ATRA + PD-1 Inhibitor for Brain Tumor

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Stephen Bagley, MD, MSCE

Must not be taking: Immunosuppressants, Antiretrovirals

Disqualifiers: Autoimmune disease, Hepatitis, HIV, 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: 3

55 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments for individuals with certain brain tumors that have returned or resist standard treatments. The goal is to determine if using All-Trans Retinoic Acid (ATRA) and a PD-1 inhibitor (Retifanlimab) together can safely enhance the body's immune response against these tumors. Participants will follow different treatment schedules based on their previous treatments and surgical needs. This trial targets those with brain tumors featuring a specific genetic mutation (IDH-mutant glioma) who have not succeeded with other chemotherapy options. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot use immunosuppressive medications other than steroids within six months of starting the study drug, and you must be on a stable or decreased dose of corticosteroids before the baseline MRI.

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

Previous studies have shown that retifanlimab is safe for patients with various cancers, such as melanoma and lung cancer. The data indicates that while generally safe, patients might experience common side effects similar to those of other immune therapies.

All-trans retinoic acid (ATRA) has also been used in cancer treatments but requires careful monitoring. Some research suggests it can be harmful if not managed properly. However, ATRA has effectively killed certain cancer cells.

Both treatments have been tested at different stages and can be used safely with proper monitoring. This trial aims to determine if using them together is safe and effective for brain tumors. Participants will have regular check-ups to quickly address any side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they involve a novel approach to targeting brain tumors. Unlike standard treatments like temozolomide, which primarily act as alkylating agents, this trial combines all-trans retinoic acid (ATRA) and the PD-1 inhibitor retifanlimab. ATRA promotes differentiation and apoptosis of tumor cells, while retifanlimab enhances the immune system's ability to fight the tumor by blocking the PD-1 pathway. This combination offers a unique dual mechanism of action, potentially increasing effectiveness against tumors that have been resistant to previous therapies. Additionally, the tailored pre-surgery use of ATRA and retifanlimab in some treatment arms may help shrink tumors before surgery, potentially improving surgical outcomes.

What evidence suggests that this trial's treatments could be effective for recurrent IDH-mutant glioma?

Research has shown that all-trans retinoic acid (ATRA) can stop brain tumor cells from growing by making them mature or die. ATRA affects cancer stem cells by causing them to change or die, which may help treat brain tumors. Retifanlimab, an anti-PD-1 drug, has effectively treated other cancers like melanoma, bladder cancer, and lung cancer by helping the immune system attack tumors.

This trial will explore combining these two treatments as a potential new way to fight recurring gliomas. Participants in different arms of this trial will receive varying regimens of ATRA and retifanlimab. ATRA targets and destroys specific cancer cells, while retifanlimab helps the immune system recognize and kill the tumor. Although this combination is new for gliomas, the individual treatments have shown promise in other cases, suggesting they could work well together. ^{5 6 7 8 9}

Who Is on the Research Team?

Stephen Bagley, MD

Principal Investigator

University of Pennsylvania

Are You a Good Fit for This Trial?

Adults with recurrent brain tumors (astrocytoma or oligodendroglioma) that have IDH mutations and have tried at least one chemo treatment can join. They must be able to perform daily activities, not pregnant, agree to contraception, and understand the study. Excluded are those with allergies to trial drugs, other serious illnesses, recent bevacizumab treatment, significant mass effect on the brain or active infections.

Inclusion Criteria

Life expectancy >3 months

Reproductive status criteria

Participant must, in the opinion of the Investigator, be able to comply with study procedures

Exclusion Criteria

Subjects who are compulsorily detained for treatment of either a psychiatric or physical illness

Prior diagnosis of immunodeficiency

Known hypersensitivity to another monoclonal antibody that cannot be controlled with standard measures

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Run-In

Subjects receive 28-day cycles of treatment with ATRA and retifanlimab to assess safety

28 days

1 visit (in-person) per cycle

Phase 2 Treatment

Participants receive 28-day cycles of ATRA and retifanlimab treatment

28 days per cycle

1 visit (in-person) per cycle

Surgical Portion

Eligible patients undergo surgery after pre-operative treatment with ATRA or ATRA plus retifanlimab

14 days pre-surgery

1 visit (in-person) for surgery

Follow-up

Participants are monitored for safety and effectiveness after treatment

26 months

What Are the Treatments Tested in This Trial?

Interventions

• All-trans retinoic acid
• Retifanlimab

Trial Overview The trial tests a combination of All-Trans Retinoic Acid (ATRA) and PD-1 inhibitor Retifanlimab in patients with specific recurrent brain tumors. It aims to see if this mix is safe and boosts the immune system's ability to fight cancer.

How Is the Trial Designed?

Group I: Arm D (surgical arm, ATRA + retifanlimab pre-operatively) Experimental Treatment 2 Interventions

Subject in Arm D will receive the combination of ATRA 45mg/m2/day orally in two equally divided doses for 14 days pre-surgery plus a 500mg IV dose of retifanlimab 14 days prior to the date of surgery. Following surgery all patients will receive 28-day cycles of treatment, with ATRA 45mg/m2/day given orally in two equally divided doses on days 1-14 and retifanlimab 500mg IV on day 1.

Group II: Arm C (surgical arm, ATRA alone pre-operatively) Experimental Treatment 2 Interventions

Subject in Arm C will receive ATRA 45mg/m2/day orally in two equally divided doses for 14 days pre-surgery, then undergo surgery. Following surgery all patients will receive 28-day cycles of treatment, with ATRA 45mg/m2/day given orally in two equally divided doses on days 1-14 and retifanlimab 500mg IV on day 1.

Group III: Arm B (failed only one prior alkylating chemotherapy) Experimental Treatment 2 Interventions

Subject in Arm B are patients who have failed only one prior alkylating chemotherapy regimen and have gone at least 12 months since the last treatment. Subjects in Arm B will receive 28-day cycles of treatment, with ATRA 45mg/m2/day given orally in two equally divided doses on days 1 through 14 and retifanlimab 500mg IV on day 1.

Group IV: Arm A (failed prior TMZ + one other alkylating chemotherapy) Experimental Treatment 2 Interventions

Subjects in Arm A are alkylator-refractory and at high risk for progression of disease, have failed temozolmide and another alkylating agent. Subjects in Arm A will receive 28-day cycles of treatment, with ATRA 45mg/m2/day given orally in two equally divided doses on days 1 through 14 and retifanlimab 500mg IV on day 1.

All-trans retinoic acid is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Tretinoin for:

• Acne vulgaris
• Acute promyelocytic leukemia (APL)

Approved in European Union as Tretinoin for:

• Acne vulgaris
• Acute promyelocytic leukemia (APL)
• Severe psoriasis

Approved in Canada as Tretinoin for:

• Acne vulgaris
• Acute promyelocytic leukemia (APL)

Who Is Running the Clinical Trial?

Stephen Bagley, MD, MSCE

Lead Sponsor

Trials

2

Recruited

70+

University of Pennsylvania

Collaborator

Trials

2,118

Recruited

45,270,000+

Incyte Corporation

Industry Sponsor

Trials

408

Recruited

66,800+

Steven Stein

Incyte Corporation

Chief Medical Officer since 2015

MD from University of Witwatersrand

Hervé Hoppenot

Incyte Corporation

Chief Executive Officer since 2014

MBA from ESSEC Business School

Published Research Related to This Trial

All-trans retinoic acid (ATRA) increases the stability and synthesis of PD-L1 in gastric cancer cells, which makes these cells more resistant to T-cell killing, highlighting a potential mechanism of cancer-associated immunosuppression.

In vivo studies showed that while PD-L1 antibodies can restrict tumor growth, ATRA can counteract their effectiveness by upregulating PD-L1, suggesting that combining PD-L1 blockade with JAK inhibitors like ruxolitinib may enhance anti-tumor immune responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ATRA promotes PD-L1 expression to control gastric cancer immune surveillance. Ma, ZL., Ding, YL., Jing, J., et al.[2022]

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]

All-trans retinoic acid (ATRA) significantly promotes the proliferation and differentiation of brain tumor stem cells (BTSCs) in vitro, leading to a higher differentiation rate compared to control groups.

Despite promoting differentiation, ATRA does not lead to complete differentiation of BTSCs, as evidenced by the continued expression of CD133 and the ability of differentiated cells to reform brain tumor spheres (BTSs).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of all-trans retinoic acid on the proliferation and differentiation of brain tumor stem cells. Niu, CS., Li, MW., Ni, YF., et al.[2021]

The review of nine retinoids for cancer prevention found that all-trans-retinoic acid, 13-cis-retinoic acid, and N-ethylretinamide are not suitable for human use due to toxicity, potential to enhance cancer, or ineffectiveness.

Conversely, 9-cis-retinoic acid, etretinate, and acitretin show some potential for cancer prevention, but further research is needed, while all-trans N-(4-hydroxyphenyl)retinamide appears particularly promising.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An International Evaluation of the Cancer-Preventive Potential of Nine Retinoids. Miller, AB., Nettesheim, P., Stewart, BW.[2019]

In a phase II trial involving 17 patients with metastatic breast cancer, all-trans retinoic acid (ATRA) showed limited efficacy, with only one patient achieving a partial response lasting 4 months and three others maintaining stable disease for a short duration.

ATRA was generally well tolerated, but there was significant variability in how patients metabolized the drug, suggesting that future research should explore the effects of different exposure levels to improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and clinical impact of all-trans retinoic acid in metastatic breast cancer: a phase II trial. Sutton, LM., Warmuth, MA., Petros, WP., et al.[2022]

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]

All-trans retinoic acid (ATRA) effectively induces differentiation in glioma stem cells (GSC), leading to a significant reduction in stem cell markers like CD133 and Nestin, while increasing markers associated with differentiated cells, such as GFAP.

ATRA not only inhibits the growth of GSC by reducing their ability to form neurospheres but also prolongs survival time in mice implanted with these cells, suggesting its potential as a targeted therapy for glioma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Differentiation treatment by all-trans retinoic acid reduces phenotype of glioma stem cells]. Zhang, SJ., Wan, F., Hu, F., et al.[2013]

A review of 331 case reports found 21 instances of intracranial hypertension linked to the retinoids tretinoin, acitretin, and etretinate, suggesting a probable causal relationship according to WHO criteria.

However, the lack of definitive rechallenge data and concurrent use of other medications like tetracycline in some cases means that the causal link to intracranial hypertension remains uncertain, indicating that while rare, retinoids may pose a risk for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evidence for a probable causal relationship between tretinoin, acitretin, and etretinate and intracranial hypertension. Fraunfelder, FW., Fraunfelder, FT.[2019]

Allicin enhances the effectiveness of all-trans retinoic acid (ATRA) in treating resistant CD44+ melanoma cells, significantly lowering the concentration needed for ATRA to induce cell death (IC50 reduced from 37.43 µM to 17.53 µM).

The combination of allicin and ATRA not only increases cell cycle arrest in melanoma cells but also alters gene expression related to cancer progression, suggesting a potential new strategy for overcoming resistance in melanoma treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular mechanism and cytotoxicity of allicin and all-trans retinoic acid against CD44+ versus CD117+ melanoma cells. Jobani, BM., Najafzadeh, N., Mazani, M., et al.[2021]

All-trans retinoic acid (ATRA), a treatment for acute promyelocytic leukemia, can cause increased intracranial pressure, leading to severe visual loss and other neurological symptoms.

In a case study of a 32-year-old woman, ATRA-induced intracranial hypertension was managed with clinical treatment and optic nerve sheath fenestration, highlighting the need for careful monitoring of patients on ATRA for signs of intracranial hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optic Nerve Sheath Fenestration as Adjuvant Treatment for Severe Pseudotumor Cerebri Syndrome Induced by All-Trans Retinoic Acid. Hokazono, K., Cunha, LP., Preti, RC., et al.[2023]

Tectorigenin is identified as a novel RAR-γ-selective agonist that effectively inhibits UV-induced skin damage, including oxidative stress and inflammation, while also reversing collagen loss, making it a promising treatment for photoaging.

In animal studies, tectorigenin demonstrated superior anti-inflammatory and anti-photoaging effects compared to all-trans retinoic acid (ATRA), with reduced skin irritation, suggesting it may be a safer alternative for treating UV-induced skin issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A non-retinol retinoic acid receptor-γ (RAR-γ/NR1B3) selective agonist, tectorigenin, can effectively inhibit the ultraviolet A-induced skin damage. Dai, X., Jin, J., Jia, Y., et al.[2022]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/9210061/

The treatment of recurrent cerebral gliomas with all-trans ... All-trans-retinoic acid as a single agent has no significant activity against recurrent cerebral gliomas. Publication types. Clinical Trial; Clinical Trial, ...

2. insight.jci.org insight.jci.org/articles/view/179530

All-trans retinoic acid inhibits glioblastoma progression and ... The findings of this study revealed that RA effectively eliminated astrocytes, which are particularly prone to senescence after radiation.

3. ar.iiarjournals.org ar.iiarjournals.org/content/30/12/4915

All-trans Retinoic Acid Modulates Cancer Stem Cells of ... Low doses of ATRA were able to cause the differentiation of CSCs, while at high doses we observed that ATRA significantly caused apoptosis as evidenced by ...

4. jeccr.biomedcentral.com jeccr.biomedcentral.com/articles/10.1186/1756-9966-29-113

Effect of all-trans retinoic acid on the proliferation and ... To investigate the effect of all-trans retinoic acid(ATRA) on the proliferation and differentiation of brain tumor stem cells(BTSCs) in ...

5. aacrjournals.org aacrjournals.org/clincancerres/article/9/11/4052/202618/All-trans-Retinoic-Acid-induced-Apoptosis-in-Human

All-trans-Retinoic Acid-induced Apoptosis in Human ... Therefore, we propose that ATRA or other retinoids might be effective in suppressing MB tumor growth in vivo by caspase-mediated apoptosis.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11601587/

All-trans retinoic acid inhibits glioblastoma progression and ... The findings of this study revealed that RA effectively eliminated astrocytes, which are particularly prone to senescence after radiation.

7. trials.braintumor.org trials.braintumor.org/trials/NCT05345002

All-Trans Retinoic Acid (ATRA) Plus PD-1 Inhibition in ... The Sponsor-Investigator hypothesizes that the proposed regimen will be safe and stimulate a robust anti-tumor immune response.

8. clinicaltrials.gov clinicaltrials.gov/study/NCT04919369

Study Details | NCT04919369 | All-Trans Retinoic Acid ... This phase Ib trial is to find out the best dose and side effects of all-trans retinoic acid (ATRA) and atezolizumab in treating patients with non-small ...

9. withpower.com withpower.com/trial/phase-2-oligodendroglioma-5-2022-fad18

ATRA + PD-1 Inhibitor for Brain Tumor Patients using ATRA should be monitored for signs of this condition. Additionally, ATRA has been found to be too toxic for cancer prevention in humans.