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.

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

2 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests L19TNF with doxorubicin in patients with severe soft tissue sarcoma. It aims to see if this combination is safe and effective. L19TNF helps target cancer cells more precisely, while doxorubicin kills the cancer cells. Selinexor is a new type of treatment that has shown promise in treating soft tissue sarcoma.

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.

What evidence supports the effectiveness of the drug L19TNF + Doxorubicin for treating soft tissue sarcoma?

Research shows that Doxorubicin, a component of the treatment, is effective in reducing tumor survival in soft tissue sarcomas. Additionally, combining Doxorubicin with other agents like TRAIL can enhance its effectiveness, even overcoming resistance in certain cancer cells. ^{1 2 3 4 5}

Is the combination of L19TNF and Doxorubicin safe for humans?

Doxorubicin, a component of the treatment, has been studied extensively and is known to have some side effects, including myelosuppression (a decrease in bone marrow activity), which can lead to low white blood cell counts and increased infection risk. However, liposomal forms of doxorubicin, like Doxil, have shown reduced toxicity compared to standard doxorubicin, with fewer cases of severe neutropenia (low white blood cell count) and less hair loss. No cardiac toxicity was observed in some studies, although monitoring is important due to potential heart-related side effects. ^{2 3 6 7 8}

What makes the drug L19TNF + Doxorubicin unique for treating soft tissue sarcoma?

L19TNF + Doxorubicin is unique because it combines doxorubicin, a key drug for soft tissue sarcoma, with L19TNF, which may enhance the drug's effectiveness by targeting the tumor more precisely. This combination aims to improve outcomes compared to doxorubicin alone, which has limited efficacy in soft tissue sarcoma. ^{2 3 9 10 11}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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 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]

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]

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]

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]

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]

References

1. Greece pubmed.ncbi.nlm.nih.gov

Doxorubicin potentiates TRAIL cytotoxicity and apoptosis and can overcome TRAIL-resistance in rhabdomyosarcoma cells. [2019]

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

A phase II study of Doxil (liposomal doxorubicin): lack of activity in poor prognosis soft tissue sarcomas. [2022]

3. United States 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. [2022]

4. Egypt pubmed.ncbi.nlm.nih.gov

Doxorubicin-based chemotherapy for the palliative treatment of adult patients with locally advanced or metastatic soft-tissue sarcoma: a meta-analysis and clinical practice guideline. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Ifosfamide in the adjuvant therapy of soft tissue sarcomas. [2017]

6. England 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. [2022]

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

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

8. United States 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. [2022]

9. United States 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. [2020]

10. Greece pubmed.ncbi.nlm.nih.gov

Insulin-like growth factor-I receptor activation blocks doxorubicin cytotoxicity in sarcoma cells. [2014]

11. Egypt 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. [2022]