DCC-3014 + Avelumab for Sarcoma

Overseen By William Tap, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Cardiovascular disease, CNS metastases, Autoimmune disease, HIV, Hepatitis, others

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

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

Compensation: Varies

Number of Visits: Unknown

32 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing the safest dose of a new drug, DCC-3014, combined with an existing drug, avelumab, for patients with advanced or spreading sarcomas. The goal is to find a dose that fights cancer without causing serious side effects. Avelumab has been effective in treating various types of cancer.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify whether you need to stop taking your current medications. However, if you are using immunosuppressive medications or have recently received certain treatments like chemotherapy or monoclonal antibodies, you may need to stop or adjust them before joining the trial. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug Avelumab, MSB0010718C, Bavencio, DCC-3014 for treating sarcoma?

Research on similar drugs, like pembrolizumab and nivolumab, which target the same PD-1 pathway as Avelumab, shows some effectiveness in treating advanced sarcomas, with certain subtypes responding better. This suggests that Avelumab might also have potential benefits for sarcoma patients. ^{1 2 3 4 5}

What safety data exists for Avelumab (Bavencio) in humans?

Avelumab, also known as Bavencio, has been approved for treating certain types of cancer, like metastatic Merkel cell carcinoma, and has been studied for safety in various cancer types. It is generally considered safe for human use, but like many cancer treatments, it can have side effects, which should be discussed with a healthcare provider. ^{1 2 4 6 7}

How is the drug DCC-3014 + Avelumab unique for treating sarcoma?

DCC-3014 + Avelumab is unique because it combines a novel macrophage-targeting agent (DCC-3014) with an immune checkpoint inhibitor (Avelumab) that helps the immune system recognize and attack cancer cells, offering a different approach compared to traditional chemotherapy or other immune therapies like pembrolizumab or nivolumab. ^{2 3 4 5 8}

Research Team

Sandra D'Angelo, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

Adults (18+) with advanced or metastatic sarcomas, specifically undifferentiated pleomorphic, myxofibrosarcoma, leiomyosarcoma, or dedifferentiated liposarcoma. Participants must have had at least one prior systemic therapy and show measurable disease progression. They should be in good health otherwise and willing to use effective contraception.

Inclusion Criteria

Age >/= 18 years at the time of informed consent

Be capable, willing, and able to provide written informed consent/assent

Be willing to comply with clinical trial instructions and requirement, including mandatory biopsies

Exclusion Criteria

History of unstable or deteriorating cardiovascular disease within the previous 6 months prior to screening including but not limited to the following: Unstable angina or myocardial infarction, CVA/stroke, Congestive heart failure (New York Heart Association [NYHA] Class III or IV), Uncontrolled clinically significant arrhythmias

Evidence or clinically significant interstitial lung disease or active, noninfectious pneumonitis related to prior immunotherapy treatment

Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases or carcinomatous meningitis may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 day prior to trial treatment

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive escalating doses of DCC-3014 in combination with avelumab to determine the maximum tolerated dose

48 weeks

Dose Expansion

Participants receive the determined dose of DCC-3014 and avelumab to evaluate the overall response rate

48 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Avelumab
• DCC-3014

Trial Overview The trial is testing the combination of DCC-3014 with Avelumab to determine the safest dose for treating advanced sarcomas without causing severe side effects. The study involves participants who meet specific criteria related to their cancer type and previous treatments.

Participant Groups

Group I: Advanced High-grade Sarcoma Experimental Treatment 2 Interventions

Dose Escalation: Up to 18 pts with locally advanced or metastatic high-grade sarcomas Dose Expansion: 10 pts per each diagnosis - undifferentiated pleomorphic sarcoma or myxofibrosarcoma, Leiomyosarcoma, Dedifferentiated liposarcoma

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

Approved in European Union as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

Approved in United States as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

Approved in Japan as Bavencio for:

• Merkel cell carcinoma
• Renal cell carcinoma
• Urothelial carcinoma

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

ENABLE MEDICINE

Collaborator

Trials

1

Recruited

30+

Findings from Research

In a phase 2 trial involving 62 patients with advanced or metastatic sarcoma, the combination of durvalumab and tremelimumab showed a promising progression-free survival rate of 49% at 12 weeks, indicating its potential efficacy as a treatment option.

While the treatment was generally active, it was associated with some serious adverse events, including one case of grade 5 pneumonitis and colitis, highlighting the need for careful monitoring of patients during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab plus tremelimumab in advanced or metastatic soft tissue and bone sarcomas: a single-centre phase 2 trial. Somaiah, N., Conley, AP., Parra, ER., et al.[2023]

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]

In a phase II study of pembrolizumab for advanced sarcoma, a 17.5% response rate was observed, particularly in undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma, indicating its potential efficacy in these subtypes.

Higher densities of activated T cells and tumor-associated macrophages expressing PD-L1 in pre-treatment biopsies were associated with better responses to pembrolizumab, suggesting that specific immune features may predict treatment outcomes and progression-free survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Correlative Analyses of the SARC028 Trial Reveal an Association Between Sarcoma-Associated Immune Infiltrate and Response to Pembrolizumab. Keung, EZ., Burgess, M., Salazar, R., et al.[2021]

In a phase 2 study involving 85 patients with metastatic sarcoma, the combination of nivolumab and ipilimumab showed a higher confirmed response rate (16%) compared to nivolumab alone (5%), indicating that the combination therapy may be more effective for certain sarcoma subtypes.

While both treatments had manageable safety profiles, serious treatment-related adverse events occurred in 19% of patients receiving nivolumab and 26% in those receiving the combination therapy, suggesting that while the combination is promising, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials. D'Angelo, SP., Mahoney, MR., Van Tine, BA., et al.[2021]

In a study of 84 patients with advanced sarcomas treated with off-label anti-PD1 immunotherapy, those with cutaneous primary tumors showed a significantly higher clinical benefit rate of 58%, compared to 11% for non-cutaneous tumors, indicating that tumor location is a key factor in treatment efficacy.

Patients with cutaneous sarcomas also experienced longer progression-free survival (8.6 months vs. 2.5 months) and overall survival (19.0 months vs. 9.2 months), suggesting that cutaneous primary site is a stronger predictor of response to immunotherapy than histological subtype.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-PD-1 therapy in advanced sarcomas: is cutaneous primary site a stronger predictor of response than histologic subtype? Miao, R., Swank, J., Melzer, D., et al.[2023]

Avelumab is an antibody that blocks programmed cell death ligand-1 (PD-L1) and has received accelerated approval in the USA for treating metastatic Merkel cell carcinoma (mMCC) in both adults and children aged 12 and older.

The drug is also undergoing regulatory reviews for other cancer treatments, including urothelial carcinoma, indicating its potential as a versatile cancer therapy in various stages of development worldwide.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab: First Global Approval. Kim, ES.[2022]

In the JAVELIN Lung 100 trial involving 1214 patients with advanced NSCLC, avelumab showed longer median progression-free survival (PFS) compared to platinum-based chemotherapy (8.4 months vs. 5.6 months), indicating its potential efficacy as a first-line treatment.

Although avelumab demonstrated longer median overall survival (OS) compared to chemotherapy (20.1 months vs. 14.9 months), the differences were not statistically significant, suggesting that while avelumab may be beneficial, it did not meet the primary objective of the trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab Versus Platinum-Based Doublet Chemotherapy as First-Line Treatment for Patients With High-Expression Programmed Death-Ligand 1-Positive Metastatic NSCLC: Primary Analysis From the Phase 3 JAVELIN Lung 100 Trial. Reck, M., Barlesi, F., Yang, JC., et al.[2023]

References

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

Durvalumab plus tremelimumab in advanced or metastatic soft tissue and bone sarcomas: a single-centre phase 2 trial. [2023]

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

Correlative Analyses of the SARC028 Trial Reveal an Association Between Sarcoma-Associated Immune Infiltrate and Response to Pembrolizumab. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials. [2021]

5. Germany pubmed.ncbi.nlm.nih.gov

Anti-PD-1 therapy in advanced sarcomas: is cutaneous primary site a stronger predictor of response than histologic subtype? [2023]

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

Avelumab: First Global Approval. [2022]

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

Avelumab Versus Platinum-Based Doublet Chemotherapy as First-Line Treatment for Patients With High-Expression Programmed Death-Ligand 1-Positive Metastatic NSCLC: Primary Analysis From the Phase 3 JAVELIN Lung 100 Trial. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Functional genomics of human clear cell sarcoma: genomic, transcriptomic and chemical biology landscape for clear cell sarcoma. [2023]