Reversing External-beam Radiotherapy-associated Fibrosis Syndrome: an Interventional Bayesian Adaptive Randomized-controlled Orphan Drug Platform Trial for Orodental Sequelae (Reverse-fibrose)

To find out if adding medication can help treat or prevent lymphedema and/or fibrosis related to radiation therapy, in survivors of head and neck cancer. Researchers will compare these drugs to find the most effective therapy for preventing or limiting these side effects.

Study Overview

• Status: Recruiting
• Conditions: Fibrosis; Lymphedema; Fibrosis Syndrome; Head &Amp; Neck Cancer
• Intervention / Treatment: Drug: Pentoxifylline; Drug: Pravastatin (drug); Drug: tocopherol; Drug: ketoprofen; Drug: Pirfenidoneone; Other: Standard of Care (SOC)

Detailed Description

Primary Objectives

1. Determine the relative utility of candidate agents to reduce clinician-rated radiation lymphedema/fibrosis

   1. Hyp 1: Participants receiving candidate agent(s) will exhibit a proportional lower rate of Common Toxicity Criteria- Adverse Event (CTC-AE v5.0) rating of Grade 2 or greater on either "Fibrosis deep connective tissue" or "Superficial soft tissue fibrosis" by formal clinician assessment at 12 months post-randomization.
   2. Hyp 2: Participants receiving candidate agent(s) will exhibit a proportional lower rate of objective lymphedema/fibrosis rated as "moderate/severe" grade at any head and neck subsite as measured by the Head and Neck External Lymphedema and Fibrosis (HN-ELAF) Assessment Criteria by a certified lymphedema specialist at 12 months post-randomization.

2. Determine the relative effect size observed of candidate agent(s) to reduce objective imaging-derived measures of radiation lymphedema/fibrosis-related sequalae [Primary]

   1. Hyp 3: Participants receiving candidate agent(s) will exhibit a proportionally lower rate of objective DIGEST-detected swallowing dysfunction 12 months post-randomization.
   2. Hyp 4: Participants receiving candidate agent(s) will exhibit a proportional lower rate of objective MRI-detected difference between 6- and 18-month post-randomization quantitative T1 (T1 mapping) intensity for paired muscle swallowing/neck/masticator muscles receiving >=40Gy post-randomization.

Secondary Objectives

1. Determine the relative effect size observed of candidate agent(s) to reduce patient reported measures of toxicity associated with lymphedema/fibrosis-related sequalae [Secondary]

   1. Hyp 5: Participants receiving candidate agent(s) will exhibit a proportionally lower rate of moderate-severe rated items "Fibrosis deep connective tissue" or "Superficial soft tissue fibrosis" by patient self-assessment using the Participant Reported Outcomes-CTCAE (PROCTCAE) Scale at 12-months post-randomization.
   2. Hyp 6: Participants receiving candidate agent(s) will exhibit a proportionally lower rate of moderate-severe rated symptom items by participant self-assessment using the Head and Neck External Lymphedema and Fibrosis (HN-ELAF) Symptom Inventory Scale at 12-months post-randomization.
   3. Hyp 7: Participants receiving candidate agent(s) will exhibit a proportionally lower rate of moderate-severe global symptom burden by participant self-assessment using the MD Anderson Symptom Inventory Scale at 12-months post-randomization.

   4. Hyp 8: Participants receiving candidate agent(s) will exhibit a proportionally improved global quality of life as denoted by patient self-assessment using the EQ-5D Visual analogue Scale at 12-months post-randomization.

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• Study Type: Interventional
• Enrollment (Estimated): 250
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Clifton Fuller, MD; Phone Number: (832) 817-8568; Email: cdfuller@mdanderson.org

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • MD Anderson Cancer Center
      • Contact: Clifton Fuller, MD; Phone Number: 832-817-8568; Email: cdfuller@mdanderson.org
      • Principal Investigator: Clifton Fuller, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Eligibility Criteria Eligibility criteria (observational registry or randomization)

1. Prior history of head and neck cancer with no active disease.
2. Treated previously with radiotherapy with prescribed dose (greater or equal to 30Gy) to unilateral or bilateral neck(s)
3. Detectable CTC-AE G2+ lymphedema/fibrosis at >6 months post-radiotherapy.
4. No active liver disease (Child-Pugh class B-C), cirrhosis, nor active alcoholism, nor history of ulcers.
5. No history of myopathy/rhabdomyolysis.
6. Creatinine clearance <30mL/min.
7. No history of acute myocardial infarction or severe coronary disease.
8. Non-pregnant/post-menopausal, or male.
9. No history of diabetes mellitus
10. Allergy/hypersensitivity to HMG Co-A reductase inhibitor and/or xanthine derivatives, e.g., caffeine, theophylline, theobromine
11. No contraindications for magnetic resonance imaging a Subject to the discretion of the treating physician and Principal Investigator (PI), as the MRI may be optional

Exclusion Criteria

1. Active liver disease (Child-Pugh class B-C), cirrhosis, nor active alcoholism.
2. History of myopathy/rhabdomyolysis.
3. History of acute myocardial infarction or severe coronary disease.
4. Pregnant/post-menopausal, or male.
5. History of diabetes mellitus.
6. Allergy/hypersensitivity to Hydroxymethylglutaryl-coenzyme A (HMG Co-A) reductase inhibitor and/or xanthine derivatives, e.g., caffeine, theophylline, theobromine.
7. Contraindications for MRI Subject to the discretion of the treating physician and Principal Investigator (PI), as the MRI may be optional
8. Participants who are receiving any other investigational agents.
9. History of allergic reactions attributed to compounds of similar chemical or biologic composition to statins, hemorheologic agents or other agents used in study
10. Participants with psychiatric illness/social situations that would limit compliance with study requirements.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Double

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment with Pravastatin QD; 40 mg/day for 12 months	Drug: Pravastatin (drug); Given PO
Experimental: Treatment with Pentoxifylline TID + Tocopherol; 400 mg/1000 IU vitamin E for 12 months	Drug: Pentoxifylline; Given PO; Drug: tocopherol; Given PO
Experimental: Treatment with Ketoprofen TID; 75 mg for 12 months	Drug: ketoprofen; Given PO
Experimental: Treatment with Pirfenidone TID; 801 mg for 12 months	Drug: Pirfenidoneone; Given PO
Experimental: Treatment with SoC (Control); No pharmacologic intervention (control)	Other: Standard of Care (SOC); SOC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and adverse events	Incidence of Adverse of Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events	Through study completion; an average of 1 year

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Investigators: Principal Investigator: Clifton Fuller, MD, M.D. Anderson Cancer Center

Publications and helpful links

Helpful Links

• MD Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): August 8, 2025
• Primary Completion (Estimated): July 31, 2030
• Study Completion (Estimated): July 31, 2031

Study Registration Dates

• First Submitted: March 24, 2025
• First Submitted That Met QC Criteria: April 2, 2025
• First Posted (Actual): April 6, 2025

Study Record Updates

• Last Update Posted (Actual): July 24, 2026
• Last Update Submitted That Met QC Criteria: July 22, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Lymphatic Diseases; Pathological Conditions, Signs and Symptoms; Hemic and Lymphatic Diseases; Lymphedema; Fibrosis; Head and Neck Neoplasms; Health Services Administration; Health Care Quality, Access, and Evaluation; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pyrans; Hydrocarbons; Hydrocarbons, Cyclic; Quality of Health Care; Carboxylic Acids; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Quality Indicators, Health Care; Purinones; Purines; Acids, Carbocyclic; Benzopyrans; Phenylpropionates; Xanthines; Vitamin E; Theobromine; Tocopherols; Ketoprofen; Pentoxifylline; Pravastatin; Standard of Care; Pharmaceutical Preparations
• Other Study ID Numbers: 2024-1521; NCI-2025-02225 (Other Identifier: NCI-CTRP Clinical Registry)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No