Combination Therapy for Sarcoma

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

41 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a combination of three drugs to treat adults with hard-to-treat sarcomas, especially a type called MPNST linked to NF1. The drugs work together to stop cancer growth and boost the immune system. The study aims to find out if this combination is safe and effective. The combination of panobinostat, venetoclax, and anti-CD40 has shown promise in preclinical models for inducing complete tumor remission.

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.

What data supports the effectiveness of the drug Selumetinib for treating sarcoma?

Research shows that Selumetinib, when combined with another drug called temsirolimus, can effectively slow down the growth of soft-tissue sarcoma cells in laboratory studies. ^{1 2 3 4 5}

What safety data exists for Selumetinib in humans?

Selumetinib has been studied in various clinical trials, showing some common side effects like diarrhea, rash, nausea, and fatigue. It has been approved for use in children with certain tumors, and safety data from trials in both children and adults indicate risks consistent with its drug class, including effects on the eyes, heart, muscles, stomach, and skin. ^{6 7 8 9 10}

How is the drug Selumetinib unique in treating sarcoma?

Selumetinib is unique in treating sarcoma because it targets the MEK pathway, which is involved in cell growth, and when combined with temsirolimus, it can more effectively inhibit the growth of sarcoma cells by overcoming resistance that develops with other treatments. ^{1 4 5 11 12}

Eligibility Criteria

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

I am 18 years old or older.

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

Exclusion Criteria

I have severe lung problems or heart conditions.

History of allogeneic organ transplantation

Patients with severe and/or uncontrolled medical conditions

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

A randomised phase II trial of selumetinib vs selumetinib plus temsirolimus for soft-tissue sarcomas. [2018]

2. England 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. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Clinical Activity of Pazopanib in Metastatic Extraosseous Ewing Sarcoma. [2020]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Case report: The activity of multi-kinase VEGF inhibitor, Pazopanib, in metastatic undifferentiated round cell sarcomas harboring EWSR1::CREM fusion: clinicopathological series of two cases and literature review. [2023]

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

Preclinical Evaluation of Vemurafenib as Therapy for BRAFV600E Mutated Sarcomas. [2018]

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

Metabolism, Excretion, and Pharmacokinetics of Selumetinib, an MEK1/2 inhibitor, in Healthy Adult Male Subjects. [2019]

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

FDA Approval Summary: Selumetinib for Plexiform Neurofibroma. [2022]

8. Germany 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. [2022]

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

A phase I dose-escalation study of Selumetinib in combination with Erlotinib or Temsirolimus in patients with advanced solid tumors. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Impact of KRAS codon subtypes from a randomised phase II trial of selumetinib plus docetaxel in KRAS mutant advanced non-small-cell lung cancer. [2018]

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

Results of an international randomized phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy. [2022]

12. United States 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. [2022]