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

Trial Summary

What is the purpose of this trial?

This is a Phase II single-center open label trial of the combination of ATRA and pembrolizumab treatment in patients with histologically proven, relapsed or refractory Hodgkin Lymphoma or B-Non-Hodgkin-lymphoma.

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.

What data supports the effectiveness of the drug combination ATRA and Pembrolizumab for treating lymphoma?

Research shows that pembrolizumab, a drug that helps the immune system fight cancer, has been effective in treating various cancers, including melanoma and Hodgkin's lymphoma. ATRA, when combined with pembrolizumab, has shown promise in treating melanoma, suggesting potential benefits for other cancers like lymphoma. ^{1 2 3 4 5}

Is the combination of ATRA and Pembrolizumab safe for humans?

Research on ATRA (All-trans retinoic acid) combined with other treatments like interferon shows that it generally has a manageable safety profile, with some studies reporting negligible side effects. However, specific safety data for the combination of ATRA and Pembrolizumab is not available in the provided research. ^{6 7 8 9 10}

How is the drug combination of ATRA and Pembrolizumab unique for treating lymphoma?

The combination of ATRA and Pembrolizumab is unique because it targets the immune system in a novel way by combining a retinoic acid (ATRA) that influences cell differentiation with an immune checkpoint inhibitor (Pembrolizumab) that helps T cells attack cancer cells. This approach is different from standard treatments as it leverages both immune modulation and direct cancer cell targeting. ^{1 3 4 11 12}

Research Team

Rita Assi, MD

Principal Investigator

Indiana University

Eligibility Criteria

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.

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

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

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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 (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 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]

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]

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. [2017]

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

Pembrolizumab in Relapsed and Refractory Mycosis Fungoides and Sézary Syndrome: A Multicenter Phase II Study. [2021]

3. 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]

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

Pembrolizumab: first global approval. [2021]

5. England 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. [2019]

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

Clinical Availability of ATRA for Patients With Suspected Acute Promyelocytic Leukemia: Why Guidelines May Not Be Followed. [2023]

8. Spain pubmed.ncbi.nlm.nih.gov

[Treatment of cutaneous T-cell lymphoma with retinoid receptor X-selective ligands: endocrine and metabolic disorders]. [2019]

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

Activity of interferon-alpha and isotretinoin in patients with advanced, refractory lymphoid malignancies. [2013]

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

Treatment of cutaneous T cell lymphoma with a combination of low-dose interferon alfa-2b and retinoids. [2019]

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

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. [2022]

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

Pembrolizumab for the treatment of diffuse large B-cell lymphoma. [2020]