Pentoxifylline + Vitamin E for Non-Small Cell Lung Cancer

(P4-PACIFIC Trial)

Overseen By Philip Wong MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University Health Network, Toronto

Must be taking: Pentoxifylline, Vitamin E

Disqualifiers: Pregnancy, Cardiac disease, Hemorrhage, others

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

150 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on Warfarin, you will need frequent monitoring to adjust your dosage.

What data supports the effectiveness of the drug Pentoxifylline + Vitamin E for Non-Small Cell Lung Cancer?

Research shows that combining Pentoxifylline and Vitamin E with radiotherapy can improve survival rates and reduce lung damage in patients with non-small cell lung cancer. Patients receiving this combination had better survival outcomes compared to those who only received radiotherapy. ^{1 2 3 4 5}

Is the combination of pentoxifylline and vitamin E safe for humans?

The combination of pentoxifylline and vitamin E has been used in clinical trials with lung cancer patients and is reported to reduce radiation-induced lung toxicity, suggesting it is generally safe for human use. ^{1 2 3 4 5}

How does the drug Pentoxifylline + Vitamin E differ from other treatments for non-small cell lung cancer?

Pentoxifylline and Vitamin E, when used together with radiotherapy, may offer a survival advantage for patients with non-small cell lung cancer by potentially reducing radiation-induced lung toxicity and improving overall survival rates compared to radiotherapy alone. ^{1 2 3 6 7}

What is the purpose of this trial?

Currently, the standard of care treatment for newly diagnosed, inoperable stage III non-small cell lung cancer is radiotherapy (RT) with concurrent chemotherapy, followed by immune checkpoint inhibitors (ICI). RT is a highly effect local treatment. However, high doses of radiation used in curative settings can cause adverse side effects. The most common RT side effect in lung cancer is Radiation Induced Lung Injury (RILI), which can manifest as pneumonitis and/or pulmonary fibrosis. Lung injury can negatively impact patients' well-being and quality of life, and may lead to increased mortality. Risk of lung injury is particularly increased when patients are treated with a combination of treatments (i.e., RT, chemotherapy, and ICI). The drug Pentoxifylline (in combination with α-Tocopherol (Vitamin E)) has been shown to prevent/alter the progression of lung injury and there is a growing body of evidence to support the safety and efficacy of phosphodiesterase inhibitors in cancer treatment. The proposed study aims to determine if the addition of Pentoxifylline, given in combination with α-Tocopherol (Vitamin E), to standard of care treatment will reduce side effects related to lung injury and improve quality of life in this study population.

Eligibility Criteria

This trial is for adults with stage III non-small cell lung cancer who can't have surgery and are about to start chemoradiation. They should not have had previous radiation therapy in the chest area or be taking other drugs that affect blood clotting.

Inclusion Criteria

* Histologically confirmed diagnosis of stage III NSCLC, planned for treatment with concurrent chemoradiation and consolidation immune checkpoint inhibitor as per standard of care with no medical contraindications to therapy.

* Patients with ECOG performance status 0-2 within 4 weeks of randomization.

* Adequate liver function (no evidence of Child-Pugh class C disease or cirrhosis) as per blood work done within 30 days of registration.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Chemoradiation Treatment

Participants receive concurrent chemoradiation therapy with either placebo or Pentoxifylline/α-Tocopherol starting on day one of radiotherapy

6 months

Regular visits as per standard chemoradiation protocol

Consolidation Therapy

Participants receive immune checkpoint inhibitor therapy as per standard of care following chemoradiation

6 months

Follow-up

Participants are monitored for safety, lung injury, oncological outcomes, and quality of life

12 months

Periodic visits for assessment

Treatment Details

Interventions

• Pentoxifylline
• α-Tocopherol

Trial Overview The study tests if Pentoxifylline combined with α-Tocopherol (Vitamin E) can prevent or lessen lung injury from radiation in patients undergoing standard chemoradiation treatment, compared to a placebo group.

Participant Groups

Group I: Experimental Arm Experimental Treatment 2 Interventions

Participants in the experimental arm will start Pentoxifylline 400 mg orally three times a day and α-Tocopherol 400 IU orally two times a day on day one of radiotherapy and continue treatment for 6 months.

Group II: Control Arm Placebo Group 1 Intervention

Participants in the control arm will start one placebo orally three times a day and another placebo orally two times a day on day one of radiotherapy and continue treatment for 6 months.

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

AstraZeneca

Industry Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Findings from Research

In a study of 66 patients with stage IIIB non-small cell lung cancer, those who received pentoxifylline (PTX) and alpha-tocopherol alongside radiotherapy had significantly better overall survival rates (55% at 1 year and 30% at 2 years) compared to the control group receiving only radiotherapy (40% at 1 year and 14% at 2 years).

The combination treatment also improved progression-free survival, with rates of 48% at 1 year and 23% at 2 years for the PTX and alpha-tocopherol group, compared to 24% and 18% in the control group, indicating a potential survival advantage from this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of concomitant use of pentoxifylline and alpha-tocopherol with radiotherapy on the clinical outcome of patients with stage IIIB non-small cell lung cancer: a randomized prospective clinical trial. Misirlioglu, CH., Erkal, H., Elgin, Y., et al.[2019]

In a study of 91 lung cancer patients, the combination of pentoxifylline and vitamin E significantly reduced radiation-induced lung toxicity compared to a control group, particularly during the acute and subacute phases of treatment.

The treatment was well-tolerated and may be especially beneficial for patients undergoing concurrent chemo-radiotherapy or those with poor respiratory function, suggesting a potential strategy for minimizing side effects of radiation therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pentoxifylline and alpha-tocopherol in prevention of radiation-induced lung toxicity in patients with lung cancer. Misirlioglu, CH., Demirkasimoglu, T., Kucukplakci, B., et al.[2019]

In a study with Wistar albino rats, vitamin E supplementation after radiation exposure significantly reduced the development of pulmonary fibrosis compared to rats that received no treatment.

The combination of vitamin E and pentoxifylline showed even greater effectiveness in reducing fibrosis, although pentoxifylline alone did not demonstrate significant benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vitamin E protects against the development of radiation-induced pulmonary fibrosis in rats. Bese, NS., Munzuroglu, F., Uslu, B., et al.[2013]

In a phase II study involving 18 patients with grade three radiation-induced toxicity, the combination of pentoxifylline and tocopherol, along with inhaled carbogen, showed a 33% response rate in improving toxicity scores.

Patients receiving prolonged treatment (12 months) had a higher response rate compared to those on short treatment, with two patients achieving complete symptom resolution maintained for up to three years, suggesting prolonged therapy may be more beneficial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized prospective study of extended tocopherol and pentoxifylline therapy, in addition to carbogen, in the treatment of radiation late effects. Brennan, S., Salib, O., O'Shea, C., et al.[2021]

In a case series of six patients with bisphosphonate-associated osteonecrosis (BON), treatment with pentoxifylline and α-tocopherol, alongside antimicrobial therapy, resulted in a significant 74% reduction in bony exposure and improved symptom control over an average follow-up of 10 months.

The findings suggest that pentoxifylline and α-tocopherol could be an effective management strategy for BON, indicating the need for further controlled trials to validate these results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of bisphosphonate-associated osteonecrosis: pentoxifylline and tocopherol in addition to antimicrobial therapy. An initial case series. Epstein, MS., Wicknick, FW., Epstein, JB., et al.[2013]

References

1. United States pubmed.ncbi.nlm.nih.gov

Effect of concomitant use of pentoxifylline and alpha-tocopherol with radiotherapy on the clinical outcome of patients with stage IIIB non-small cell lung cancer: a randomized prospective clinical trial. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Pentoxifylline and alpha-tocopherol in prevention of radiation-induced lung toxicity in patients with lung cancer. [2019]

3. England pubmed.ncbi.nlm.nih.gov

Vitamin E protects against the development of radiation-induced pulmonary fibrosis in rats. [2013]

4. Ireland pubmed.ncbi.nlm.nih.gov

Effect of pentoxifylline on radiation response of non-small cell lung cancer: a phase III randomized multicenter trial. [2019]

5. Germany pubmed.ncbi.nlm.nih.gov

Pentoxifylline and tocopherol as prophylaxis for osteonecrosis of the jaw due to bone-modifying agents in patients with cancer submitted to tooth extraction: a case series. [2023]

6. England pubmed.ncbi.nlm.nih.gov

A randomized prospective study of extended tocopherol and pentoxifylline therapy, in addition to carbogen, in the treatment of radiation late effects. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Management of bisphosphonate-associated osteonecrosis: pentoxifylline and tocopherol in addition to antimicrobial therapy. An initial case series. [2013]