time-to-event Bayesian optimal interval design (TITE-BOIN) to find the maximum tolerated dose (MTD).
Late DLT
时间窗: From the start of CC week 5 treatment to 12 months from week 0
As assessed by NCI CTCAE v5.0. A defined adverse event considered to be possibly, probably, or definitely related to study treatment (radiation therapy or PPV). Will employ the TITE-BOIN design to find the MTD.
Incidence of treatment related adverse events during acute DLT period
时间窗: From time of single-agent PPV week 0 treatment to start of CC, assessed up to 4 weeks
As assessed by NCI CTCAE v5.0. Will be delineated by grade and attribution. A defined adverse event considered to be possibly, probably, or definitely related to study treatment (radiation therapy or PPV).
Incidence of treatment related adverse events during late DLT period
时间窗: From the start of CC week 5 treatment to 12 months from week 0
As assessed by NCI CTCAE v5.0. Will be delineated by grade and attribution. A defined adverse event considered to be possibly, probably, or definitely related to study treatment (radiation therapy or PPV).
次要结局
- Clinical complete response rate(From time of single agent papaverine (PPV) week 0 treatment to completion of consolidation chemotherapy (CC), assessed up to 20 weeks.)
- Local-regional control rate(From time of single agent papaverine (PPV) week 0 treatment to completion of consolidation chemotherapy (CC), assessed up to 20 weeks.)
- Local-regional recurrence free survival(From enrollment to date of first local regional recurrence, death as a result of any cause or being censored at last contact, assessed up to 5 years)
- Total mesorectal excision free survival(From enrollment to date of total mesorectal surgical excision, death as result of any cause or being censored at last contact, assessed up to 5 years)
- Disease-free survival(From enrollment to date of first disease recurrence, death as a result of any cause or being censored at last contact, assessed up to 5 years)
- Distant-metastasis-free survival(From enrollment to date of first distant metastases occurrence, death as a result of any cause or being censored at last contact, assessed up to 5 years)
- Overall survival(From enrollment to date of death as a result of any cause or being censored at last contact, assessed up to 5 years)