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

24 Participants Needed

Trial Summary

What is the purpose of this trial?

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 cachexia.

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.

What data supports the idea that Pioglitazone for Lung Cancer with Cachexia is an effective drug?

The available research shows that Pioglitazone may help increase survival and prevent weight loss in animals with tumors, which suggests it could be effective for treating cachexia in lung cancer. In one study, Pioglitazone treatment increased the average survival by 27.3% in tumor-bearing animals. Additionally, when combined with insulin, Pioglitazone was more effective in preventing advanced cachexia than when used alone. This suggests that Pioglitazone could be a promising option, especially when used with other treatments, although more research is needed to confirm its effectiveness in humans. ^{1 2 3 4 5}

What evidence supports the effectiveness of the drug Pioglitazone for treating lung cancer with cachexia?

Research on animals has shown that Pioglitazone may help increase survival and prevent weight loss in cases of cancer-related cachexia, which is a condition involving severe weight loss and muscle wasting. This suggests it might have potential benefits for people with lung cancer experiencing similar symptoms. ^{1 2 3 4 5}

What safety data exists for pioglitazone in treating lung cancer with cachexia?

Pioglitazone is generally well tolerated, with weight gain and edema being the most common adverse events. It has been studied primarily as an antihyperglycemic agent for type 2 diabetes, showing improvements in glycemic control and cardiovascular risk. Its effects on cancer cachexia have been less studied, but it has shown potential in improving insulin sensitivity and reducing tumor load in animal models. No specific safety data for pioglitazone in lung cancer with cachexia is available from the provided research. ^{1 3 6 7 8}

Is pioglitazone generally safe for humans?

Pioglitazone is generally well tolerated in humans, with weight gain and swelling being the most common side effects. It has been used safely in people with type 2 diabetes to improve blood sugar control and reduce some heart disease risks. ^{1 3 6 7 9}

Is the drug Pioglitazone a promising treatment for lung cancer with cachexia?

Yes, Pioglitazone shows promise as a treatment for lung cancer with cachexia. It has been found to reduce tumor growth in lung cancer and improve survival and body weight in animals with cancer, suggesting potential benefits in managing cancer-related weight loss and improving overall outcomes. ^{2 3 6 7 10}

What makes the drug pioglitazone unique for treating lung cancer with cachexia?

Pioglitazone is unique because it not only targets lung cancer by inhibiting tumor growth but also addresses cachexia (a condition of severe weight loss and muscle wasting) by improving insulin sensitivity and reducing fat and muscle loss, which are not typically targeted by standard cancer treatments. ^{2 3 6 7 10}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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]

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]

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]

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]

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]

References

1. Germany 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. [2021]

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

Pioglitazone treatment increases survival and prevents body weight loss in tumor-bearing animals: possible anti-cachectic effect. [2018]

3. Switzerland 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. [2023]

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

Randomized comparison of megestrol acetate versus dexamethasone versus fluoxymesterone for the treatment of cancer anorexia/cachexia. [2017]

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

Treatment of cachexia in oncology. [2022]

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

Chemopreventive effects of pioglitazone on chemically induced lung carcinogenesis in mice. [2020]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Spotlight on pioglitazone in type 2 diabetes mellitus. [2019]

8. Germany pubmed.ncbi.nlm.nih.gov

Phase I/II trial of formoterol fumarate combined with megestrol acetate in cachectic patients with advanced malignancy. [2021]

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

Rosiglitazone delayed weight loss and anorexia while attenuating adipose depletion in mice with cancer cachexia. [2021]

10. New Zealand pubmed.ncbi.nlm.nih.gov

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