PPALM-Palm Oil and Pentoxifylline Against Late Morbidity (PPALM)

Randomised Double-blind Placebo Controlled Phase II Trial of Tocovid SupraBio in Combination With Pentoxifylline (PTX) in Patients Suffering Long-term Adverse Effects of Radiotherapy for Pelvic Cancer

Side effects are common after treatment with radiotherapy for tumours in the pelvis and can affect the way the bowel and urinary system work as well as causing sexual difficulties, skin damage and bone problems. Problems in the bowel, bladder, sexual organs and skin mostly result from thickening of the tissues in response to radiotherapy, a process called "fibrosis". Fibrosis often worsens over time.

There has been progress in treating bowel symptoms which usually are the worst problem after radiotherapy. However, even after receiving the best possible treatments, while many patients are better, they are often not cured of all their difficult problems.

For some years, it has been hypothesised that if fibrosis could be treated then symptoms would improve. Recent research in laboratory animals has suggested that an effective treatment for radiation-induced fibrosis is combination therapy with a drug called Pentoxifylline together with a nutritional supplement containing gamma-tocotrienol (Tocovid SupraBio), a substance derived from palm oil. Both of these agents are simple to take and side effects are rare.

This study will recruit volunteers who continue to have difficult side effects after previous radiotherapy to the pelvis despite receiving the best treatments available from a unique clinic at The Royal Marsden which has pioneered treatment for bowel problems after radiotherapy. Two out of every three volunteers who take part, will be randomly assigned to treatment with Pentoxifylline and Tocovid SupraBio, while one out of three will receive dummy pills. Neither the patients nor the staff assessing them will know which treatment they have been given. Volunteers take the active treatments or dummy tablets for a year and will be assessed regularly while on treatment and for a year afterwards. This study will show whether active treatment is more effective than dummy pills in improving the symptoms caused by radiation-induced fibrosis.

Study Overview

• Status: Completed
• Conditions: Long-term Adverse Effects of Radiotherapy for Pelvic Cancer
• Intervention / Treatment: Drug: Tocovid SupraBio plus pentoxifylline; Drug: Matching placebos

• Study Type: Interventional
• Enrollment (Actual): 62
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, SW3 6JJ
    • The Royal Marsden NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria -

• Age over 18 years.
• Past history of a malignant pelvic neoplasm (T1-4 N0-2 M0) of the rectum, prostate, testis, bladder, uterine cervix, uterus, vagina, vulva, anal canal or ovary.
• A minimum 12 months follow-up post-radiotherapy (24 months for patients with past history of stage T4 and/or N2 disease).
• A maximum 7 years post-radiotherapy
• No evidence of cancer recurrence.
• Gastrointestinal symptoms attributable to prior radiotherapy: grade 2 or higher in any CTCAE Version 4 category, or grade 1 with difficult intermittent symptoms.
• Symptoms are not relieved by appropriate life-style advice and medication over a 3-month period.
• Physical and psychological fitness for Tocovid SupraBio+PTX therapy.
• Written informed consent and availability for follow up.
• Willingness to keep to a specified level of dietary fat intake during the study.

Exclusion Criteria -

• Surgery for rectal cancer.
• Contra-indication or other inability to undergo magnetic resonance imaging, if required to rule out malignancy.
• Dietary supplementation containing alpha-tocopherol above a daily dose of 30mg at any time during the last three months.
• Medication with pentoxifylline at any time since radiotherapy.
• Pregnancy or breast feeding.
• Ischaemic heart disease, uncontrolled hypertension, hypotension, acute myocardial infarction, cerebral haemorrhage, retinal haemorrhage, renal failure, liver failure and medication with insulin, ketorolac or vitamin K.
• Allergy to soya.
• Known hypersensitivity to the active constituent, pentoxifylline other methyl xanthines or any of the excipients', as per SmPC for pentoxifylline.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tocovid SupraBio plus pentoxifylline (PTX); Tocovid SupraBio* 200mg po bd plus pentoxifylline (PTX) 400mg po bd for 12 months.	Drug: Tocovid SupraBio plus pentoxifylline
Placebo Comparator: Matching placebos; Matching placebos bd for 12 months.	Drug: Matching placebos

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change at 12 months in the bowel disease subset of the Modified IBDQ Quality of Life questionnaire.	Endpoint will be assessed pre-treatment and 3, 6, 9, 12, 18 & 24 months post-treatment.

Secondary Outcome Measures

Outcome Measure	Time Frame
Change at 12 months in rectal IBDQ bleeding score between the two groups in those patients presenting with grade 2, 3 or 4 bleeding.	Endpoint will be assessed pre-treatment and 3, 6, 9, 12, 18 & 24 months post-treatment.
Change at 12 months in IBDQ faecal incontinence score between the two groups in those patients presenting with grade 1 or greater incontinence.	Endpoint will be assessed pre-treatment and 3, 6, 9, 12, 18 & 24 months post-treatment.
Proportion of items graded as marked or severe (grade 3 or 4).	Endpoint will be assessed pre-treatment and 3, 6, 9, 12, 18 & 24 months post-treatment.
Physician assessment of rectal dysfunction based on the modified CTCAE Version 4 grading.	Endpoint will be assessed pre-treatment and 6, 12 & 24 months post-treatment.
Patient self-assessments: QLQ-C30 and CR29 and the Gastrointestinal Symptom Rating Scale.	Endpoint will be assessed pre-treatment and 3, 6, 9, 12, 18 & 24 months post-treatment.
Photographic assessment of rectal mucosa.	Endpoint will be assessed pre-treatment and 12 & 24 months post-treatment
Serum fibrosis marker levels.	Endpoint will be assessed pre-treatment and 3, 6, 9, 12, 18 & 24 months post-treatment.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Translational endpoint: Rectal biopsies (optional)	Tissue samples will be banked until after the final analysis of the trial, when funding will be sought to identify molecular and cellular correlates of therapeutic response in the event of a statistically significant benefit for Tocovid SupraBio/ PTX combination.	Endpoint will be assessed pre-treatment and 12 & 24 months post-treatment.
Translational endpoint: Blood samples	Development of novel markers of fibrosis.	Endpoint will be assessed pre-treatment and 12 & 24 months post-treatment.

Collaborators and Investigators

• Sponsor: Royal Marsden NHS Foundation Trust
• Collaborators: Malaysia Palm Oil Board
• Investigators: Principal Investigator: Alexandra Taylor, Royal Marsden NHS Foundation Trust

Publications and helpful links

General Publications

• Andreyev HJN, Matthews J, Adams C, Gothard L, Lucy C, Tovey H, Boyle S, Anbalagan S, Musallam A, Yarnold J, Abraham D, Bliss J, Abdi BA, Taylor A, Hauer-Jensen M. Randomised single centre double-blind placebo controlled phase II trial of Tocovid SupraBio in combination with pentoxifylline in patients suffering long-term gastrointestinal adverse effects of radiotherapy for pelvic cancer: The PPALM study. Radiother Oncol. 2022 Mar;168:130-137. doi: 10.1016/j.radonc.2022.01.024. Epub 2022 Jan 29.

Study record dates

Study Major Dates

• Study Start (Actual): November 25, 2014
• Primary Completion (Actual): December 20, 2019
• Study Completion (Actual): December 20, 2019

Study Registration Dates

• First Submitted: August 29, 2014
• First Submitted That Met QC Criteria: September 2, 2014
• First Posted (Estimate): September 3, 2014

Study Record Updates

• Last Update Posted (Actual): December 23, 2019
• Last Update Submitted That Met QC Criteria: December 20, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Neoplasms by Site; Pelvic Neoplasms; Long Term Adverse Effects; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Protective Agents; Micronutrients; Vitamins; Antioxidants; Phosphodiesterase Inhibitors; Free Radical Scavengers; Radiation-Protective Agents; Pentoxifylline; Tocovid
• Other Study ID Numbers: CCR3894