L19TNF + Doxorubicin for Metastatic Leiomyosarcoma

(FIBROSARC US Trial)

Recruiting at 7 trial locations

Overseen By Mahesh Seetharam, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Philogen S.p.A.

Must not be taking: Corticosteroids, Anticoagulants, others

Disqualifiers: Cardiac arrhythmias, Hypertension, others

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

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 27

Duration: 18 weeks

114 Participants Needed

Trial Summary

What is the purpose of this trial?

The present study is an open-label, randomized, controlled, two-arm multi-center study of the efficacy of L19TNF treatment in combination with doxorubicin versus doxorubicin alone in metastatic leiomyosarcoma patients.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you require chronic corticosteroids, other immunosuppressants, or anticoagulants, and you should not use other anti-cancer treatments during the study.

What data supports the effectiveness of the drug L19TNF + Doxorubicin for treating metastatic leiomyosarcoma?

Doxorubicin is commonly used as a first-line treatment for leiomyosarcoma, but it is often not effective on its own. However, in other studies, doxorubicin has shown some activity against different types of cancer, such as malignant mesothelioma, when used in a modified form. This suggests that doxorubicin might have potential when combined with other treatments like L19TNF. ^{1 2 3 4 5}

Is the combination of L19TNF and Doxorubicin safe for humans?

Doxorubicin is known to cause heart-related side effects, such as cardiotoxicity (damage to the heart muscle), which can be severe. Liposomal formulations of Doxorubicin may have lower risks of these side effects compared to conventional forms. There is no specific safety data available for L19TNF in combination with Doxorubicin. ^{6 7 8 9 10}

What makes the drug L19TNF + Doxorubicin unique for treating metastatic leiomyosarcoma?

L19TNF + Doxorubicin is unique because it combines Doxorubicin, a standard first-line treatment for metastatic leiomyosarcoma, with L19TNF, which may enhance the drug's effectiveness by targeting tumor cells more precisely. This combination aims to improve outcomes by potentially increasing the drug's ability to attack cancer cells while minimizing side effects. ^{1 3 11 12 13}

Research Team

Scott Okuno, MD

Principal Investigator

Mayo Clinic, Rochester, MN

Eligibility Criteria

This trial is for adults and fully grown minors (16+) with stage IV high-grade leiomyosarcoma, a type of soft tissue sarcoma. Participants must have a life expectancy over 3 months, be HIV/HBV/HCV negative, not pregnant or breastfeeding, and willing to use effective contraception. They should not have had previous anthracycline chemo, certain heart conditions or severe diseases that could affect study participation.

Inclusion Criteria

Life expectancy of at least 3 months in the judgment of the investigator

I have tested negative for HIV, hepatitis B, and C.

I am 16 or older and, if under 18, my growth plates have fused.

Exclusion Criteria

Abnormalities observed during baseline ECG and Echocardiogram investigations that are considered clinically significant by the investigator

My high blood pressure is not controlled, even with treatment.

Pregnancy or breast-feeding

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive doxorubicin or L19TNF plus doxorubicin in 21-day cycles

18 weeks

Every 3 weeks (in-person)

Maintenance

Participants continue treatment with monitoring every 12 weeks

54 weeks

Every 12 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 72 weeks

Every 12 weeks (in-person)

Treatment Details

Interventions

• Doxorubicin
• L19TNF

Trial Overview The study compares the effectiveness of L19TNF in combination with doxorubicin versus doxorubicin alone in treating metastatic leiomyosarcoma. It's an open-label trial where patients are randomly assigned to one of two groups: one receiving the combined treatment and the other just doxorubicin.

Participant Groups

Group I: Arm 2: L19TNF plus doxorubicin Experimental Treatment 1 Intervention

Patients will receive a fixed dose of L19TNF in combination with a fixed dose doxorubicin. Doxorubicin will be administered as a 15 ± 5 minutes i.v. infusion on day 1 of each 21-day cycle followed by at least 30 minutes pause before starting infusion of L19TNF.

Group II: Arm 1: Doxorubicin Active Control 1 Intervention

Patients will receive a fixed dose doxorubicin, administered as a 15 ± 5 minutes i.v. infusion.

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?

Philogen S.p.A.

Lead Sponsor

Trials

42

Recruited

2,400+

Findings from Research

In a study of 51 women with metastatic uterine leiomyosarcoma, the combination of fixed-dose rate gemcitabine and docetaxel as a second-line treatment showed an overall objective response rate of 27%, with a median duration of response lasting over 9 months.

The treatment was generally well-tolerated, with manageable side effects primarily involving myelosuppression, and a median progression-free survival of 5.6 months, indicating its potential effectiveness in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fixed-dose rate gemcitabine plus docetaxel as second-line therapy for metastatic uterine leiomyosarcoma: a Gynecologic Oncology Group phase II study. Hensley, ML., Blessing, JA., Degeest, K., et al.[2022]

In a phase II study involving 33 patients with malignant pleural mesothelioma, Caelyx (a liposomal form of doxorubicin) was found to be well tolerated, with mild toxicity primarily manifesting as palmar plantar erythrodysesthesia in 62% of patients.

Despite being well tolerated, Caelyx showed limited efficacy, with only 6% of patients achieving a partial response and a median survival of 13 months, indicating that it may not be a promising single-agent treatment for chemotherapy-naive mesothelioma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Caelyx in malignant mesothelioma: a phase II EORTC study. Baas, P., van Meerbeeck, J., Groen, H., et al.[2020]

The patient-derived orthotopic xenograft (PDOX) mouse model was developed to test treatments for leiomyosarcoma, a rare and difficult-to-treat cancer, using a tumor from a patient's thigh.

In this study, the combination of gemcitabine and docetaxel, trabectedin, and temozolomide were found to be highly effective against leiomyosarcoma, while the commonly used first-line treatment, doxorubicin, was ineffective, highlighting the PDOX model's ability to identify effective therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A patient-derived orthotopic xenograft (PDOX) nude-mouse model precisely identifies effective and ineffective therapies for recurrent leiomyosarcoma. Zhang, Z., Hu, K., Kiyuna, T., et al.[2020]

In a phase II trial involving 40 women with recurrent Müllerian malignancies, the combination of liposomal doxorubicin and paclitaxel showed an overall objective response rate of 29%, with a higher response rate of 54% in patients whose tumors recurred at least 6 months after platinum-based therapy.

The combination treatment was associated with increased skin toxicity, specifically palmar plantar erythrodysesthesia, but did not affect the pharmacokinetics of paclitaxel, indicating that while effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of liposomal doxorubicin and weekly paclitaxel for recurrent Müllerian tumors. Campos, SM., Matulonis, UA., Penson, RT., et al.[2019]

In a phase II clinical trial involving 37 patients with advanced uterine leiomyosarcoma, the MAP chemotherapy regimen (mitomycin, doxorubicin, and cisplatin) showed some efficacy, with 9% of patients achieving a complete response and 14% a partial response after a median of three treatment cycles.

While MAP demonstrated activity against this type of cancer, it also had significant side effects, including leukopenia and thrombocytopenia, and caused pulmonary toxicity in some patients, indicating a need for further refinement of treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of mitomycin, doxorubicin, and cisplatin in the treatment of advanced uterine leiomyosarcoma: a Gynecologic Oncology Group study. Edmonson, JH., Blessing, JA., Cosin, JA., et al.[2019]

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]

This study analyzed over 7.5 million reports from the FDA Adverse Event Reporting System and found that conventional doxorubicin (DOX) has a higher incidence of adverse events compared to liposomal formulations, particularly in terms of myelosuppression and cardiotoxicity.

Liposomal DOX, especially the PEGylated version, showed lower reporting odds ratios for serious side effects like myelosuppression and cardiotoxicity, but a higher risk for palmar-plantar erythrodysesthesia (PPE), indicating the need for careful monitoring when using these formulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the adverse event profiles of conventional and liposomal formulations of doxorubicin using the FDA adverse event reporting system. Fukuda, A., Tahara, K., Hane, Y., et al.[2022]

Doxorubicin (DOX) is a powerful chemotherapy drug, but it can cause serious heart damage (cardiotoxicity), which limits its use in treating solid tumors.

Research has identified several natural products and herb extracts that may help reduce DOX-induced heart damage without compromising its cancer-fighting ability, but more studies are needed to confirm their effectiveness in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent progress in doxorubicin-induced cardiotoxicity and protective potential of natural products. Yu, J., Wang, C., Kong, Q., et al.[2018]

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]

In a phase II study involving 35 patients with advanced uterine leiomyosarcomas, liposomal doxorubicin showed limited efficacy, with only 1 complete response and 4 partial responses, indicating it may not be more effective than traditional doxorubicin.

The treatment was associated with significant toxicity, including grade 3 or 4 neutropenia in 16.1% of patients and gastrointestinal issues in several cases, highlighting the need for careful monitoring of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II evaluation of liposomal doxorubicin (Doxil) in recurrent or advanced leiomyosarcoma of the uterus: a Gynecologic Oncology Group study. Sutton, G., Blessing, J., Hanjani, P., et al.[2022]

Liposomal formulations of anthracycline antibiotics, like Doxil and DaunoXome, improve the pharmacokinetics of these drugs, leading to longer circulation times and reduced toxicity compared to their free forms.

These liposomal formulations are effective in treating certain cancers, such as AIDS-related Kaposi's sarcoma, and their design allows for enhanced uptake by tumor cells when coupled with monoclonal antibodies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Liposomal formulations of anthracycline antibiotics]. Berezov, TT., Iaglova, NV., Chekhonin, VP., et al.[2014]

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]

References

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

Fixed-dose rate gemcitabine plus docetaxel as second-line therapy for metastatic uterine leiomyosarcoma: a Gynecologic Oncology Group phase II study. [2022]

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

Caelyx in malignant mesothelioma: a phase II EORTC study. [2020]

3. Netherlands pubmed.ncbi.nlm.nih.gov

A patient-derived orthotopic xenograft (PDOX) nude-mouse model precisely identifies effective and ineffective therapies for recurrent leiomyosarcoma. [2020]

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

Phase II study of liposomal doxorubicin and weekly paclitaxel for recurrent Müllerian tumors. [2019]

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

Phase II study of mitomycin, doxorubicin, and cisplatin in the treatment of advanced uterine leiomyosarcoma: a Gynecologic Oncology Group study. [2019]

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

Comparison of the adverse event profiles of conventional and liposomal formulations of doxorubicin using the FDA adverse event reporting system. [2022]

9. Germany pubmed.ncbi.nlm.nih.gov

Recent progress in doxorubicin-induced cardiotoxicity and protective potential of natural products. [2018]

10. Germany pubmed.ncbi.nlm.nih.gov

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

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

Phase II evaluation of liposomal doxorubicin (Doxil) in recurrent or advanced leiomyosarcoma of the uterus: a Gynecologic Oncology Group study. [2022]

12. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Liposomal formulations of anthracycline antibiotics]. [2014]

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

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