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: 1

17 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new method to deliver chemotherapy directly to the lungs during surgery for sarcoma that has spread there. The goal is to determine if this method, called In Vivo Lung Perfusion (IVLP), can eliminate tiny cancer cells in the lungs while minimizing side effects on the rest of the body. Researchers will test different doses of the chemotherapy drug doxorubicin to identify the safest and most effective one. This trial may suit individuals under 65 with soft tissue or bone sarcoma that has spread to both lungs, with no other areas affected by cancer. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative approach.

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 prior data suggests that this technique is safe for delivering chemotherapy directly into the lungs?

Research has shown that using doxorubicin with a method called In Vivo Lung Perfusion (IVLP) is generally safe for treating lung cancer. One study found this approach safe and feasible for patients with sarcomas that have spread to the lungs. Another study demonstrated that IVLP with doxorubicin was well-tolerated by patients and did not harm the lungs during treatment.

Doxorubicin, the drug used in this treatment, has been used for other cancers and is known to be safe, although its use with IVLP is new. In animal studies, higher doses of doxorubicin proved safe and effective for treating lung tumors.

Overall, early evidence suggests that this new method of delivering chemotherapy directly to the lungs might reduce some common side effects. While this treatment is still in the early stages, these findings are promising for its safety. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about these treatments because they use a unique delivery method called in vivo lung perfusion, which administers Doxorubicin directly to the lungs during the surgical removal of cancerous growths. This targeted approach could potentially enhance the drug's effectiveness against lung cancer while minimizing side effects typically associated with systemic chemotherapy. Unlike traditional chemotherapy, which circulates throughout the entire body, this method focuses the treatment directly where it's needed most, offering hope for improved outcomes in patients with pulmonary metastases.

What evidence suggests that this technique is effective for lung cancer?

Research shows that using doxorubicin with a method called In Vivo Lung Perfusion (IVLP) may help treat lung tumors that have spread from sarcoma. In some studies, doxorubicin successfully eliminated lung tumors in animal tests and extended their lifespan. This trial will test different concentrations of doxorubicin delivered via IVLP during surgical resection of pulmonary metastases. This technique targets the chemotherapy directly to the lungs, potentially reducing side effects on other parts of the body. Early findings suggest that using doxorubicin in this way can be safe and maintains lung function during treatment. Although this method is still under investigation, these early results offer hope for better outcomes. ^{1 3 4 5 6}

Who Is on the Research Team?

Marcelo Cypel, MD MSc

Principal Investigator

University Health Network, Toronto

Are You a Good Fit for This Trial?

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

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Surgery and IVLP Treatment

Participants undergo surgical resection of pulmonary metastases with In Vivo Lung Perfusion (IVLP) using Doxorubicin

3 hours for IVLP during surgery

1 visit (in-person)

Post-Surgery Care

Participants are cared for post-surgery according to institutional standards

Varies based on recovery

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. sciencedirect.com sciencedirect.com/science/article/pii/S2950247024000574

Phase I dose escalation study for In Vivo Lung Perfusion ... Conclusions. Here, we demonstrate the safety and feasibility of doxorubicin as a treatment during IVLP for resectable limited pulmonary metastases for sarcomas.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/26952295/

Modified In Vivo Lung Perfusion for Local Chemotherapy Results: Lungs treated with Dox 75 mg/m(2) alone or combined with Ifos showed stable function throughout the procedure, without evidence of ALI (p = 0.12 and p ...

3. jtcvs.org jtcvs.org/article/S0022-5223(94)70452-X/fulltext

Isolated single lung perfusion with doxorubicin is effective ... Isolated lung perfusion with doxorubicin 320 μg/ml is safe and effective in eradicating experimental pulmonary sarcoma metastases in this model.

4. annalsthoracicsurgery.org annalsthoracicsurgery.org/article/S0003-4975(15)02034-2/fulltext

Modified In Vivo Lung Perfusion for Local Chemotherapy Isolated lung perfusion with doxorubicin prolongs survival in a rodent model of pulmonary metastases. Ann Thorac Surg. 1997; 64:181-184. Full ...

5. clinicaltrial.be clinicaltrial.be/en/details/10086?per_page=100&only_recruiting=1&enrolling_by_invitation=1&active_not_recruiting=1&completed=0&only_eligible=0&only_active=0

In Vivo Lung Perfusion for Pulmonary Metastases of ... After 3 hours of IVLP, the lung metastases will be removed in the usual fashion. Patients will be cared for post-surgery according to ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02811523

In Vivo Lung Perfusion for Pulmonary Metastases of Sarcoma It identifies the role of the intervention that participants receive. Types of arms include experimental arm, active comparator arm, placebo comparator arm, ...