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

NCT06834126 | Recruiting Phase 1 DMC FDA Drug

• 4 other identifiers: 24405NCI-2024-10075P30CA033572R01CA297752
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Locally Advanced Rectal Adenocarcinoma; Stage II Rectal Cancer AJCC v8; Stage III Rectal Cancer AJCC v8

Outcome Measures

Primary Outcomes (4)

• Acute dose limiting toxicity (DLT)

  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).

  From time of single-agent papaverine (PPV) week 0 treatment to start of consolidation chemotherapy (CC), assessed up to 4 weeks

• Late DLT

  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.

  From the start of CC week 5 treatment to 12 months from week 0

• Incidence of treatment related adverse events during acute DLT period

  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).

  From time of single-agent PPV week 0 treatment to start of CC, assessed up to 4 weeks

• Incidence of treatment related adverse events during late DLT period

  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).

  From the start of CC week 5 treatment to 12 months from week 0

Secondary Outcomes (7)

• 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

Study Arms (2)

Cohort 1 (RT, CC)

ACTIVE COMPARATOR

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.

Procedure: Biospecimen Collection; Procedure: Computed Tomography; Drug: Consolidation Therapy; Procedure: Functional Magnetic Resonance Imaging; Procedure: Gastrointestinal Endoscopy; Procedure: Magnetic Resonance Imaging; Radiation: Radiation Therapy; Procedure: Total Mesorectal Excision

Cohort 2 (PPV, RT, CC)

EXPERIMENTAL

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.

Procedure: Biospecimen Collection; Procedure: Computed Tomography; Drug: Consolidation Therapy; Procedure: Functional Magnetic Resonance Imaging; Procedure: Gastrointestinal Endoscopy; Procedure: Magnetic Resonance Imaging; Drug: Papaverine; Radiation: Radiation Therapy; Procedure: Total Mesorectal Excision

Interventions

Biospecimen Collection PROCEDURE

Undergo blood and tissue sample collection

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Cohort 1 (RT, CC); Cohort 2 (PPV, RT, CC)

Computed Tomography PROCEDURE

Undergo CT

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, tomography

Cohort 1 (RT, CC); Cohort 2 (PPV, RT, CC)

Consolidation Therapy DRUG

Receive CC with mFOLFOX6 or CAPOX

Also known as: Consolidation, intensification therapy, Post Remission Therapy, Postremission Therapy

Cohort 1 (RT, CC); Cohort 2 (PPV, RT, CC)

Functional Magnetic Resonance Imaging PROCEDURE

Undergo fMRI

Also known as: fMRI, Functional MRI

Cohort 1 (RT, CC); Cohort 2 (PPV, RT, CC)

Gastrointestinal Endoscopy PROCEDURE

Undergo endoscopy

Also known as: Enteroscopy

Cohort 1 (RT, CC); Cohort 2 (PPV, RT, CC)

Magnetic Resonance Imaging PROCEDURE

Undergo MRI

Also known as: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI

Cohort 1 (RT, CC); Cohort 2 (PPV, RT, CC)

Papaverine DRUG

Given IV

Also known as: Cerebid, Cerespan, Pavabid, Pavacap, Pavatym, Robaxapap

Cohort 2 (PPV, RT, CC)

Radiation Therapy RADIATION

Undergo RT

Also known as: Cancer Radiotherapy, Energy Type, ENERGY_TYPE, Irradiate, Irradiated, Irradiation, Radiation, Radiation Therapy, NOS, Radiotherapeutics, Radiotherapy, RT, Therapy, Radiation

Cohort 1 (RT, CC); Cohort 2 (PPV, RT, CC)

Total Mesorectal Excision PROCEDURE

Undergo ToME

Also known as: TME

Cohort 1 (RT, CC); Cohort 2 (PPV, RT, CC)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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)

Sponsors & Collaborators

• City of Hope Medical Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

City of Hope Medical Center

Duarte, California, 91010, United States

RECRUITING

MeSH Terms

Conditions

Rectal Neoplasms

Interventions

Specimen Handling; Consolidation Chemotherapy; Endoscopy, Gastrointestinal; Magnetic Resonance Spectroscopy; Papaverine; Radiotherapy; Radiation

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Drug Therapy; Therapeutics; Endoscopy, Digestive System; Diagnostic Techniques, Digestive System; Endoscopy; Diagnostic Techniques, Surgical; Digestive System Surgical Procedures; Surgical Procedures, Operative; Minimally Invasive Surgical Procedures; Spectrum Analysis; Chemistry Techniques, Analytical; Benzylisoquinolines; Alkaloids; Heterocyclic Compounds; Opiate Alkaloids; Isoquinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Physical Phenomena

Study Officials

• Terence M Williams

  City of Hope Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 27, 2024
• First Posted: February 19, 2025
• Study Start: April 7, 2025
• Primary Completion (Estimated): September 19, 2028
• Study Completion (Estimated): September 19, 2028
• Last Updated: July 18, 2025

Record last verified: 2025-07

Locations

US (1)