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

M.D. Anderson Cancer Center

Status and phase: Enrolling; Phase 2

Conditions: Lymphedema; Fibrosis Syndrome; Fibrosis; Head &Amp; Neck Cancer

Treatments: Drug: tocopherol; Drug: Pentoxifylline; Drug: Pirfenidoneone; Drug: Pravastatin (drug); Drug: ketoprofen; Other: Standard of Care (SOC)

Study type: Interventional

Funder types: Other

Identifiers

NCT06912763

2024-1521

NCI-2025-02225 (Other Identifier)

Details and patient eligibility

About

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.

Full 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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Enrollment: 250 estimated patients

Sex: Female

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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.

Trial design

Primary purpose: Supportive Care

Allocation: Randomized

Interventional model: Single Group Assignment

Masking: Double Blind

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250 participants in 5 patient groups

Treatment with Pravastatin QD

Experimental group

Description:

40 mg/day for 12 months

Treatment:

Drug: Pravastatin (drug)

Treatment with Pentoxifylline TID + Tocopherol

Experimental group

Description:

400 mg/1000 IU vitamin E for 12 months

Treatment:

Drug: Pentoxifylline

Drug: tocopherol

Treatment with Ketoprofen TID

Experimental group

Description:

75 mg for 12 months

Treatment:

Drug: ketoprofen

Treatment with Pirfenidone TID

Experimental group

Description:

801 mg for 12 months

Treatment:

Drug: Pirfenidoneone

Treatment with SoC (Control)

Experimental group

Description:

No pharmacologic intervention (control)

Treatment:

Other: Standard of Care (SOC)