ATRA + PD-1 Inhibitor for Brain Tumor

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Stephen Bagley, MD, MSCE

Must not be taking: Immunosuppressants, Antiretrovirals

Disqualifiers: Autoimmune disease, Hepatitis, HIV, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial tests a combination of a vitamin A derivative and an immune-boosting drug in patients with recurring brain tumors. The treatment aims to normalize cancer cell behavior and enhance the immune system's ability to fight the tumor.

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.

What data supports the effectiveness of the drug ATRA + PD-1 Inhibitor for brain tumors?

Research shows that all-trans retinoic acid (ATRA) can reduce the aggressive nature of glioma stem cells, which are a type of brain tumor cell. Additionally, ATRA has been studied in combination with other treatments for different cancers, like melanoma, showing potential benefits in enhancing immune response. ^{1 2 3 4 5}

What safety data exists for ATRA and PD-1 inhibitors in humans?

ATRA (All-trans retinoic acid) can cause increased intracranial pressure (pressure inside the skull), which may lead to visual problems. 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. ^{2 6 7 8 9}

What makes the ATRA + PD-1 inhibitor drug unique for brain tumors?

The combination of all-trans retinoic acid (ATRA) and a PD-1 inhibitor like Retifanlimab is unique because ATRA can influence immune responses by affecting PD-L1 expression, potentially enhancing the effectiveness of immunotherapy. This approach targets both the immune system and the tumor cells, which may offer a novel way to treat brain tumors compared to traditional therapies. ^{1 2 3 10 11}

Research Team

Stephen Bagley, MD

Principal Investigator

University of Pennsylvania

Eligibility Criteria

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

I am 18 years old or older.

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

Trial Timeline

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

Treatment Details

Interventions

• All-trans retinoic acid (Other)
• Retifanlimab (PD-1 Inhibitor)

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.

Participant Groups

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 Canada for the following indications:

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

Findings from Research

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]

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) 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]

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]

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]

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]

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]

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]

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]

References

1. China pubmed.ncbi.nlm.nih.gov

[Differentiation treatment by all-trans retinoic acid reduces phenotype of glioma stem cells]. [2013]

2. 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]

3. Netherlands pubmed.ncbi.nlm.nih.gov

ATRA promotes PD-L1 expression to control gastric cancer immune surveillance. [2022]

4. Germany pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and clinical impact of all-trans retinoic acid in metastatic breast cancer: a phase II trial. [2022]

5. 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]

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

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

7. Switzerland pubmed.ncbi.nlm.nih.gov

Optic Nerve Sheath Fenestration as Adjuvant Treatment for Severe Pseudotumor Cerebri Syndrome Induced by All-Trans Retinoic Acid. [2023]

8. England 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. [2022]

9. Thailand pubmed.ncbi.nlm.nih.gov

An International Evaluation of the Cancer-Preventive Potential of Nine Retinoids. [2019]

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

Effect of all-trans retinoic acid on the proliferation and differentiation of brain tumor stem cells. [2021]

11. Germany pubmed.ncbi.nlm.nih.gov

Molecular mechanism and cytotoxicity of allicin and all-trans retinoic acid against CD44+ versus CD117+ melanoma cells. [2021]