Lurbinectedin + Doxorubicin for Leiomyosarcoma

(SaLuDo Trial)

Recruiting at 79 trial locations

Overseen By Gaston Federico Boggio, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: PharmaMar

Must not be taking: Anthracyclines, Lurbinectedin, Trabectedin

Disqualifiers: Cardiac disease, Immunodeficiency, Hepatitis, 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

Compensation: Varies

Number of Visits: 3

Duration: 9-12 weeks

360 Participants Needed

Trial Summary

What is the purpose of this trial?

The primary objective of this phase IIb/III study is to evaluate whether the combination of lurbinectedin plus doxorubicin given as first line treatment for metastatic leiomyosarcoma (LMS) prolongs the progression-free survival (PFS) by Independent Review Committee (IRC) when compared to doxorubicin administered as a single agent.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but you must not use strong or moderate inhibitors or strong inducers of CYP3A4 activity within two weeks before starting the trial. There is also a required washout period of at least three weeks since your last systemic treatment.

Is the combination of Lurbinectedin and Doxorubicin safe for humans?

Doxorubicin, a component of the treatment, is known to cause heart-related side effects, but there are formulations like Myocet® and Doxil® that are designed to be less harmful to the heart. Common side effects include low white blood cell counts and eye-related issues, but these often resolve quickly after stopping the drug. ^{1 2 3 4 5}

What makes the drug combination of Lurbinectedin and Doxorubicin unique for treating leiomyosarcoma?

The combination of Lurbinectedin and Doxorubicin is unique because it has shown a 35% objective response rate in leiomyosarcoma, which is promising compared to typical chemotherapy response rates of 20-40% in soft tissue sarcomas. Lurbinectedin is a new anticancer agent that works by inhibiting oncogenic transcription, and when combined with Doxorubicin, it has demonstrated synergistic antitumor activity. ^{6 7 8 9 10}

Eligibility Criteria

Adults with metastatic Leiomyosarcoma who haven't had systemic therapy for their metastasis can join. They should have good organ function, no history of certain heart diseases or infections like HIV, and not be on drugs that affect liver enzymes. Women must not be pregnant and participants must use effective contraception.

Inclusion Criteria

I haven't had systemic therapy or anthracyclines for my metastatic disease.

It has been over two weeks since my last radiation treatment.

You have a hemoglobin level of 9.0 or higher, an ANC above 2.0 x 10^9/L, and a platelet count greater than 100 x 109/L (after any RBC transfusions).

Exclusion Criteria

I have previously been treated with anthracyclines, lurbinectedin, or trabectedin.

I have an infection that is not under control.

I had cancer before, but it was either skin cancer, cervical, breast, or superficial bladder cancer and was cured over 3 years ago.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive doxorubicin and lurbinectedin intravenously every three weeks on day 1 of each treatment cycle

9-12 weeks

3-4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

Treatment Details

Interventions

• Doxorubicin
• Lurbinectedin

Trial Overview The trial is testing if adding Lurbinectedin to Doxorubicin improves the time patients live without their cancer getting worse compared to using Doxorubicin alone. It's a phase IIb/III study where one group gets both drugs and another only gets Doxorubicin.

Participant Groups

Group I: Phase IIb (& Phase III if selected), Doxorubicin (dose C) + Lurbinectedin (dose D) Experimental Treatment 2 Interventions

Participants will receive doxorubicin intravenously q3wk on day 1 of each treatment cycle (treatment cycle = three weeks).

Group II: Phase IIb (& Phase III if selected), Doxorubicin (dose A) + Lurbinectedin (dose B) Experimental Treatment 2 Interventions

Participants will receive doxorubicin and lurbinectedin intravenously every three weeks (q3wk) on day 1 of each treatment cycle (treatment cycle = three weeks).

Group III: Phase IIb & Phase III, Doxorubicin Active Control 1 Intervention

Participants will receive doxorubicin intravenously q3wk on day 1 of each treatment cycle (treatment cycle = three weeks).

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?

PharmaMar

Lead Sponsor

Trials

93

Recruited

11,800+

José María Fernández de Sousa-Faro

PharmaMar

Chief Executive Officer since 1986

PhD in Biochemistry, Complutense University of Madrid

Carmen Cuevas Marchante

PharmaMar

Chief Medical Officer since 2002

MD, University of Navarra

Findings from Research

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 is associated with ocular adverse reactions, with conjunctivitis being the most common, but these reactions typically resolve quickly after stopping the drug, often within 24 hours.

The infrequent occurrence and rapid resolution of ocular side effects suggest that doxorubicin can be cautiously reintroduced in patients if further cancer treatment is necessary, despite the potential for these reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ocular adverse reactions associated with adriamycin (doxorubicin). Curran, CF., Luce, JK.[2019]

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]

Myocet®, a non-pegylated liposome-encapsulated form of doxorubicin, is designed to enhance the effectiveness of doxorubicin while reducing its cardiotoxicity, making it a safer option for breast cancer and other tumors.

Clinical evidence indicates that Myocet® has a lower incidence of hematological toxicity compared to conventional doxorubicin, and it effectively reduces the severity of cardiac events associated with treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Non-pegylated doxorubicin (Myocet®) as the less cardiotoxic alternative of free doxorubicin]. Nagykálnai, T.[2018]

Doxorubicin (DOX) is an effective chemotherapy drug for breast cancer that works by damaging DNA and inducing apoptosis, but it has a risk of cardiotoxicity, limiting the total dose patients can receive.

The PEGylated liposomal formulation of DOX (L-DOX), known as Doxil® or Caelyx®, has been developed to improve cardiovascular safety and increase circulation time, although it is not yet FDA approved for metastatic breast cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anticancer and cardio-protective effects of liposomal doxorubicin in the treatment of breast cancer. Franco, YL., Vaidya, TR., Ait-Oudhia, S.[2020]

In a phase II study involving 42 patients with metastatic soft tissue sarcoma, lurbinectedin combined with doxorubicin showed a disease control rate of 40% at 24 weeks, indicating promising efficacy, especially in patients with leiomyosarcoma.

Lurbinectedin was well tolerated, with the most common side effects being hematologic, and there were no treatment-related deaths, suggesting a favorable safety profile for this new anticancer agent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II multi-strata study of lurbinectedin as a single agent or in combination with conventional chemotherapy in metastatic and/or unresectable sarcomas. Cote, GM., Choy, E., Chen, T., et al.[2022]

In a phase I study involving 34 patients with recurrent advanced endometrial cancer, the combination of lurbinectedin and doxorubicin showed a favorable response rate of 42% in the expansion cohort, with a median duration of response of 7.5 months.

The treatment was associated with manageable side effects, primarily fatigue and reversible myelosuppression, indicating that while the therapy is effective, monitoring for these toxicities is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Doxorubicin plus lurbinectedin in patients with advanced endometrial cancer: results from an expanded phase I study. Kristeleit, R., Moreno, V., Boni, V., et al.[2022]

Lurbinectedin, at a dose of 3.2 mg/m2, shows superior efficacy as a monotherapy for relapsed small cell lung cancer (SCLC) compared to standard therapies, with a predicted hazard ratio for overall survival of 0.54 based on data from 387 patients.

The study indicates that the combination of lurbinectedin and doxorubicin also contributes positively to treatment outcomes, but lurbinectedin alone is effective enough to warrant its use as a primary treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A model-based head-to-head comparison of single-agent lurbinectedin in the pivotal ATLANTIS Study. Fudio, S., Pérez-Ramos, L., Asín-Prieto, E., et al.[2023]

The recommended dose for the combination of doxorubicin (50 mg/m2) and PM01183 (4.0 mg) was found to be manageable in patients with relapsed small-cell lung cancer (SCLC), with manageable side effects primarily including transient myelosuppression and mild to moderate fatigue and nausea.

This combination therapy demonstrated significant antitumor activity, especially in patients with sensitive relapsed SCLC, achieving a response rate of 91.7% and a median progression-free survival of 5.8 months, indicating its potential for further evaluation in larger trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of lurbinectedin (PM01183) and doxorubicin in relapsed small-cell lung cancer: results from a phase I study. Calvo, E., Moreno, V., Flynn, M., et al.[2022]

In a phase I study involving 31 patients with advanced solid tumors, lurbinectedin (PM01183) was safely administered at escalating doses, with a recommended dose of 7.0 mg for a 1-hour infusion every three weeks, showing manageable side effects.

While severe neutropenia was observed in 40% of patients, it was transient and did not lead to any clinical complications, indicating that PM01183 is both tolerated and has potential efficacy, as evidenced by a partial response in one patient with pancreatic adenocarcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-human phase I study of Lurbinectedin (PM01183) in patients with advanced solid tumors. Elez, ME., Tabernero, J., Geary, D., et al.[2022]

References

1. 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]

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

Ocular adverse reactions associated with adriamycin (doxorubicin). [2019]

3. Germany pubmed.ncbi.nlm.nih.gov

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

4. Hungary pubmed.ncbi.nlm.nih.gov

[Non-pegylated doxorubicin (Myocet®) as the less cardiotoxic alternative of free doxorubicin]. [2018]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Anticancer and cardio-protective effects of liposomal doxorubicin in the treatment of breast cancer. [2020]

6. England pubmed.ncbi.nlm.nih.gov

A phase II multi-strata study of lurbinectedin as a single agent or in combination with conventional chemotherapy in metastatic and/or unresectable sarcomas. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Doxorubicin plus lurbinectedin in patients with advanced endometrial cancer: results from an expanded phase I study. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

A model-based head-to-head comparison of single-agent lurbinectedin in the pivotal ATLANTIS Study. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Antitumor activity of lurbinectedin (PM01183) and doxorubicin in relapsed small-cell lung cancer: results from a phase I study. [2022]

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

First-in-human phase I study of Lurbinectedin (PM01183) in patients with advanced solid tumors. [2022]