L19TNF + Doxorubicin for Metastatic Leiomyosarcoma

(FIBROSARC US Trial)

Recruiting at 8 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial compares two treatments for individuals with advanced leiomyosarcoma, a cancer affecting smooth muscle tissue. It tests the effectiveness of a new drug, L19TNF (also known as Onfekafusp alfa or Fibromun), combined with the existing chemotherapy drug doxorubicin, against doxorubicin alone. Participants should have stage IV high-grade leiomyosarcoma that is not treatable with surgery or radiation. This trial may suit those with at least one measurable tumor who have not received certain prior treatments. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research is exploring whether combining L19TNF with doxorubicin can improve treatment for metastatic leiomyosarcoma, a type of cancer. Earlier studies tested whether this combination is more effective than doxorubicin alone and assessed patient tolerance.

Other studies have examined the use of L19TNF with doxorubicin in advanced soft tissue sarcoma, which is similar to leiomyosarcoma. These studies help determine the treatment's safety and patient response. Although specific safety details aren't provided here, the treatment's progression to later research stages suggests it has shown some safety and tolerance in earlier tests.

Doxorubicin is already a common cancer treatment with known side effects. The goal of adding L19TNF is to enhance its effectiveness, but potential side effects should be considered when contemplating trial participation. Consulting a healthcare provider is essential to understand the implications of joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for metastatic leiomyosarcoma, like traditional chemotherapy, focus on targeting rapidly dividing cells. But L19TNF works differently by delivering tumor necrosis factor (TNF) directly to the tumor using a targeting molecule called L19, which binds to blood vessels in tumors. This unique approach aims to enhance the tumor-killing effects of the standard chemotherapy drug doxorubicin. Researchers are excited because this combination could potentially increase the effectiveness of treatment while reducing damage to healthy tissues.

What evidence suggests that this trial's treatments could be effective for metastatic leiomyosarcoma?

Research has shown that doxorubicin alone is a common treatment for advanced leiomyosarcoma, a type of cancer. In this trial, one group of participants will receive doxorubicin alone, while another group will receive a combination of L19TNF and doxorubicin. Studies are exploring whether adding L19TNF to doxorubicin enhances treatment effectiveness. L19TNF targets the blood vessels supplying the tumor, potentially aiding doxorubicin in attacking cancer cells more successfully. Some early results suggest that this combination could be more effective than doxorubicin alone. The goal is to improve overall treatment, potentially leading to better patient outcomes. ^{1 3 6 7 8}

Who Is on the Research Team?

Scott Okuno, MD

Principal Investigator

Mayo Clinic, Rochester, MN

Are You a Good Fit for This Trial?

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 for a Trial Participant

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)

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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]

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]

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]

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]

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]

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 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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03420014

Study Details | NCT03420014 | Treatment of Metastatic Soft ... The primary objective of the trial is to evaluate if L19TNF in combination with doxorubicin (Arm 2) given for metastatic leiomyosarcoma improves efficacy ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04650984

NCT04650984 | A Study Comparing the Efficacy of L19TNF ... The present study is an open-label, randomized, controlled, two-arm multi-center study of the efficacy of L19TNF treatment in combination with doxorubicin ...

3. sarcoma-patients.org sarcoma-patients.org/fibrosarc-l19tnf/

FIBROSARC: L19TNF+Doxorubicin vs Doxorubicin alone ... This study is comparing the efficacy of L19TNF treatment in combination with doxorubicin versus doxorubicin alone in advanced or metastatic soft tissue sarcoma ...

4. trialfinder.panfoundation.org trialfinder.panfoundation.org/en-US/trial/listing/261216

A Study Comparing the Efficacy of L19TNF+Doxorubicin vs ... In the study, 102 patients will be randomized in a 1:1 ratio to receive doxorubicin treatment (Arm 1) or L19TNF treatment in combination with ...

5. synapse.patsnap.com synapse.patsnap.com/blog/preliminary-phase-iii-outcomes-of-onfekafusp-alfa-for-advanced-soft-tissue-sarcoma

Preliminary Phase III Outcomes of Onfekafusp Alfa for ... The FIBROSARC clinical study is a stage III investigation that randomly allocates participants on a 1:1 basis to assess the impact of combining L19TNF with ...

6. clin.larvol.com clin.larvol.com/trial-detail/NCT04650984

A Study Comparing the Efficacy of L19TNF+Doxorubicin vs ... GlobeNewswire 2024 - Philogen provides update on pre-planned interim analysis of the Phase III FIBROSARC trial investigating Onfekafusp alfa (L19TNF) in ...

7. clinicaltrials.eu clinicaltrials.eu/trial/study-on-l19tnf-and-doxorubicin-for-patients-with-advanced-or-metastatic-soft-tissue-sarcoma/

Study on L19TNF and Doxorubicin for Patients with ... In this trial, L19TNF is combined with doxorubicin to see if it improves the treatment outcomes for patients with advanced or metastatic soft tissue sarcoma.

8. philochem.ch philochem.ch/philochem/wp-content/uploads/2024/02/Press_release_Fibromun-FIBROSARC-interim-analysis-ENG.pdf

Philogen provides update on pre-planned interim analysis ... The Phase III FIBROSARC trial was designed to demonstrate a significant clinical benefit of L19TNF plus doxorubicin compared to doxorubicin ...