Chemotherapy for Lung Cancer

Overseen By Jennifer Lister, BSc CCRP

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: University Health Network, Toronto

Disqualifiers: Significant pulmonary disease, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

17 Participants Needed

Trial Summary

What is the purpose of this trial?

Sarcoma which has spread to the lungs is most often treated with surgery. Even with surgery, most patients will not be cured and will die from their disease, probably because of small cancer cells that are present in the lungs at the time of surgery, but cannot be seen or detected. It is for this reason that we are looking for a better treatment. Giving chemotherapy after surgery is generally not recommended because it has significant side effects and no benefit has been proven. This study is investigating a new technique for delivering chemotherapy directly into the lungs at the time of surgery. Delivering chemotherapy directly to the lungs could potentially kill any microscopic cancer cells that are present in the lungs at the time of surgery, while sparing other major organs in the body from the side effects of chemotherapy. This technique is called In Vivo Lung Perfusion (IVLP). This is a Phase I, non-randomized, dose escalation study that will act as a pilot study for a larger prospective, multicenter, controlled clinical trial. Patients who have bilateral disease will have one lung undergo IVLP and the other lung will remain untreated with the IVLP (the other lung will be treated as current standard of care - either surgery or radiation) as a control lung. The patients will undergo a posterolateral thoracotomy. Lung metastases will be identified by visualization or palpation. After surgical isolation of the lung by proximal control of pulmonary artery and veins, IVLP will be initiated. After 3 hours of IVLP, the lung metastases will be removed in the usual fashion. Patients will be cared for post-surgery according to institutional standards. The patients will be followed for up to 2 years. The primary endpoint is safety. Secondary endpoints include additional safety endpoints and efficacy.

Do I have to stop taking my current medications for this trial?

The trial protocol does not specify if you need to stop taking your current medications. However, since this is a surgical and chemotherapy trial, it's best to discuss your medications with the trial team.

What data supports the idea that Chemotherapy for Lung Cancer is an effective treatment?

The available research shows that doxorubicin, a drug used in chemotherapy, can be delivered directly to the lungs using a method called in vivo lung perfusion (IVLP). This allows for high doses of the drug to target lung cancer cells while minimizing exposure to the rest of the body. In studies involving pigs and humans, doxorubicin levels in lung tissue were effectively monitored and maintained within a therapeutic range, suggesting that this method can be effective in treating lung cancer. However, other studies indicate that while isolated lung perfusion with doxorubicin increases drug exposure in the lungs, it may not significantly improve tumor penetration, which is crucial for effectiveness. Therefore, while there is some evidence supporting the use of doxorubicin for lung cancer, its effectiveness may depend on the method of delivery and the ability to penetrate tumors. ^{1 2 3 4 5}

What safety data exists for doxorubicin in lung cancer treatment?

Doxorubicin is known for its dose-dependent cardiotoxicity, which limits its clinical use. Studies have shown that dexrazoxane is the only FDA-approved medication to mitigate this cardiotoxicity, although it may reduce chemotherapy effectiveness. Probucol and paeonol have been studied for their potential cardioprotective effects against doxorubicin-induced cardiotoxicity. Additionally, the combination of doxorubicin with paclitaxel can cause adverse cardiac effects, but dexrazoxane may reduce these risks. However, treatments like amifostine combined with doxorubicin can lead to bone density loss in animal models. Liposomal formulations like Lipodox® and Doxil® have been evaluated for their toxicity profiles in other cancer treatments. ^{6 7 8 9 10}

Is the drug Doxorubicin a promising treatment for lung cancer?

Doxorubicin is a powerful cancer-fighting drug that has been effective in treating many types of cancer, including lung cancer. It is known for its strong ability to kill cancer cells, making it a promising option for chemotherapy in lung cancer treatment. ^{6 11 12 13 14}

Research Team

Marcelo Cypel, MD MSc

Principal Investigator

University Health Network, Toronto

Eligibility Criteria

This trial is for people under 65 with sarcoma that has spread to both lungs, where one lung can be treated with surgery or radiation. They must have at least three lung lesions and no cancer outside the lungs. Patients should be relatively fit (ECOG 0-2) and not have had a lot of doxorubicin before.

Inclusion Criteria

I am under 65 years old.

I have three or more spots on my lungs.

I can take care of myself and am up and about more than half of the day.

Exclusion Criteria

Your heart's pumping ability is less than 50%.

Inability to understand the informed consent process

Current participation in another therapeutic clinical trial

Treatment Details

Interventions

• Doxorubicin
• In Vivo Lung Perfusion

Trial Overview The study tests In Vivo Lung Perfusion (IVLP), a technique delivering chemotherapy directly into the lungs during surgery, aiming to kill unseen cancer cells while reducing harm to other organs. One lung gets IVLP; the other is treated normally as a control.

Participant Groups

Group I: Doxorubicin 9 mcg/ml Experimental Treatment 1 Intervention

Doxorubicin 9mcg/ml by in vivo lung perfusion during surgical resection of pulmonary metastases

Group II: Doxorubicin 7 mcg/ml - expansion Experimental Treatment 1 Intervention

Expansion group at ideal dose

Group III: Doxorubicin 7 mcg/ml Experimental Treatment 1 Intervention

Doxorubicin 7mcg/ml by in vivo lung perfusion during surgical resection of pulmonary metastases

Group IV: Doxorubicin 5 mcg/ml Experimental Treatment 1 Intervention

Doxorubicin 5mcg/ml by in vivo lung perfusion during surgical resection of pulmonary metastases

Doxorubicin is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Adriamycin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Approved in European Union as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Approved in Canada as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Approved in Japan as Doxorubicin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Lymphomas
• Leukemias
• Multiple myeloma
• Kaposi's sarcoma
• Soft tissue sarcomas

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Findings from Research

The combination of Doxil (40 mg/m2) and vinorelbine (30 mg/m2) was found to be effective in treating metastatic breast cancer in a phase I study involving 30 women, with a recommended schedule for further testing.

This combination therapy demonstrated a favorable toxicity profile, with minimal severe side effects like neutropenia and a low incidence of significant nausea, vomiting, or hair loss, making it a promising option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of Doxil and vinorelbine in metastatic breast cancer. Burstein, HJ., Ramirez, MJ., Petros, WP., et al.[2020]

The proposed generic doxorubicin hydrochloride liposome injection (SPIL) demonstrated comparable antitumor efficacy to the reference product (Caelyx) in mouse models, significantly reducing tumor volume without significant differences in effectiveness at any tested dose.

Both SPIL and the reference injection exhibited similar toxicity profiles and pharmacokinetics, confirming their bioequivalence and supporting the development of affordable cancer treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lipodox® (generic doxorubicin hydrochloride liposome injection): in vivo efficacy and bioequivalence versus Caelyx® (doxorubicin hydrochloride liposome injection) in human mammary carcinoma (MX-1) xenograft and syngeneic fibrosarcoma (WEHI 164) mouse models. Burade, V., Bhowmick, S., Maiti, K., et al.[2018]

4'-deoxy-4'-iodo-doxorubicin (4'-deoxy-4'-I-DX) shows comparable anti-tumor activity to doxorubicin but is not cardiotoxic, making it a potentially safer alternative for cancer treatment.

The pharmacokinetics of 4'-deoxy-4'-I-DX differ from doxorubicin, with a shorter half-life and higher tissue concentrations in several organs, which may contribute to its reduced side effects while maintaining efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of 4'-deoxy-4'-iodo-doxorubicin in plasma and tissues of tumor-bearing mice compared with doxorubicin. Formelli, F., Carsana, R., Pollini, C.[2016]

The novel in vivo lung perfusion (IVLP) procedure allows for targeted delivery of high-dose doxorubicin (DOX) to treat residual lung micrometastatic disease, with effective monitoring of drug levels using a biocompatible nitinol wire coated with a sorbent (Bio-SPME).

In clinical trials involving pigs and two patients with metastatic osteosarcoma, DOX tissue concentrations were successfully monitored in real-time, showing levels between 15 and 293 μg/g, which helps ensure that drug delivery remains within the therapeutic window and allows for personalized treatment adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Solid phase microextraction chemical biopsy tool for monitoring of doxorubicin residue during in vivo lung chemo-perfusion. Bojko, B., Looby, N., Olkowicz, M., et al.[2021]

In a study using isolated lung perfusion (ILP) with doxorubicin in rats with pulmonary sarcoma, the addition of P-glycoprotein (P-gp) inhibitors did not enhance the tumor uptake of doxorubicin, indicating that P-gp modulation is not effective in this context.

Doxorubicin concentrations in tumors were significantly lower than in lung tissues, suggesting that factors other than P-gp, such as high interstitial fluid pressure or tumor vasculature barriers, may be responsible for the poor penetration of the drug into tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

P-glycoprotein modulation by valspodar and cyclosporin does not increase tumor uptake of doxorubicin administered via isolated lung perfusion to rats bearing sarcoma lung metastases. Kuemmerle, A., Yan, H., Krueger, T., et al.[2018]

Probucol pretreatment significantly increased the clearance of doxorubicin (DOX) in plasma and altered its distribution in various tissues, suggesting it affects the pharmacokinetics of DOX.

Probucol also provided cardioprotection against DOX-induced toxicity by improving the ATP/ADP ratio and reducing markers of heart damage, indicating its potential as a protective agent during chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New aspects in probucol cardioprotection against doxorubicin-induced cardiotoxicity. El-Demerdash, E., Ali, AA., Sayed-Ahmed, MM., et al.[2013]

Paeonol (Pae) has been shown to protect against doxorubicin (Dox)-induced cardiotoxicity in both rat models and primary cardiomyocytes by enhancing mitochondrial fusion and restoring cardiac function.

The protective mechanism involves the PKCε-Stat3-Mfn2 signaling pathway, where Pae activates Stat3 to promote Mfn2-mediated mitochondrial fusion, without compromising the anticancer efficacy of Dox.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paeonol protects against doxorubicin-induced cardiotoxicity by promoting Mfn2-mediated mitochondrial fusion through activating the PKCε-Stat3 pathway. Ding, M., Shi, R., Fu, F., et al.[2023]

In a study involving male rats treated with doxorubicin (DOX) and paclitaxel (PTX), the addition of dexrazoxane (DZR) significantly reduced the cardiotoxic effects of DOX, demonstrating its cardioprotective properties.

The combination of DOX and PTX did not worsen the heart damage caused by DOX alone, and DZR maintained its protective effects without increasing noncardiac toxicity, suggesting a safer treatment regimen for solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardioprotection by dexrazoxane in rats treated with doxorubicin and paclitaxel. Della Torre, P., Imondi, AR., Bernardi, C., et al.[2015]

Doxorubicin (DOX) is effective for treating childhood cancers but can cause heart damage, and while Dexrazoxane (DXR) is a known cardioprotectant, Amifostine (AMF) also shows protective properties but may negatively impact bone health.

In a study with female rats, treatments involving AMF, with or without DOX and DXR, led to significant decreases in bone mineral density and deterioration of bone microarchitecture, highlighting the need for careful consideration in cancer treatment combinations to avoid bone damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amifostine and dexrazoxane enhance the rapid loss of bone mass and further deterioration of vertebrae architecture in female rats. Mwale, F., Ciobanu, I., Demers, CN., et al.[2013]

In a study comparing 40 patients treated with Lipodox® to 120 matched patients treated with Doxil®, Lipodox® showed a significantly lower overall response rate of 4.3% compared to 18% for Doxil®, indicating reduced efficacy in treating recurrent ovarian cancer.

Despite similar toxicity profiles between Lipodox® and Doxil®, the lack of equivalent efficacy suggests that further prospective clinical studies are needed before Lipodox® can be considered a suitable substitute for Doxil®.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is it equivalent? Evaluation of the clinical activity of single agent Lipodox® compared to single agent Doxil® in ovarian cancer treatment. Smith, JA., Costales, AB., Jaffari, M., et al.[2019]

Doxorubicin and paclitaxel, when administered to rats, caused significant ultrastructural changes in normal lung tissues, with doxorubicin increasing collagen fiber content and paclitaxel leading to degeneration of cellular organelles.

The combination of doxorubicin and paclitaxel resulted in both types of damage, but the effects of paclitaxel were more pronounced, while the diluent Cremophor EL did not contribute to these degenerative changes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ultrastructural damage in lung tissues in rats treated with doxorubicin and paclitaxel. Take, G., Yamaç, D., Ozoğul, C., et al.[2015]

Anthracyclines, particularly doxorubicin (DOX), are highly effective antitumor drugs with a broad spectrum of activity against human cancers, although they can cause significant cardiotoxicity.

While several analogs of DOX have been developed to reduce toxicity and improve administration, none have demonstrated superior antitumor efficacy compared to DOX, which remains the most effective drug in this class despite ongoing efforts to mitigate its side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The anthracyclines: will we ever find a better doxorubicin? Weiss, RB.[2022]

In isolated lung perfusion studies, using 6% buffered hetastarch as the perfusate resulted in optimal conditions for delivering doxorubicin, leading to effective lung concentration levels.

The final concentration of doxorubicin in the lung is primarily influenced by the concentration of the drug in the perfusate and the duration of the perfusion, rather than the total dose or rate of perfusion, suggesting a more efficient approach to chemotherapy delivery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Isolated single-lung perfusion: a study of the optimal perfusate and other pharmacokinetic factors. Weksler, B., Ng, B., Lenert, JT., et al.[2016]

Naringin (NR) demonstrated significant cardioprotective effects against doxorubicin (Dox)-induced cardiac toxicity in male Wistar rats, as shown by improved oxidative stress markers and mitochondrial function after NR treatment.

The study suggests that combining NR with Dox could enhance the safety of Dox chemotherapy by mitigating its harmful effects on the heart, making it a potential adjunct therapy in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ameliorative effect of naringin against doxorubicin-induced acute cardiac toxicity in rats. Kwatra, M., Kumar, V., Jangra, A., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Phase I study of Doxil and vinorelbine in metastatic breast cancer. [2020]

2. England pubmed.ncbi.nlm.nih.gov

Lipodox® (generic doxorubicin hydrochloride liposome injection): in vivo efficacy and bioequivalence versus Caelyx® (doxorubicin hydrochloride liposome injection) in human mammary carcinoma (MX-1) xenograft and syngeneic fibrosarcoma (WEHI 164) mouse models. [2018]

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

Pharmacokinetics of 4'-deoxy-4'-iodo-doxorubicin in plasma and tissues of tumor-bearing mice compared with doxorubicin. [2016]

4. China pubmed.ncbi.nlm.nih.gov

Solid phase microextraction chemical biopsy tool for monitoring of doxorubicin residue during in vivo lung chemo-perfusion. [2021]

5. Greece pubmed.ncbi.nlm.nih.gov

P-glycoprotein modulation by valspodar and cyclosporin does not increase tumor uptake of doxorubicin administered via isolated lung perfusion to rats bearing sarcoma lung metastases. [2018]

6. Germany pubmed.ncbi.nlm.nih.gov

New aspects in probucol cardioprotection against doxorubicin-induced cardiotoxicity. [2013]

7. Egypt pubmed.ncbi.nlm.nih.gov

Paeonol protects against doxorubicin-induced cardiotoxicity by promoting Mfn2-mediated mitochondrial fusion through activating the PKCε-Stat3 pathway. [2023]

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

Cardioprotection by dexrazoxane in rats treated with doxorubicin and paclitaxel. [2015]

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

Amifostine and dexrazoxane enhance the rapid loss of bone mass and further deterioration of vertebrae architecture in female rats. [2013]

10. England pubmed.ncbi.nlm.nih.gov

Is it equivalent? Evaluation of the clinical activity of single agent Lipodox® compared to single agent Doxil® in ovarian cancer treatment. [2019]

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

Ultrastructural damage in lung tissues in rats treated with doxorubicin and paclitaxel. [2015]

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

The anthracyclines: will we ever find a better doxorubicin? [2022]

13. Netherlands pubmed.ncbi.nlm.nih.gov

Isolated single-lung perfusion: a study of the optimal perfusate and other pharmacokinetic factors. [2016]

14. England pubmed.ncbi.nlm.nih.gov

Ameliorative effect of naringin against doxorubicin-induced acute cardiac toxicity in rats. [2022]