Combination Therapy for Sarcoma

Not yet recruiting at 13 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Alabama at Birmingham

Must not be taking: Immunosuppressants, Vitamin E

Disqualifiers: Organ transplant, Autoimmune disorders, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore the effectiveness of a new combination treatment for different types of sarcoma, which are cancers affecting connective tissues like muscles or bones. The trial specifically examines how the drugs selumetinib (Koselugo), BI, and durvalumab work together against these cancers. Individuals with sarcomas that have not responded to standard treatments or whose tumors cannot be surgically removed might be suitable candidates for this study. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, it advises avoiding medications that may interfere with the study drugs, particularly those affecting liver enzymes CYP1A2, CYP2C19, and CYP3A4. It's best to discuss your current medications with the trial team.

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

Research has shown that selumetinib, one of the treatments in this trial, is generally well-tolerated by patients with certain types of sarcomas, such as malignant peripheral nerve sheath tumors (MPNST). While some patients may experience side effects, many of these can be managed. Common side effects include skin rashes and tiredness. Selumetinib is already approved by the FDA for other conditions, indicating a certain level of known safety.

Regarding durvalumab, another treatment in this trial, previous studies suggest it is also generally well-tolerated. Durvalumab helps the immune system fight cancer. Some patients might feel tired or have mild skin reactions, but these are often manageable.

The trial is in phase 2, meaning earlier phases have already tested the safety of these treatments. Existing safety information is available, but ongoing studies continue to monitor and evaluate how well patients handle the treatment combinations. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination therapy involving Selumetinib, BI, and Durvalumab for treating sarcoma because it offers a novel approach compared to standard treatments. Unlike traditional chemotherapy, which attacks cancer cells indiscriminately, Selumetinib targets specific pathways involved in cell growth, potentially leading to fewer side effects. Additionally, Durvalumab is an immunotherapy that helps the immune system recognize and attack cancer cells more effectively. This combination could offer a more targeted and effective treatment for patients with unresectable or metastatic neurofibromatosis-associated malignant peripheral nerve sheath tumors (MPNST), a condition with limited current options.

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

Research has shown that selumetinib, one of the treatments in this trial, may help treat certain sarcomas, including malignant peripheral nerve sheath tumors (MPNST), when combined with other treatments. Studies have found that selumetinib improves patient response to treatment compared to a placebo. Specifically, it has reduced the size of plexiform neurofibromas, which are nerve tumors, in patients with neurofibromatosis type 1 (NF1). This combination treatment targets specific parts of the tumor's growth process. While more research is needed, these findings offer hope for individuals with difficult-to-treat sarcomas. ^{1 2 6 7 8}

Are You a Good Fit for This Trial?

Adults (18+ years) with specific sarcomas, including MPNST and no standard treatment options left. They must have measurable disease, be over 30 kg in weight, recovered from previous treatments' side effects, not used certain inhibitors or immunosuppressants recently, and have proper organ function. Women of childbearing potential must use effective birth control.

Inclusion Criteria

Patients must have a life expectancy of at least 12 weeks

My cancer is a specific type of sarcoma in the soft tissue or bone.

I meet the criteria for receiving treatments like chemotherapy or immunotherapy.

Exclusion Criteria

I have severe lung problems or heart conditions.

History of allogeneic organ transplantation

Patients with severe and/or uncontrolled medical conditions

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Part A: Dose Escalation

Phase 1 dose escalation study of the combination with selumetinib and BI

6 months

Phase 1 Part B: Combination with Durvalumab

Phase 1 study combining the determined dose of selumetinib and BI from Part A with durvalumab

6 months

Phase 2: Simon's Two-Stage Design

Phase 2 study combining selumetinib, BI with durvalumab in MPNST patients to determine clinical benefit

24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

What Are the Treatments Tested in This Trial?

Interventions

• Selumetinib

Trial Overview The trial is testing Selumetinib combined with a Bromodomain Inhibitor and Durvalumab on patients with refractory/unresectable sarcomas. It's an open-label phase 1/2 study where all participants receive the experimental drugs to see how well they work and what the side effects are.

How Is the Trial Designed?

Group I: Phase 1 and 2 Study of Selumentinib, BI and Durvalumab Experimental Treatment 1 Intervention

Part A will be a phase 1 dose escalation study of the combination with selumetinib and BI, and, Part B will be phase 1 study combining the determined dose of selumetinib and BI from Part A with durvalumab. Part C will be a phase 2 study combining selumetinib, BI with durvalumab in MPNST patients at the recommended doses from part B. A Simon's two-stage design will be used in the phase 2 trial to determine the clinical benefit in patients with unresectable or metastatic NF associated MPNST.

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

Approved in United States as Koselugo for:

• Neurofibromatosis type 1 (NF1) in pediatric patients 2 years of age and older with symptomatic, inoperable plexiform neurofibromas (PN)

Approved in European Union as Koselugo for:

• Neurofibromatosis type 1 (NF1) in pediatric patients 2 years of age and older with symptomatic, inoperable plexiform neurofibromas (PN)

Who Is Running the Clinical Trial?

University of Alabama at Birmingham

Lead Sponsor

Trials

1,677

Recruited

2,458,000+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Published Research Related to This Trial

Vemurafenib showed a strong cytostatic effect in a liposarcoma cell line (SA-4) by causing cell cycle arrest, but required higher doses compared to its effects in melanoma cells, indicating a need for continuous treatment for sustained growth inhibition.

Overall, vemurafenib had limited effectiveness in other sarcoma cell lines with the BRAFV600E mutation, suggesting that it may not be a sufficient standalone therapy and highlighting the potential for exploring combination treatments with other drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Evaluation of Vemurafenib as Therapy for BRAFV600E Mutated Sarcomas. Gouravan, S., Meza-Zepeda, LA., Myklebost, O., et al.[2018]

In a phase 2 study involving 86 patients with advanced soft-tissue or bone sarcoma, pembrolizumab demonstrated some efficacy, particularly in undifferentiated pleomorphic sarcoma (40% response rate) and dedifferentiated liposarcoma (20% response rate), although the overall response rate did not meet the primary endpoint.

The treatment was associated with some serious adverse events, including immune-related conditions like adrenal insufficiency and pneumonitis, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Tawbi, HA., Burgess, M., Bolejack, V., et al.[2022]

Selumetinib (KOSELUGO) was approved by the FDA for treating pediatric patients aged 2 and older with inoperable plexiform neurofibromas, showing a 66% overall response rate in a trial of 50 patients, with many experiencing significant symptom relief for at least 12 months.

While selumetinib is effective, it carries risks typical of MEK inhibitors, including potential ocular, cardiac, and gastrointestinal side effects, but the overall benefit-risk assessment is considered favorable for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Selumetinib for Plexiform Neurofibroma. Casey, D., Demko, S., Sinha, A., et al.[2022]

In a phase II trial involving 212 patients with advanced sarcomas, ridaforolimus demonstrated a clinical benefit response rate of 28.8%, indicating its potential effectiveness in this heavily pretreated population.

The treatment was associated with manageable side effects, primarily mild to moderate, such as stomatitis and fatigue, suggesting that ridaforolimus is a relatively safe option for patients with advanced sarcomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of the mammalian target of rapamycin inhibitor ridaforolimus in patients with advanced bone and soft tissue sarcomas. Chawla, SP., Staddon, AP., Baker, LH., et al.[2022]

In a phase I/II trial involving 32 patients with K-RAS mutated colorectal cancer, the combination of selumetinib and irinotecan showed promising efficacy, with a 9.7% partial response rate and 51.6% of patients achieving stable disease for at least 4 weeks.

The recommended dose of selumetinib was established at 75 mg twice daily, and while the study was terminated early, the results suggest that further research into MEK inhibitors for treating metastatic colorectal cancer is warranted.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of selumetinib (AZD6244, ARRY-142886) plus irinotecan as second-line therapy in patients with K-RAS mutated colorectal cancer. Hochster, HS., Uboha, N., Messersmith, W., et al.[2022]

Citations

1. thelancet.com thelancet.com/journals/lancet/article/PIIS0140-6736(25)00986-9/fulltext?rss=yes

Efficacy and safety of selumetinib in adults with ... Data from the primary analysis of KOMET indicate that selumetinib treatment achieved a significant objective response rate versus placebo by ...

2. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK595153/

Clinical Review - Selumetinib (Koselugo) - NCBI - NIH The objective of the current report is to review the beneficial and harmful effects of selumetinib 10 mg and 25 mg twice daily for the treatment of pediatric ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03433183

SARC031: MEK Inhibitor Selumetinib (AZD6244) in ... I. Primary Objective. • To determine the clinical benefit rate of selumetinib in combination with sirolimus in patients with unresectable or metastatic NF1 ...

4. esmo.org esmo.org/oncology-news/efficacy-of-selumetinib-in-reducing-plexiform-neurofibroma-volume-in-adults-with-neurofibromatosis-type-1

Efficacy of Selumetinib in Reducing Plexiform ... Selumetinib is effective at treating plexiform neurofibromas in adults with NF1 according to Dr. Alice P Chen of the Division of Cancer Treatment and Diagnosis.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11392982/

Malignant Peripheral Nerve Sheath Tumor, a Heterogeneous ... The median OS and progression-free survival (PFS) in patients with unresectable MPNST are less than 5 and 2 months, respectively, in trials of ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06763315

Low-dose Selumetinib for the Treatment of Plexiform ... Presence of optic nerve glioma, malignant glioma, malignant peripheral nerve sheath tumor, or other cancers requiring chemotherapy or radiotherapy;; Presence ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2020/213756Orig1s000RiskR.pdf

center for drug evaluation and research - accessdata.fda.gov PNs may compress the vital structures (e.g., airway), or spinal cord and may transform into malignant peripheral nerve sheath tumors (MPNSTs).

8. nature.com nature.com/articles/s41598-025-92741-y

Disproportionality analysis of post-marketing safety ... ... malignant peripheral nerve sheath tumors (MPNST), which further complicates the condition. Selumetinib is a mitogen-activated protein ...