L19TNF + Doxorubicin for Soft Tissue Sarcoma

(DOXO75 Trial)

Overseen By Serena Bettarini, Dr

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Philogen S.p.A.

Must not be taking: Corticosteroids, Anticoagulants, others

Disqualifiers: GIST, Kaposi sarcoma, others

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

Compensation: Varies

Number of Visits: 3

Duration: Up to 18 cycles

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety of a new treatment combination for individuals with advanced soft tissue sarcoma, a type of cancer. The treatment combines L19TNF, an experimental therapy, with doxorubicin, a standard cancer treatment, to determine the optimal dose. Individuals with soft tissue sarcoma that surgery or radiation cannot cure, and whose condition has recently worsened, may be suitable candidates for this study. 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 new therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does exclude participants who require chronic use of corticosteroids or other immunosuppressant drugs, and those using medications that prolong the QT/QTc interval. It's best to discuss your specific medications with the trial team.

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

Research has shown that using L19TNF with doxorubicin may help treat soft tissue sarcoma. Studies have found that patients with this condition can safely use this combination, and most tolerated the treatment well. In some cases, tumors even shrank, which is a positive sign.

Doxorubicin, a chemotherapy drug, already has FDA approval for treating various cancers, so its safety is well-known. However, all treatments can have side effects. Researchers are carefully studying the combination with L19TNF to ensure it is safe and effective. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of L19TNF and doxorubicin for soft tissue sarcoma because it offers a novel approach to treatment. Unlike standard chemotherapy options, which typically focus solely on killing cancer cells, L19TNF is a targeted therapy that combines with the body's immune system to attack tumors more effectively. This treatment harnesses the power of TNF (tumor necrosis factor), a protein that targets and disrupts the blood vessels feeding the tumor, potentially enhancing the effectiveness of doxorubicin. By combining these mechanisms, the treatment aims to improve outcomes for patients with soft tissue sarcoma in a way that standard treatments alone may not achieve.

What evidence suggests that L19TNF + Doxorubicin could be an effective treatment for soft tissue sarcoma?

This trial will evaluate the combination of L19TNF with doxorubicin for treating advanced soft tissue sarcoma. Research has shown that this combination may treat the condition more effectively than doxorubicin alone. Some patients experienced better cancer control with this combination. L19TNF aids the immune system in attacking the cancer, potentially enhancing the effects of doxorubicin. Early results are promising, suggesting this combination could be a good treatment option for people with this type of cancer. ^{1 3 4 6 7}

Are You a Good Fit for This Trial?

Adults aged 18-85 with advanced soft tissue sarcoma, excluding Kaposi's sarcoma and GIST, who haven't had certain prior treatments or have uncontrolled diseases. They must not be pregnant, agree to use effective contraception, have a measurable lesion by CT scan per RECIST criteria, an ECOG ≤ 2, and a life expectancy of at least 3 months.

Inclusion Criteria

Informed consent signed and dated to participate in the study

Histologically confirmed diagnosis of advanced unresectable or metastatic soft tissue sarcoma not amenable to curative treatment with surgery or radiotherapy. Participants with Kaposi's sarcoma and gastrointestinal stromal tumors (GIST) will be excluded. Note: Evidence of disease progression is required for participants that are not newly diagnosed

Documented negative test for HIV-HBV-HCV. For HBV serology: the determination of HBsAg, anti-HBsAg-Ab and anti-HBcAg-Ab is required. In patients with serology documenting previous exposure to HBV (i.e., anti-HBs Ab with no history of vaccination and/or anti-HBc Ab), negative serum HBV-DNA is required. For HCV: HCV-RNA or HCV antibody test. Subjects with a positive test for HCV antibody but no detection of HCV-RNA indicating no current infection are eligible

Exclusion Criteria

Inadequate liver function (ALT, AST, ALP or total bilirubin ≥ 2.5 x ULN)

Prior therapy (except surgery and radiation) for this presentation of unresectable or metastatic malignant soft tissue sarcoma

Previous treatment with anthracycline- or anthracenedione-containing chemotherapy

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive L19TNF and doxorubicin in 21-day cycles, with L19TNF administered on days 1, 3, and 5, and doxorubicin on day 1 of each cycle

Up to 18 cycles

3 visits per cycle (in-person)

Maintenance Therapy

Participants with stable or partial response after 6 cycles receive maintenance therapy with L19TNF every 3 weeks and doxorubicin in the first two maintenance cycles

Up to 18 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 72 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Doxorubicin
• L19TNF

Trial Overview The trial is testing the safety of combining L19TNF with doxorubicin in patients with soft tissue sarcoma. The goal is to find the best dose of doxorubicin that can be safely used alongside L19TNF.

How Is the Trial Designed?

Group I: Arm L19TNF + DOXO Experimental Treatment 2 Interventions

Patients will be treated with: * doxorubicin 75 mg/m2 i.v. on day 1 of each 21-day cycle; * L19TNF 13 µg/kg i.v. on day 1, 3 and 5 of each 21-day cycle

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

Doxorubicin, a common chemotherapy drug, shows limited survival benefits for patients with localized or metastatic soft tissue sarcoma, despite causing some tumor responses.

Activation of the insulin-like growth factor-I receptor (IGF-I-R) in sarcoma cells can lead to resistance against doxorubicin, suggesting that targeting IGF-I-R may improve the effectiveness of chemotherapy in treating soft tissue sarcoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Insulin-like growth factor-I receptor activation blocks doxorubicin cytotoxicity in sarcoma cells. Beech, DJ., Perer, E., Helms, J., et al.[2014]

The IVADo regimen, which combines doxorubicin with ifosfamide, vincristine, and actinomycin D, showed a 76% response rate in treating pediatric soft tissue sarcoma, indicating its efficacy in reducing tumor volume.

While the treatment was effective, it also resulted in significant toxicity, particularly myelosuppression, with 67% of cycles causing Grade 4 neutropenia, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The IVADo regimen--a pilot study with ifosfamide, vincristine, actinomycin D, and doxorubicin in children with metastatic soft tissue sarcoma: a pilot study of behalf of the European pediatric Soft tissue sarcoma Study Group. Bisogno, G., Ferrari, A., Bergeron, C., et al.[2022]

In a phase II study involving 16 patients with recurrent or metastatic soft tissue sarcomas, liposomal doxorubicin (Doxil) showed no significant responses, indicating limited efficacy in this specific patient population.

Despite the lack of effectiveness, Doxil was well tolerated, with no grade 4 toxicities and only a few instances of grade 3 toxicities, suggesting a favorable safety profile for future studies in different patient groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of Doxil (liposomal doxorubicin): lack of activity in poor prognosis soft tissue sarcomas. Garcia, AA., Kempf, RA., Rogers, M., et al.[2022]

ALGP-doxorubicin (ALGP-doxo) demonstrated significantly higher antitumoral efficacy compared to standard doxorubicin in patient-derived xenograft models of synovial sarcoma and dedifferentiated liposarcoma, leading to tumor shrinkage and stabilization.

The prodrug ALGP-doxo was well-tolerated at doses 30- to 40-fold higher than doxorubicin, with no significant adverse events reported, suggesting it may be a safer alternative for treating soft tissue sarcomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In Vivo Antitumoral Efficacy of PhAc-ALGP-Doxorubicin, an Enzyme-Activated Doxorubicin Prodrug, in Patient-Derived Soft Tissue Sarcoma Xenograft Models. Cornillie, J., Wozniak, A., Pokreisz, P., et al.[2020]

In a study of 504 patients with soft-tissue sarcomas receiving doxorubicin, the incidence of significant cardiotoxicity was low, even at high cumulative doses (>450 mg/m2), suggesting that doxorubicin can be safely administered with careful monitoring.

The use of the cardioprotectant dexrazoxane did not impact the efficacy of doxorubicin treatment, indicating that it can be an effective strategy to mitigate cardiotoxic risks without compromising cancer treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospective Evaluation of Doxorubicin Cardiotoxicity in Patients with Advanced Soft-tissue Sarcoma Treated in the ANNOUNCE Phase III Randomized Trial. Jones, RL., Wagner, AJ., Kawai, A., et al.[2022]

In a trial involving 94 patients with advanced soft-tissue sarcoma, CAELYX (pegylated liposomal doxorubicin) demonstrated a significantly lower incidence of severe myelosuppression and alopecia compared to standard doxorubicin, indicating a better safety profile.

Both CAELYX and doxorubicin showed similar antitumor activity, with response rates of 10% and 9% respectively, suggesting that CAELYX is a viable alternative for treatment with reduced toxicity, warranting further investigation in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL/CAELYX) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group. Judson, I., Radford, JA., Harris, M., et al.[2022]

The combination regimen of doxorubicin (DOX), ifosfamide (IFF), and dacarbazine (DTIC) demonstrated significant activity against previously untreated inoperable or metastatic sarcoma, with a partial response rate of 44% among evaluable patients.

The treatment was associated with acceptable toxicity, primarily myelosuppression, but no serious cardiac or renal toxicity was observed, suggesting a favorable safety profile for further evaluation in larger studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Doxorubicin, ifosfamide, and dacarbazine (AID) with mesna uroprotection for advanced untreated sarcoma: a phase I study. Elias, AD., Antman, KH.[2013]

TRAIL, a protein that induces cell death, was found to be effective in killing rhabdomyosarcoma cells, especially when combined with doxorubicin (DOX), which enhanced its cytotoxic effects across different cell lines, including those resistant to TRAIL.

In resistant cell lines, DOX was able to overcome TRAIL resistance, suggesting that combining TRAIL with DOX could be a promising strategy for treating soft tissue sarcomas that do not respond to standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Doxorubicin potentiates TRAIL cytotoxicity and apoptosis and can overcome TRAIL-resistance in rhabdomyosarcoma cells. Komdeur, R., Meijer, C., Van Zweeden, M., et al.[2019]

In a study of 75 patients with advanced soft tissue sarcoma treated with doxorubicin, combination therapy resulted in a better time to treatment failure (TTF) and overall response rate compared to doxorubicin monotherapy.

However, there was no significant difference in overall survival (OS) between combination therapy and monotherapy, suggesting that while combination therapy may improve short-term outcomes, it does not extend long-term survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcome for Advanced or Metastatic Soft Tissue Sarcoma of Nonextremities Treated with Doxorubicin-Based Chemotherapy: A Retrospective Study from a Single Cancer Institution. Marshall, S., Nakano, K., Sugiura, Y., et al.[2022]

Citations

1. 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 ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03420014

Study Details | NCT03420014 | Treatment of Metastatic Soft ... 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. 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 ... This clinical trial investigates the efficacy of combining L19TNF and Doxorubicin in treating patients with advanced or metastatic soft ...

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. 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 ... L19TNF is a biopharmaceutical product, proprietary to Philogen, studied for the treatment of advanced Soft Tissue Sarcoma and Glioblastoma.

7. sciencedirect.com sciencedirect.com/science/article/pii/S0959804921002057

Dose escalation and expansion phase I studies with the ... Conclusion. L19TNF can be safely applied in combination with doxorubicin and induces encouraging tumour remissions in patients with soft tissue sarcomas.