Lurbinectedin + Doxorubicin for Leiomyosarcoma

Not currently recruiting at 5 trial locations

Overseen By Gregory Cote, M.D. Ph.D

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Massachusetts General Hospital

Must not be taking: CYP3A inhibitors, CYP2D6 inducers

Disqualifiers: CNS disease, Cardiomyopathy, others

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines the effectiveness of the drug combination lurbinectedin and doxorubicin for treating leiomyosarcoma, a type of soft tissue cancer. The first phase assesses the safety of using these drugs together. The second phase compares the effectiveness of the combination against lurbinectedin alone. Individuals with advanced leiomyosarcoma who have not responded to other treatments may be suitable candidates for this trial. As a Phase 1, Phase 2 trial, the research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot take medications that strongly affect certain liver enzymes (CYP3A, CYP2D6) or P-gp. It's important to discuss your current medications with the study team to avoid any interactions.

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

Research shows that the combination of lurbinectedin and doxorubicin is generally well tolerated by patients. Previous studies found this drug combination effective in treating certain types of soft tissue sarcoma, a kind of cancer. Most patients in these studies experienced the treatment without serious side effects, indicating a positive safety profile. However, as with all medications, some side effects might still occur, so discussing any concerns with the study team is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Lurbinectedin and Doxorubicin for treating leiomyosarcoma because it offers a novel approach compared to current treatments like Doxorubicin alone. Lurbinectedin works by inhibiting the transcription of cancer cells, potentially enhancing the effectiveness of Doxorubicin, which damages DNA in cancer cells. This combination could provide a more powerful attack against tumor growth, potentially leading to better outcomes for patients. Additionally, by using a defined phase 2 dose, the treatment aims to maximize benefits while managing side effects, setting it apart from existing options.

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

Research has shown that using lurbinectedin with doxorubicin may help treat leiomyosarcoma, a type of soft tissue cancer. In this trial, participants will receive either the combination of lurbinectedin and doxorubicin or doxorubicin alone. Studies have found the combination to be effective, especially in patients who have not previously received anthracyclines, a type of chemotherapy. Early trials demonstrated that using lurbinectedin with a low dose of doxorubicin worked well and was manageable for patients with advanced soft tissue sarcomas. Specifically, patients using this combination experienced tumor shrinkage, indicating its effectiveness. These findings suggest that lurbinectedin with doxorubicin could be a helpful treatment option for leiomyosarcoma. ^{1 2 5 6 7}

Who Is on the Research Team?

Gregory Cote, MD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

Adults with measurable soft tissue sarcoma, specifically leiomyosarcoma, who have no curative treatment options available. They must be over 18, not pregnant or breastfeeding, willing to use contraception, and have adequate organ function and bone marrow reserves. Prior cancer treatments are restricted.

Inclusion Criteria

My hepatitis B virus load is undetectable with treatment.

My organs and bone marrow are functioning well.

Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

I am not taking strong or moderate drugs that affect enzyme activity.

I have had interstitial pneumonitis or pulmonary fibrosis.

Pregnant women

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1b Treatment

Participants receive lurbinectedin with doxorubicin to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D)

21 days per cycle

Outpatient basis

Phase 2 Treatment

Randomized study to compare the efficacy of lurbinectedin with doxorubicin versus doxorubicin alone

Up to 12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Doxorubicin
• Lurbinectedin

Trial Overview The trial is testing the combination of lurbinectedin and doxorubicin versus lurbinectedin alone for treating leiomyosarcoma. It has two parts: one for tolerability assessment and another randomized part to compare effectiveness.

How Is the Trial Designed?

Group I: Lurbinectedin + Doxorubicin at RP2D Experimental Treatment 2 Interventions

The randomized two arm phase 2 trial will begin following the determination of the RP2D for lurbinectedin and doxorubicin. * Participants will be randomized 1:1 to enroll to either Arm 1 or Arm 2 * Participants enrolled to Arm 1 will receive Lurbinectedin with Doxorubicin at the RP2D defined during the phase 1b portion of the trial.

Group II: Lurbinectedin + Doxorubicin Phase I Experimental Treatment 2 Interventions

The phase 1b trial will follow a standard 3+3 design. Upon determination of the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of lurbinectedin plus doxorubicin. A treatment cycle will be defined as 21 consecutive days. Treatment will be administered on an outpatient basis * Lurbinectedin * Doxorubicin

Group III: Doxorubicin Monotherapy Active Control 1 Intervention

The randomized two arm phase 2 trial will begin following the determination of the RP2D for lurbinectedin and doxorubicin. * Participants will be randomized 1:1 to enroll to either Arm 1 or Arm 2 * Participants enrolled to Arm 2 will receive Doxorubicin at the standard dose of 75 mg/m2

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?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

Jazz Pharmaceuticals

Industry Sponsor

Trials

252

Recruited

35,100+

Bruce C. Cozadd

Jazz Pharmaceuticals

Chief Executive Officer since 2009

BA in Economics from Yale University, MBA from Stanford University

Dr. Austin

Jazz Pharmaceuticals

Chief Medical Officer since 2023

MD from the Royal College of Surgeons in Ireland

Published Research Related to This Trial

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]

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 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]

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]

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]

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 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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05099666

Lurbinectedin + Doxorubicin In Leiomyosarcoma This research study involves the study drug lurbinectedin in combination with doxorubicin. This research has two parts. The first part is being done to ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38723278/

Safety and Efficacy of the Combination Lurbinectedin plus ... In this phase 1b study, the recommended dose is lurbinectedin 3.2 mg/m2 in combination with doxorubicin 25 mg/m2 every 3 weeks.

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.TPS11590

Randomized controlled, open-label, phase IIb/III study of ... Preliminary results from two trials showed efficacy for LUR/DOX in anthracycline-naïve advanced Leiomyosarcoma (LMS) (1st or 2nd line) at ...

4. onclive.com onclive.com/view/lurbinectedin-plus-doxorubicin-shows-early-efficacy-and-safety-in-soft-tissue-sarcomas

Lurbinectedin Plus Doxorubicin Shows Early Efficacy and ... A full dose of lurbinectedin plus a low dose of doxorubicin was clinically active and tolerable in patients with advanced or metastatic soft tissue sarcomas.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5834091/

Antitumor activity of lurbinectedin (PM01183) and doxorubicin ... This manuscript describes the efficacy and safety of doxorubicin and lurbinectedin in a subgroup of 27 patients with relapsed SCLC from a phase I trial. Durable ...

6. aacrjournals.org aacrjournals.org/clincancerres/article/30/13/2702/746009/Safety-and-Efficacy-of-the-Combination

Safety and Efficacy of the Combination Lurbinectedin plus ... Our prior study showed lurbinectedin plus doxorubicin is well tolerated with promising clinical activity in STS.

7. fda.gov fda.gov/media/105933/download

PM01183 preliminary safety data from phase 2 studies has suggested that lurbinectedin given at 3.2 ... DOX, doxorubicin; ES, Ewing sarcoma; MTD ...