Pioglitazone for Lung Cancer with Cachexia

(TRACE-1 Trial)

Overseen By Justin Brown

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Pennington Biomedical Research Center

Must not be taking: Thiazolidinediones, CYP2C inhibitors

Disqualifiers: Type 2 diabetes, Heart failure, Bladder cancer, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines whether pioglitazone, a medication that improves insulin sensitivity, can aid individuals with lung or gastrointestinal cancer who also suffer from cachexia, a condition causing severe weight and muscle loss. Researchers aim to determine if pioglitazone enhances muscle insulin use, which may be crucial for managing cachexia. Participants will receive either pioglitazone or a placebo (a pill with no active drug) to compare outcomes. The trial seeks individuals with advanced lung or gastrointestinal cancer, who experience muscle wasting and have insulin use issues but do not have diabetes. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to significant findings.

Do I have to stop taking my current medications?

The trial requires you to stop taking any current CYP2C inhibitors (like gemfibrozil) or CYP2C inducers (like rifampin). Other medications are not specifically mentioned, so consult with the trial team for more details.

Will I have to stop taking my current medications?

The trial requires that you stop taking any medications that are CYP2C inhibitors or inducers, like gemfibrozil or rifampin. If you are on these medications, you will need to discuss alternatives with your doctor.

Is there any evidence suggesting that pioglitazone is likely to be safe for humans?

Previous studies have shown that pioglitazone is generally safe for people. Research indicates no clear link between pioglitazone use and a higher cancer risk, suggesting it is well-tolerated. The FDA has already approved pioglitazone for treating diabetes, providing some assurance about its safety. It has positive effects on blood pressure and bone health. While no treatment is without risk, current evidence suggests pioglitazone is relatively safe for use in trials. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for lung cancer with cachexia?

Unlike the standard treatments for lung cancer with cachexia, which often focus on managing symptoms and improving nutrition, Pioglitazone takes a different approach by targeting the underlying metabolic processes. Pioglitazone is unique because it is a thiazolidinedione, typically used to treat type 2 diabetes, that works by activating PPAR-gamma receptors. This activation can potentially improve muscle and weight loss issues associated with cancer cachexia. Researchers are excited about Pioglitazone because it offers a novel mechanism that could address the root causes of cachexia, potentially improving quality of life for patients beyond what current care options achieve.

What evidence suggests that pioglitazone might be an effective treatment for lung cancer with cachexia?

Research has shown that pioglitazone, a drug typically used for diabetes, might benefit cancer patients with cachexia, a condition causing severe weight loss and muscle wasting. Animal studies suggest it could increase survival rates and prevent weight loss in those with tumors. Although human studies provide limited information, the drug is believed to improve muscle health by enhancing the body's insulin use, crucial for energy use and storage. In this trial, participants will receive either pioglitazone or a placebo to evaluate its potential in managing muscle loss in cancer patients with cachexia. ^{1 3 6 7 8}

Are You a Good Fit for This Trial?

This trial is for adults over 18 with advanced non-small-cell lung cancer and cachexia, a condition causing weight loss and muscle wasting. Participants must have insulin resistance but not diabetes, be able to follow the study plan, and consent to biospecimen collection. Exclusions include heart failure, pregnancy, MRI contraindications, prior TZD therapy or sensitivity, bladder cancer history, certain drug use, and inadequate liver function.

Inclusion Criteria

You have a condition called insulin resistance, which can be detected using a test called HOMA-IR.

My lung cancer is advanced and cannot be removed by surgery.

Allow the collection and storage of biospecimens and data for future use

Exclusion Criteria

Any other condition that, in the investigator's opinion, would preclude participation or successful compliance with the protocol

I have heart failure ranging from no symptoms to severe symptoms.

I have or am being treated for bladder cancer.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either pioglitazone or placebo to evaluate the effect on skeletal muscle insulin sensitivity

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Pioglitazone

Trial Overview The study tests if Pioglitazone (a medication) improves muscle insulin sensitivity in patients with lung cancer-related cachexia versus a placebo (inactive substance). Patients are randomly assigned to receive either Pioglitazone or placebo to compare effects on their body's response to insulin.

How Is the Trial Designed?

Group I: Pioglitazone Experimental Treatment 1 Intervention

Group II: Placebo Placebo Group 1 Intervention

Pioglitazone is already approved in United States for the following indications:

Approved in United States as Actos for:

• Type 2 diabetes mellitus

Who Is Running the Clinical Trial?

Pennington Biomedical Research Center

Lead Sponsor

Trials

314

Recruited

183,000+

Published Research Related to This Trial

Pioglitazone effectively increases insulin sensitivity and improves glycemic control in patients with type 2 diabetes, whether used alone or in combination with other medications, based on clinical trials.

The medication is generally well tolerated, with weight gain and edema being the most common side effects, and it also shows potential benefits in reducing cardiovascular risk and arteriosclerosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spotlight on pioglitazone in type 2 diabetes mellitus. Waugh, J., Keating, GM., Plosker, GL., et al.[2019]

Progestagens are currently the most effective and approved treatment for cancer-related cachexia in Europe, while several other proposed treatments have proven ineffective or inconclusive in clinical trials.

A multimodal approach that combines different therapies is suggested to be more effective in managing cancer-related cachexia due to its complex and multifactorial nature.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of cachexia in oncology. Tazi, E., Errihani, H.[2022]

The ACT-ONE trial is investigating the efficacy of MT-102, a novel treatment for cancer-associated cachexia, in 132 patients with late-stage non-small cell lung cancer or colorectal cancer, focusing on changes in body weight over a 16-week period.

MT-102 aims to reduce catabolism and increase anabolism through its unique mechanism of action, which includes non-selective β-blockade and partial β-2 receptor agonism, potentially offering a new therapeutic option for a condition that currently lacks widely approved treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The ACT-ONE trial, a multicentre, randomised, double-blind, placebo-controlled, dose-finding study of the anabolic/catabolic transforming agent, MT-102 in subjects with cachexia related to stage III and IV non-small cell lung cancer and colorectal cancer: study design. Stewart Coats, AJ., Srinivasan, V., Surendran, J., et al.[2021]

In a study of 13 patients with advanced cancer cachexia, a combination of the anabolic β2-agonist formoterol and the appetite stimulant megestrol acetate was found to be safe and well tolerated over an 8-week period, with few adverse reactions reported.

Of the patients who completed the treatment, 86% showed significant improvements in muscle size and/or function, indicating that this combination therapy could effectively address muscle loss in cancer cachexia and should be explored further in larger trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II trial of formoterol fumarate combined with megestrol acetate in cachectic patients with advanced malignancy. Greig, CA., Johns, N., Gray, C., et al.[2021]

Pioglitazone, a drug approved for type II diabetes, significantly reduced tumor load in lung adenocarcinoma by 64% and in squamous cell carcinoma by 35% when administered after tumor development had begun, indicating its potential as a cancer treatment.

The drug's anticancer effects were linked to its ability to induce apoptosis in cancer cells, demonstrating its dual role in managing diabetes and potentially inhibiting lung cancer progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemopreventive effects of pioglitazone on chemically induced lung carcinogenesis in mice. Wang, Y., James, M., Wen, W., et al.[2020]

In a study involving Walker-256 tumor-bearing rats, a combination of insulin (INS) and pioglitazone (PIO) significantly prevented weight loss and preserved fat mass, demonstrating a synergistic effect that was more effective than either treatment alone.

The combination therapy improved insulin sensitivity, as shown by better blood glucose clearance and reduced levels of factors that induce insulin resistance, highlighting the potential of this approach in treating cancer-related cachexia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Insulin in combination with pioglitazone prevents advanced cachexia in 256-Walker tumor-bearing rats: effect is greater than treatment alone and is associated with improved insulin sensitivity. Miksza, DR., Biazi, GR., Frasson, IG., et al.[2023]

Pioglitazone (PGZ) treatment in cancer cachexia significantly increased survival by 27.3% and preserved body mass in rats, indicating its potential as an effective intervention for cachexia-related weight loss.

PGZ also reduced tumor mass by 53.4% and improved glucose uptake in adipose tissue, suggesting it may counteract both the metabolic and physical effects of cachexia in cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pioglitazone treatment increases survival and prevents body weight loss in tumor-bearing animals: possible anti-cachectic effect. Beluzi, M., Peres, SB., Henriques, FS., et al.[2018]

In a study of 18,974 patients with type 2 diabetes, those who used pioglitazone had a significantly lower risk of developing chronic obstructive pulmonary disease (COPD), with a hazard ratio of 0.778 compared to non-users.

Longer durations of pioglitazone therapy were associated with even lower risks of COPD, suggesting that the medication may have protective effects against this respiratory condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pioglitazone and Risk of Chronic Obstructive Pulmonary Disease in Patients with Type 2 Diabetes Mellitus: A Retrospective Cohort Study. Tseng, CH.[2022]

In a trial comparing treatments for cancer anorexia/cachexia, megestrol acetate and dexamethasone both effectively enhanced appetite, but megestrol acetate showed a trend towards better outcomes in weight gain and appetite improvement.

Dexamethasone had a higher rate of side effects leading to treatment discontinuation compared to megestrol acetate, which also had a higher risk of deep venous thrombosis, indicating that while both medications are effective, their safety profiles differ significantly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized comparison of megestrol acetate versus dexamethasone versus fluoxymesterone for the treatment of cancer anorexia/cachexia. Loprinzi, CL., Kugler, JW., Sloan, JA., et al.[2017]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05919147

The Neuroendocrine Effects of Pioglitazone in Patients ... The goal of this clinical trial is evaluate the effect of pioglitazone compared with placebo on skeletal muscle insulin sensitivity in subjects with cancer and ...

2. app.trialscreen.org app.trialscreen.org/trials/phase-2-neuroendocrine-effects-pioglitazone-patients-lung-cancer-cachexia-trial-nct05919147

A Phase 2 study of pioglitazone in cancer cachexia A Phase 2 study of pioglitazone in cancer cachexia. Evaluating the effects of the diabetes drug pioglitazone on muscle health in cancer patients with cachexia.

3. withpower.com withpower.com/trial/phase-2-lung-neoplasms-6-2023-dccb0

Pioglitazone for Lung Cancer with Cachexia (TRACE-1 Trial) The available research shows that Pioglitazone may help increase survival and prevent weight loss in animals with tumors, which suggests it could be effective ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12321403/

Cancer therapy and cachexia - PMC - PubMed Central - NIH Affecting up to 80% of patients with advanced cancer and contributing to 20% of cancer-related deaths (3, 4), cachexia remains underdiagnosed in ...

5. frontiersin.org frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.599598/full

A Randomized Phase II Trial Comparing the Efficacy and ... A study reported that long-term treatment with clarithromycin increased the median survival of patients with non-small cell lung cancer (Mikasa ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3064052/

Cohort Study of Pioglitazone and Cancer Incidence in ... We found no clear evidence of an association between use of pioglitazone and risk of the incident cancers examined.

7. mdpi.com mdpi.com/2076-3417/15/4/1925

Therapeutic Potential and Challenges of Pioglitazone in ... Pioglitazone displays positive effects on lipid metabolism, blood pressure, endothelial function, bone density, and apoptosis of cancer cells.

8. jci.org jci.org/articles/view/191934

Cancer therapy and cachexia Affecting up to 80% of patients with advanced cancer and contributing to 20% of cancer-related deaths (3, 4), cachexia remains underdiagnosed in ...