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

Trial Summary

What is the purpose of this trial?

A phase 2 study assessing the efficacy of all-trans retinoic acid (ATRA) and Cemiplimab in patients with metastatic/locally advanced - unresectable leiomyosarcoma (LMS) who have progressed standard-of-care therapy. Patients will be enrolled in cohorts according to a Bayesian Optimal Phase II design (BOP2). Study treatment will consist of 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.

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).

What data supports the effectiveness of the drug ATRA + Cemiplimab for sarcoma?

Research suggests that drugs similar to Cemiplimab, like pembrolizumab, have shown some effectiveness in treating advanced sarcomas, particularly in certain subtypes. Additionally, combining PD-1/L1 inhibitors with chemotherapy has been effective in other cancers, indicating potential for sarcoma treatment. ^{1 2 3 4 5}

Is the combination of ATRA and Cemiplimab safe for humans?

Cemiplimab has been found to be generally safe and well-tolerated in most patients, with common side effects like fatigue, diarrhea, itching, and rash. Severe side effects are rare but can include immune-related issues like lung inflammation and heart problems. ATRA has been studied in combination with other treatments, but specific safety data for its combination with Cemiplimab is not available. ^{6 7 8 9 10}

How is the drug ATRA + Cemiplimab unique for treating sarcoma?

The combination of ATRA (All-Trans Retinoic Acid) and Cemiplimab is unique because ATRA promotes cell differentiation and has shown antitumor activity, while Cemiplimab is an immune checkpoint inhibitor that helps the immune system attack cancer cells. This combination leverages both differentiation and immune system activation, offering a novel approach compared to traditional chemotherapy for sarcoma. ^{6 11 12 13 14}

Research Team

Gabriel Tinoco, MD

Principal Investigator

Ohio State University Comprehensive Cancer Center

Eligibility Criteria

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)

Ability to understand and sign the informed consent document

Anticipated life expectancy of ≥ 6 months

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

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

Treatment Details

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.

Participant Groups

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+

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 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]

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-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]

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]

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]

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. Switzerland pubmed.ncbi.nlm.nih.gov

PD-1/L1 inhibitor plus chemotherapy in the treatment of sarcomas. [2022]

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

The indications and efficacy of conventional chemotherapy in primary and recurrent sarcoma. [2022]

5. 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]

6. United States 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. [2018]

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

Cemiplimab Approved for Treatment of CSCC. [2019]

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

Cemiplimab for the Treatment of Advanced Cutaneous Squamous Cell Carcinoma: Appropriate Patient Selection and Perspectives. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Cemiplimab-rwlc as first and only treatment for advanced cutaneous squamous cell carcinoma. [2019]

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

Cemiplimab: First Global Approval. [2023]

11. United States 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. [2023]

12. England pubmed.ncbi.nlm.nih.gov

Treatment of early AIDS-related Kaposi's sarcoma with oral all-trans-retinoic acid: results of a sequential non-randomized phase II trial. Kaposi's Sarcoma ANRS Study Group. Agence Nationale de Recherches sur le SIDA. [2019]

13. Spain pubmed.ncbi.nlm.nih.gov

Effects of all-trans retinoic acid on tumor recurrence and metastasis. [2019]

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

The synthetic retinoid ST1926 as a novel therapeutic agent in rhabdomyosarcoma. [2016]