ATRA + Pembrolizumab for Lymphoma

Recruiting at 1 trial location

Overseen By Kat Ton, RN

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Rita Assi

Must not be taking: Antifibrinolytics, Antifungals, Antidepressants, others

Disqualifiers: Brain metastases, Immunodeficiency, Active infection, 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: 5

Duration: 12 weeks

24 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—ATRA (All-trans retinoic acid) and pembrolizumab (an immunotherapy drug)—to determine its effectiveness for certain types of lymphoma that have not responded to previous treatments. The focus is on Hodgkin Lymphoma and several types of B-Cell Non-Hodgkin Lymphoma. Individuals who have tried at least one other treatment for Hodgkin or two for B-cell NHL without success might be suitable candidates. The study aims to assess how well these drugs work together in shrinking or controlling cancer. As a Phase 2 trial, the research measures the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial requires you to stop taking Vitamin A supplements and certain medications that affect liver enzymes (CYP3A modulators) at least 3 days before starting the treatment and during the trial. If you're on a micro-dosed progesterone contraceptive, you'll need to switch to another form of birth control.

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

Research has shown that the combination of ATRA (all-trans retinoic acid) and pembrolizumab is safe and well-tolerated by patients. In a previous study with lymphoma patients, this treatment was well-received, helping to establish a recommended dosage for future research. Another study found that this combination was also safe for people with melanoma, a type of skin cancer.

These findings suggest that patients generally tolerate the treatment well, with no major safety concerns reported. While every treatment can have side effects, past research indicates that most people handle this combination without serious problems. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for lymphoma?

Researchers are excited about the combination of ATRA and pembrolizumab for lymphoma because it brings a fresh approach to treatment. Unlike traditional chemotherapy or radiation, which target cancer cells indiscriminately, this combination leverages pembrolizumab's ability to boost the immune system to recognize and attack cancer cells more effectively. ATRA, known for its role in differentiation therapy, is used here to enhance pembrolizumab's effects, potentially leading to better outcomes. This combination aims to harness the body's own defenses to combat lymphoma, offering a potentially more targeted and less toxic alternative to current treatments.

What evidence suggests that ATRA and Pembrolizumab could be effective for lymphoma?

Research shows that combining ATRA (a form of vitamin A) with pembrolizumab (a type of immune therapy) may help treat certain lymphomas. Previous studies found this combination safe and manageable, and it might work well for patients with relapsed or difficult-to-treat Hodgkin Lymphoma and B-Non-Hodgkin Lymphoma. In one study, 58% of patients remained alive after receiving this treatment, indicating a possible long-term benefit. This trial will evaluate the combination of ATRA and pembrolizumab, suggesting it could be a promising treatment option for these challenging cancers. ^{1 3 5 6 7}

Who Is on the Research Team?

Rita Assi, MD

Principal Investigator

Indiana University

Are You a Good Fit for This Trial?

This trial is for people with certain types of lymphoma (Hodgkin's and B-Non-Hodgkin's) that have come back or didn't respond to previous treatments. Specific eligibility details are not provided, but typically participants would need a confirmed diagnosis and may be required to meet other health criteria.

Inclusion Criteria

My Hodgkin's lymphoma or B-cell non-Hodgkin's lymphoma has returned or is not responding to treatment.

I can take care of myself and am up and about more than half of my waking hours.

Willingness to comply with all study procedures and be available for the duration of the trial

Exclusion Criteria

I have not received a live vaccine in the last 30 days.

Known history of Human Immunodeficiency Virus (HIV)

Known sensitivity to retinoic acid derivatives

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 200mg Q3W pembrolizumab treatment plus 150 mg/m2 ATRA orally for 3 days surrounding each of the first four infusions

12 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

90 days

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• ATRA
• Pembrolizumab

Trial Overview The study is testing the effectiveness of combining two drugs: ATRA (a vitamin A derivative) and Pembrolizumab (an immunotherapy drug), in treating relapsed Hodgkin Lymphoma and B-Non-Hodgkin Lymphoma. It's an open-label trial, meaning both researchers and participants know what treatment is being given.

How Is the Trial Designed?

Group I: ATRA and Pembrolizumab Experimental Treatment 2 Interventions

Patients will receive 200mg Q3W pembrolizumab treatment plus the supplemental treatment of 150 mg/m2 ATRA orally for 3 days surrounding each of the first four infusions of pembrolizumab (day -1, day 0, day +1).

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

Approved in United States as Tretinoin for:

• Acute promyelocytic leukemia (APL)

Approved in European Union as Tretinoin for:

• Acute promyelocytic leukemia (APL)

Who Is Running the Clinical Trial?

Rita Assi

Lead Sponsor

Trials

1

Recruited

20+

Published Research Related to This Trial

The combination of interferon-alpha (IFN-alpha) and isotretinoin demonstrated antitumor activity in patients with advanced lymphoid malignancies, achieving an overall response rate of 38.6% among 44 evaluable patients, including complete responses in 11.3% of cases.

This treatment was well tolerated, with manageable side effects such as low-grade fever and fatigue, indicating that it can be a viable option for heavily pretreated patients with limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity of interferon-alpha and isotretinoin in patients with advanced, refractory lymphoid malignancies. Tsimberidou, AM., Giles, F., Romaguera, J., et al.[2013]

Pembrolizumab, a PD-1 inhibitor used in cancer treatment, can lead to rare but serious immune-related adverse events, including type 1 diabetes mellitus, occurring in about 0.2% of cases.

A review of 42 cases revealed that patients may develop diabetic ketoacidosis during treatment, highlighting the need for blood glucose monitoring and awareness of this potential side effect among clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. Clotman, K., Janssens, K., Specenier, P., 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]

Pembrolizumab is a monoclonal antibody that effectively blocks the PD-1 receptor on T cells, enhancing their ability to attack cancer cells, particularly in melanoma patients.

In a Phase I study involving 411 patients, pembrolizumab demonstrated high durable response rates with minimal toxicity, indicating its potential as a safe and effective treatment option for melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. Hersey, P., Gowrishankar, K.[2017]

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]

Only 31% of hospitals surveyed had all-trans retinoic acid (ATRA) in stock, which is critical for treating acute promyelocytic leukemia (APL), highlighting a significant gap in access to this lifesaving medication.

Among hospitals that refer patients with APL, only 14% had ATRA readily available, indicating that many patients may not receive timely treatment, which could affect their outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Availability of ATRA for Patients With Suspected Acute Promyelocytic Leukemia: Why Guidelines May Not Be Followed. Geer, MJ., Foucar, CE., Devata, S., et al.[2023]

In a pilot study involving 7 patients with cutaneous T cell lymphoma, a combination of low-dose interferon alfa-2b and a retinoid led to two complete and two partial remissions, demonstrating promising efficacy.

The treatment was well-tolerated, with negligible side effects that did not require any patient to discontinue therapy, and responses were maintained for up to 15 months even after dose reductions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of cutaneous T cell lymphoma with a combination of low-dose interferon alfa-2b and retinoids. Knobler, RM., Trautinger, F., Radaszkiewicz, T., et al.[2019]

Bexarotene, a retinoid X receptor-selective ligand, is used to treat advanced cutaneous T-cell lymphoma but can cause significant side effects, including central hypothyroidism and dyslipidemia, as seen in two reported cases.

Both patients achieved total clinical remission and resolution of their side effects after discontinuing bexarotene, highlighting the importance of monitoring for adverse effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment of cutaneous T-cell lymphoma with retinoid receptor X-selective ligands: endocrine and metabolic disorders]. Avilés Pérez, MD., Luna López, V., Rodríguez Nevado, I., et al.[2019]

Pembrolizumab, a monoclonal antibody targeting PD-1, has shown significant clinical efficacy in treating Hodgkin Lymphoma and promising early results in certain subtypes of Non-Hodgkin Lymphoma, particularly those with genetic similarities to HL.

Current data suggest that pembrolizumab has a favorable safety profile and efficacy as a single agent in treating diffuse large B cell lymphomas, with future strategies likely to focus on biomarker-driven approaches and combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of diffuse large B-cell lymphoma. Sheikh, S., Kuruvilla, J.[2020]

Pembrolizumab (Keytruda) is the first anti-PD-1 therapy approved in the US for treating advanced malignant melanoma, specifically for patients who have progressed after prior treatments.

It is designed to target the PD-1 protein, enhancing the immune system's ability to fight cancer, and is currently under review for approval in the EU.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab: first global approval. Poole, RM.[2021]

In a phase II trial involving 24 patients with advanced mycosis fungoides or Sézary syndrome, pembrolizumab showed an overall response rate of 38%, with two complete responses and seven partial responses, indicating its efficacy in treating these conditions.

The treatment had a favorable safety profile, with immune-related adverse events leading to discontinuation in only four patients, and while 53% experienced a temporary worsening of skin symptoms, this did not result in treatment discontinuation and was associated with high PD-1 expression on Sézary cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in Relapsed and Refractory Mycosis Fungoides and Sézary Syndrome: A Multicenter Phase II Study. Khodadoust, MS., Rook, AH., Porcu, P., et al.[2021]

In patients with relapsed and refractory classical Hodgkin's lymphoma who have previously failed treatment with brentuximab vedotin, pembrolizumab significantly improves progression-free survival (PFS) compared to standard of care, with hazard ratios indicating a much lower risk of disease progression.

The study involved a systematic literature review and comparisons of outcomes from pembrolizumab's KEYNOTE-087 trial against an observational study of standard care, confirming that pembrolizumab is a more effective treatment option for this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus the standard of care for relapsed and refractory classical Hodgkin's lymphoma progressing after brentuximab vedotin: an indirect treatment comparison. Keeping, S., Wu, E., Chan, K., et al.[2019]

Citations

1. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-08682

Pembrolizumab and All-Trans Retinoic Acid for the ... Giving pembrolizumab with ATRA may be safe, tolerable and/or effective in treating patients with relapsed or refractory Hodgkin lymphoma and B non-Hodgkin ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12198584/

Pembrolizumab and all-trans retinoic acid combination ... These results underscore the long-term clinical benefit of combining anti-PD-1 with ATRA, with survival rates comparable to anti-PD-1/combinations but with ...

3. withpower.com withpower.com/trial/phase-2-lymphoma-7-2024-c892d

ATRA + Pembrolizumab for Lymphoma 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 ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03200847

NCT03200847 | Pembrolizumab and All-Trans Retinoic ... To determine the clinical outcomes with tumor-specific T cell responses. Official Title. Pembrolizumab and All-Trans Retinoic Acid in Combination Treatment of ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40574966/

Pembrolizumab and all-trans retinoic acid combination ... Results: At data cutoff (May 14, 2024), all patients had completed treatment, and 58% (n = 14) remained alive with a median follow-up of 48 ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10073240/

Targeting MDSC differentiation using ATRA: a phase I/II ... In this single arm, single institution clinical trial we found that the combination of ATRA and pembrolizumab was safe and well tolerated. Furthermore, the ...

7. journals.sagepub.com journals.sagepub.com/doi/10.1177/17588359251349321

Pembrolizumab and all-trans retinoic acid combination ... These results underscore the long-term clinical benefit of combining anti-PD-1 with ATRA, with survival rates comparable to anti-PD-1/ ...