Lurbinectedin + Immunotherapy for Soft Tissue Sarcoma

(LINNOVATE Trial)

Overseen By Victoria Chua-Alcala, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: ERLINDA M GORDON

Must not be taking: Corticosteroids, Chemotherapy, Immunotherapy, others

Disqualifiers: CNS metastases, Autoimmune disease, HIV, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment combination for individuals with advanced soft tissue sarcoma, a cancer that forms in the body's soft tissues. The study examines the effectiveness of a drug called Lurbinectedin when combined with two immunotherapy drugs, Ipilimumab and Nivolumab. Participants will receive varying doses to determine the safest and most effective levels. Individuals with soft tissue sarcoma that cannot be surgically removed, regardless of previous treatments, may qualify 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 combination therapy.

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 have had anticancer treatment within 2-3 weeks before starting the trial, and you should not be on certain immunotherapies or systemic immunosuppressants.

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

Research has shown that lurbinectedin, the main treatment under study, has been safe and generally well-tolerated in past studies. In one study, combining lurbinectedin with doxorubicin (another cancer drug) showed promise in treating soft tissue sarcomas, and patients tolerated the combination well. Another study found that lurbinectedin was safe for patients with advanced cancers at certain doses.

Ipilimumab and nivolumab, used with lurbinectedin in this trial, have FDA approval for other conditions, indicating a known safety record. However, the safety of the combination and doses used in this trial for soft tissue sarcoma remains under investigation.

This trial is in an early stage, so researchers are closely monitoring safety and determining the best dose. Participants should consider the possible risks and benefits before joining. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of lurbinectedin with immunotherapy agents like ipilimumab and nivolumab for treating advanced soft tissue sarcoma. Unlike traditional chemotherapy, lurbinectedin targets cancer cells by binding to their DNA, disrupting transcription processes, which is a unique mechanism compared to existing treatments. Additionally, the use of immunotherapy drugs ipilimumab and nivolumab, which enhance the body's immune response to cancer, represents a promising approach that could work synergistically with lurbinectedin to improve outcomes. This combination therapy aims to offer a more effective and potentially safer option by leveraging both direct cancer cell targeting and immune system activation.

What evidence suggests that this trial's treatments could be effective for soft tissue sarcoma?

Research has shown that lurbinectedin may help treat soft tissue sarcomas. In a study where lurbinectedin was combined with doxorubicin, patients responded well to the treatment, and it was generally safe. On average, patients' cancer did not worsen for 16.5 months. Some patients even saw their tumors shrink or stop growing. In this trial, participants will receive lurbinectedin in combination with ipilimumab and nivolumab. These results suggest that lurbinectedin could be effective, especially when used with other treatments like ipilimumab and nivolumab, for managing advanced soft tissue sarcomas. ^{1 3 4 5 6}

Who Is on the Research Team?

Erlinda M Gordon, MD

Principal Investigator

Sarcoma Oncology Research Center

Are You a Good Fit for This Trial?

Adults over 18 with advanced soft tissue sarcoma, either previously treated (for Phase 1) or untreated (for Phase 2), can join this trial. They must have measurable disease, good blood counts and organ function, understand the study risks, consent in writing, be willing to follow procedures for the study's duration, use effective contraception, and have a life expectancy of at least 3 months. Those with certain health conditions or treatments are excluded.

Inclusion Criteria

All women of childbearing potential must have a negative pregnancy test and all subjects must agree to use highly effective means of contraception (surgical sterilization or the use of barrier contraception with either a condom or diaphragm in conjunction with spermicidal gel or an IUD) with their partner from entry into the study through 5 months for women and 7 months for men after the last dose

Willingness to comply with all study procedures and availability for the duration of the study

Measurable disease by RECIST v1.1

Exclusion Criteria

Current, active, or previous history of heavy alcohol abuse

I haven't had vaccines for infectious diseases in the last 4 weeks.

I am on immunosuppressive therapy or I am HIV positive.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation Phase 1

Participants receive escalating doses of LURBINECTEDIN with fixed doses of IPILIMUMAB and NIVOLUMAB to determine the maximum tolerated dose (MTD).

6 weeks

Visits every 3 weeks for dose administration

Phase 2

Participants receive LURBINECTEDIN at the MTD and fixed doses of IPILIMUMAB and NIVOLUMAB to assess overall safety and potential efficacy.

12 months

Regular visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• Lurbinectedin

Trial Overview The LINNOVATE trial is testing different doses of Lurbinectedin given through IV along with set doses of Ipilimumab and Nivolumab also administered via IV. It's an open-label phase 1/2 study which means everyone knows what treatment they're getting and there are two parts: dose-finding followed by effectiveness testing.

How Is the Trial Designed?

Group I: Phase 1/2 study using lurbinectedin, ipilimumab and nivolumab for advanced soft tissue sarcoma Experimental Treatment 1 Intervention

This is an open label, dose-seeking phase 1/2 study using escalating doses of LURBINECTEDIN administered intravenously with fixed doses of IPILIMUMAB and NIVOLUMAB administered intravenously. I. Dose Escalation Phase 1 of Study: The study will employ the standard "cohort of three" design (Storer, 1989). II.Phase 2 of Study: Following completion of dose escalation, an additional 28-34 previously untreated participants will receive LURBINECTEDIN at the MTD and fixed doses of IPILIMUMAB and NIVOLUMAB to assess overall safety and potential efficacy in a larger number of participants.

Lurbinectedin is already approved in United States, European Union for the following indications:

Approved in United States as Zepzelca for:

• Metastatic small-cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy

Approved in European Union as Zepzelca for:

• Metastatic small-cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy

Who Is Running the Clinical Trial?

ERLINDA M GORDON

Lead Sponsor

Trials

1

Recruited

40+

Published Research Related to This Trial

In a phase II study involving 8 patients with advanced cutaneous T-cell lymphoma, alemtuzumab showed a modest overall response rate of 38%, with some patients achieving partial remission, but responses were short-lived, lasting less than 3 months.

The treatment was associated with significant toxicity, including severe cytopenias and infectious complications, indicating that while alemtuzumab has some biological activity, its safety profile and limited efficacy suggest the need for further research into combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of patients with advanced mycosis fungoides and Sézary syndrome with alemtuzumab. Kennedy, GA., Seymour, JF., Wolf, M., et al.[2021]

Alemtuzumab is highly effective for treating refractory Sézary syndrome (SS), showing an overall response rate of 81% and a complete response rate of 38% in a meta-analysis of 308 patients, compared to lower response rates in mycosis fungoides (MF).

Patients receiving alemtuzumab experienced more side effects, particularly with intravenous administration and higher doses, but low-dose subcutaneous administration resulted in fewer adverse events, making it a safer option for SS treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alemtuzumab is an effective third-line treatment versus single-agent gemcitabine or pralatrexate for refractory Sézary syndrome: a systematic review. Stewart, JR., Desai, N., Rizvi, S., et al.[2022]

Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma, and while there are various treatment options for early-stage disease, advanced-stage MF still lacks effective therapies, highlighting a significant unmet medical need.

Current research is focused on novel agents like brentuximab vedotin and mogamulizumab in randomized phase 3 trials, which may lead to more effective targeted therapies for advanced MF and Sézary syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How I treat mycosis fungoides and Sézary syndrome. Whittaker, S., Hoppe, R., Prince, HM.[2021]

In a phase II pilot study involving 24 patients with chronic lymphocytic leukemia (CLL) who had previously undergone chemotherapy, alemtuzumab demonstrated significant efficacy, with 33% of patients achieving a major response and a median survival time of 35.8 months.

Despite its effectiveness, the treatment was associated with a high incidence of opportunistic infections due to low lymphocyte counts, suggesting that future studies should implement mandatory antimicrobial prophylaxis to enhance patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine. Rai, KR., Freter, CE., Mercier, RJ., et al.[2017]

In a study of 44 mycosis fungoides patients treated with chlormethine/mechlorethamine, those on maintenance therapy achieved a 65.22% progression-free survival rate, with a median time to progression of 29.45 months.

Both active and maintenance treatments with chlormethine/mechlorethamine led to significant improvements in skin condition (measured by mSWAT) and quality of life, suggesting its efficacy as a maintenance therapy for patients in remission.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Response to Chlormethine/Mechlorethamine gel Maintenance Treatment Regimen in Patients With Mycosis Fungoides: A Single-center Retrospective Study. Correia, E., Krishnasamy, S., Suriano, JG., et al.[2022]

Citations

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

Safety and Efficacy of the Combination Lurbinectedin plus ... Our prior study showed lurbinectedin plus doxorubicin is well tolerated with promising clinical activity in STS. We designed this phase 1b trial ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2018.36.15_suppl.11519

Efficacy and safety of lurbinectedin (PM1183) in Ewing ... Efficacy: 4 pts (14.3%) had a partial response and 12 (42.8%) had disease stabilization, 6 of them for ≥4 months. Median duration of the ...

3. 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.

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

Safety and Efficacy of the Combination Lurbinectedin plus ... At the time of data cutoff, the estimated median progression-free survival is 16.5 months [95% confidence interval (CI), 6.0–ND]. The objective response rate ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT02611024

NCT02611024 | Pharmacokinetic Study of Lurbinectedin in ... Following the finding of promising efficacy to date, two expansion cohorts in the Lurbinectedin Escalation Group will be further expanded: The cohort of ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6386594/

Safety and tolerability of lurbinectedin (PM01183) in ... The phase 1 trial reported here found lurbinectedin to be safe and tolerated in patients with advanced AML/MDS at up to 3 mg when dosed on days 1–3, and up to 5 ...