ATRA + Cemiplimab for Sarcoma

Overseen By The Ohio State University Comprehensive Cancer Center

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Gabriel Tinoco

Must not be taking: Systemic steroids, Immunosuppressants

Disqualifiers: Autoimmune disease, Immunodeficiency, Cirrhosis, CNS metastases, 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

Compensation: Varies

Number of Visits: 16

Duration: Up to 24 months

16 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a combination of two treatments, ATRA (All-Trans Retinoic Acid) and Cemiplimab, can benefit individuals with advanced leiomyosarcoma (a type of cancer that starts in smooth muscles) who have not responded to standard treatments. Participants will take ATRA orally for three days, followed by Cemiplimab via IV every three weeks for three cycles, then continue with Cemiplimab alone. The goal is to determine if this combination can slow or halt the cancer's progression. Ideal participants have leiomyosarcoma that cannot be surgically removed and have already undergone chemotherapy. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

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

The trial protocol does not specify if you need to stop taking your current medications. However, there is a required 'washout period' (time without taking certain medications) for some prior therapies, such as Pembrolizumab, Nivolumab, and Durvalumab (3 weeks), and Ipilimumab (4 weeks).

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

Studies are testing the safety of using All-Trans Retinoic Acid (ATRA) with Cemiplimab in patients with advanced leiomyosarcoma. Research has shown that ATRA has been used in other conditions, such as certain cancers, with manageable side effects.

Cemiplimab is already approved for some skin cancers, indicating it is generally well-tolerated. However, like any treatment, it can cause side effects, such as tiredness, nausea, or skin reactions.

This trial is in phase 2, meaning the treatment has already passed initial safety tests. This phase focuses on evaluating the treatment's effectiveness and identifying any less common side effects. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for sarcoma?

Researchers are excited about the combination of All-Trans Retinoic Acid (ATRA) and Cemiplimab for treating sarcoma because it offers a novel approach to tackling this cancer. Unlike traditional treatments like chemotherapy and radiation, which often target rapidly dividing cells indiscriminately, ATRA is derived from vitamin A and can influence gene expression to promote cancer cell differentiation and death. Additionally, Cemiplimab is an immune checkpoint inhibitor that enhances the body's immune response against cancer cells. This combination harnesses both the differentiation-inducing properties of ATRA and the immune-boosting effects of Cemiplimab, potentially leading to more effective and targeted cancer treatment.

What evidence suggests that ATRA and Cemiplimab might be effective for leiomyosarcoma?

This trial tests the combination of All-Trans Retinoic Acid (ATRA) with Cemiplimab for treating advanced leiomyosarcoma (LMS). Studies have shown that ATRA can reduce certain immune cells that tumors use to evade the body's defense system, enhancing the immune response against cancer. Cemiplimab is an immune therapy that boosts the body's ability to detect and destroy cancer cells. This trial examines whether these treatments together can benefit patients whose cancer hasn't responded to standard treatments. Early results suggest this combination might slow the disease and improve control over it. ^{1 2 3 4 6}

Who Is on the Research Team?

Gabriel Tinoco, MD

Principal Investigator

Ohio State University Comprehensive Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients with advanced leiomyosarcoma, a type of sarcoma, who have not responded to standard treatments. Participants must have metastatic or locally advanced disease that cannot be surgically removed.

Inclusion Criteria

Measurable disease based on RECIST 1.1. (At least one target lesion)

Anticipated life expectancy of ≥ 6 months

Ability to understand and sign the informed consent document

Exclusion Criteria

I have not received any vaccines within the prohibited time frame.

Presence of any condition, therapy, or abnormality that may interfere with trial results or patient participation

I have an autoimmune disease or immune deficiency, with some exceptions.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive ATRA orally for 3 days followed by Cemiplimab IV every 3 weeks for three cycles, then Cemiplimab monotherapy until disease progression or unacceptable toxicity

Up to 24 months

Every 3 weeks for the first 3 cycles, then every 6 weeks for the first year, and every 12 weeks thereafter

Follow-up

Participants are monitored for safety and effectiveness after treatment

Every 12-16 weeks

Follow-up visits every 12-16 weeks

What Are the Treatments Tested in This Trial?

Interventions

• All-Trans Retinoic Acid (ATRA)
• Cemiplimab

Trial Overview The study tests the combination of all-trans retinoic acid (ATRA) taken orally and Cemiplimab given intravenously in cycles. The effectiveness will be measured using imaging techniques like CT and MRI scans following a specific study design called BOP2.

How Is the Trial Designed?

Group I: Treatment (all-trans retinoic acid [ATRA] and cemiplimab) Experimental Treatment 5 Interventions

Patients recieve ATRA at a starting dose of 150 mg/m2/day for 3 days orally prior to each cycle of Cemiplimab 350 mg IV q3 weeks for three cycles and then Cemiplimab monotherapy until the progress of disease or unacceptable toxicities develops. Peripheral blood samples will be collected. Patients will undergo physical examination and imaging scans at baseline and then approximately every 6 weeks (2 cycles) for the first year of treatment and every 12 weeks thereafter

All-Trans Retinoic Acid (ATRA) is already approved in United States, European Union for the following indications:

Approved in United States as Vesanoid for:

• Acute promyelocytic leukemia

Approved in European Union as Tretinoin for:

• Acute promyelocytic leukemia

Who Is Running the Clinical Trial?

Gabriel Tinoco

Lead Sponsor

Trials

1

Recruited

20+

Published Research Related to This Trial

Cemiplimab-rwlc (Libtayo) is an FDA-approved immunotherapy for advanced cutaneous squamous cell carcinoma (CSCC) that works by blocking the PD-1 receptor, enhancing the immune system's ability to fight tumors.

Clinical trials have shown that cemiplimab is effective in treating CSCC, although common side effects and safety issues were noted, highlighting the need for ongoing research to improve treatment outcomes and reduce toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cemiplimab-rwlc as first and only treatment for advanced cutaneous squamous cell carcinoma. Ahmed, SR., Petersen, E., Patel, R., et al.[2019]

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]

The combination of all-trans retinoic acid (ATRA) and pembrolizumab was well tolerated in a phase Ib/II trial with 24 patients, establishing a recommended phase II dose of 150 mg/m2 ATRA plus 200 mg pembrolizumab every three weeks.

This treatment showed a high overall response rate of 71%, with 50% of patients achieving a complete response and a median progression-free survival of 20.3 months, indicating its potential as an effective frontline therapy for advanced melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting MDSC Differentiation Using ATRA: A Phase I/II Clinical Trial Combining Pembrolizumab and All-Trans Retinoic Acid for Metastatic Melanoma. Tobin, RP., Cogswell, DT., Cates, VM., et al.[2023]

In a phase I/II study involving 13 patients with HIV-associated Kaposi's sarcoma, intermittent oral all-trans-retinoic acid (ATRA) therapy was found to be reasonably well tolerated, although it primarily caused headaches and dry skin.

Despite the tolerability, the study did not demonstrate significant antitumor activity in patients treated with ATRA alone, as most patients had progressive disease, and only one patient showed a partial response when ATRA was combined with interferon alfa-2a.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II study of intermittent all-trans-retinoic acid, alone and in combination with interferon alfa-2a, in patients with epidemic Kaposi's sarcoma. Bailey, J., Pluda, JM., Foli, A., 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]

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]

Cemiplimab is the first FDA-approved treatment specifically for patients with metastatic or locally advanced cutaneous squamous cell carcinoma who cannot undergo surgery or radiation.

This PD-1 inhibitor offers a new therapeutic option for patients with this type of skin cancer, highlighting its potential efficacy in a challenging treatment population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cemiplimab Approved for Treatment of CSCC. [2019]

Cemiplimab, an antibody treatment for locally advanced and metastatic cutaneous squamous cell carcinoma, shows promising efficacy with objective response rates between 32% and 77%, indicating it is a viable option for patients who cannot undergo surgery or radiation.

The treatment is generally safe and well-tolerated, with only 9.8% of patients experiencing adverse events severe enough to stop therapy, although there is a 3% risk of treatment-related death due to immune-mediated side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cemiplimab for the Treatment of Advanced Cutaneous Squamous Cell Carcinoma: Appropriate Patient Selection and Perspectives. Mager, L., Gardeen, S., Carr, DR., et al.[2023]

Cemiplimab is a PD-1 monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, which is crucial for enhancing the immune response against cancer cells.

In September 2018, cemiplimab received FDA approval for treating patients with metastatic or locally advanced cutaneous squamous cell carcinoma who cannot undergo curative surgery or radiation, marking a significant advancement in cancer treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cemiplimab: First Global Approval. Markham, A., Duggan, S.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06528769

Study of All-Trans Retinoic Acid (ATRA) and Cemiplimab in ... To study the efficacy of the combination of ATRA and Cemiplimab in patients with advanced LMS, including progression-free survival (PFS), disease control rate ( ...

2. trialx.com trialx.com/clinical-trials/listings/321394/study-of-all-trans-retinoic-acid-atra-and-cemiplimab-in-patients-with-advanced-leiomyosarcoma/

Study of All-Trans Retinoic Acid (ATRA) and Cemiplimab in ... A phase 2 study assessing the efficacy of all-trans retinoic acid (ATRA) and Cemiplimab in patients with metastatic/locally advanced ...

3. gatewaycr.org gatewaycr.org/for-researchers/clinical-trials/phase-ii-study-of-all-trans-retinoic-acid-and-cemiplimab-in-leiomyosarcoma/

Phase II study of All-trans retinoic acid and Cemiplimab in ... Summary: Soft-tissue sarcomas encompass a group of rare malignant tumors and account for less than 1% of all adult malignancies in the United States.

4. centerwatch.com centerwatch.com/clinical-trials/listings/search?q=leiomyosarcoma

leiomyosarcoma Clinical Research Trials Retrospective clinical data of 2185 patients with sarcoma treated with epirubicin showed that the response rate of leiomyosarcoma was low (11%). Therefore, this ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/27549124/

Reduction of MDSCs with All-trans Retinoic Acid ... - PubMed Treatment of sarcoma-bearing mice with all-trans retinoic acid (ATRA) largely eradicated monocytic MDSCs and diminished the suppressive capacity of ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/7808021/

All-trans retinoic acid for the treatment of AIDS ... - PubMed - NIH We conclude that tRA has activity in patients with mucocutaneous AIDS-related Kaposi's sarcoma with acceptable toxicity. tRA has immunological effects without ...