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RecruitingNCT06834126

Papaverine in Combination With Radiation Therapy for the Treatment of Locally Advanced Rectal Cancer, DINOMITE Trial

DINOMITE (Decreasing Hypoxia With Mitochondrial Inhibition in Locally Advanced Rectal Cancer): Phase 1 Trial of Papaverine in Combination With Radiation

Status
Recruiting
Phase
Phase 1
Study type
Interventional
Enrollment
36 (estimated)
Sponsor
City of Hope Medical Center · Academic / Other
Sex
All
Age
18 Years
Healthy volunteers
Not accepted

Summary

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.

Detailed description

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. II. Determine the total mesorectal excision (ToME)-free survival, local-regional recurrence free survival (LRRFS), disease-free survival (DFS), distant-metastasis-free survival (DMFS) and overall survival (OS) of PPV in combination with RT for LARC. EXPLORATORY OBJECTIVES: I. Determine whether PPV in combination with RT for LARC directly results in reduced tumor hypoxia. II. Explore whether RT with and without mitochondrial oxygen consumption (MOC) inhibition alters the tumor immune microenvironment (TIME) in patients receiving SOC RT for LARC. III. Explore whether molecular profiling (changes in hypoxia-induced gene expression, immune cell tumor infiltrates and peripheral immune profiling) can predict which patients may respond best to PPV in combination with SOC RT for LARC. IV. Explore whether stool microbial signatures are associated with response to or progression after PPV in combination with SOC RT for LARC. OUTLINE: This is a dose escalation study of PPV in combination with RT followed by a dose-expansion study. Patients are randomized to 1 of 2 cohorts. COHORT 1: Patients undergo RT once daily (QD) on days 1-5 (Monday-Friday) of week 1. Starting at week 5, patients receive SOC consolidation chemotherapy (CC) with either modified leucovorin, fluorouracil, oxaliplatin-6 (mFOLFOX6) or capecitabine-oxaliplatin (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 functional magnetic resonance imaging (fMRI) on study as well as computed tomography (CT), magnetic resonance imaging (MRI), endoscopy, and blood and tissue sample collection throughout the trial. COHORT 2: Patients receive PPV intravenously (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. After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for an additional 3 years.

Conditions

Interventions

TypeNameDescription
PROCEDUREBiospecimen CollectionUndergo blood and tissue sample collection
PROCEDUREComputed TomographyUndergo CT
DRUGConsolidation TherapyReceive CC with mFOLFOX6 or CAPOX
PROCEDUREFunctional Magnetic Resonance ImagingUndergo fMRI
PROCEDUREGastrointestinal EndoscopyUndergo endoscopy
PROCEDUREMagnetic Resonance ImagingUndergo MRI
DRUGPapaverineGiven IV
RADIATIONRadiation TherapyUndergo RT
PROCEDURETotal Mesorectal ExcisionUndergo ToME

Timeline

Start date
2025-04-07
Primary completion
2028-09-19
Completion
2028-09-19
First posted
2025-02-19
Last updated
2025-07-18

Locations

1 site across 1 country: United States

Regulatory

Source: ClinicalTrials.gov record NCT06834126. Inclusion in this directory is not an endorsement.