Azacytidine + Romidepsin for Peripheral T-Cell Lymphoma

(PTCL Trial)

Recruiting at 4 trial locations

Overseen By Marian Abdelmalek, MS

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Virginia

Must not be taking: CYP3A4 inhibitors, QT prolongation drugs

Disqualifiers: HIV, Hepatitis, 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: Unknown

Duration: 72 weeks

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if a combination of two drugs, azacytidine (a chemotherapy drug) and romidepsin (a histone deacetylase inhibitor), is safe and effective for treating Peripheral T-Cell Lymphoma (PTCL). Participants will receive either this new combination treatment or one of several existing single-drug treatments selected by the study doctor. Suitable candidates for this trial are those with PTCL who have undergone up to three different treatments and have experienced a return or lack of response in their disease. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you must stop all current medications, but you cannot use certain drugs like CYP3A4 inhibitors or systemic steroids above a certain dose. You also need to avoid other investigational agents within 2 weeks of joining the trial.

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

Research has shown that the combination of azacytidine and romidepsin is generally safe for people with Peripheral T-Cell Lymphoma (PTCL). Studies have found that this treatment not only works well but is also tolerated by patients whose PTCL has returned or is resistant to other treatments. Previous research did not identify any unexpected or severe side effects, suggesting a level of safety for patients.

However, like any treatment, side effects may occur, and individual reactions can vary. This combination remains under testing to ensure its safety and effectiveness for a broader population. It is important to discuss the possible risks and benefits with a healthcare provider before deciding to join a clinical trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Azacytidine and Romidepsin are unique because they offer a novel combination approach for treating peripheral T-cell lymphoma. Unlike standard treatments that often focus on single-agent chemotherapy, this combination targets cancer cells in two distinct ways. Azacytidine works by modifying the DNA of cancer cells to stop their growth, while Romidepsin inhibits enzymes that cancer cells need to survive. Researchers are excited about this duo because it could enhance effectiveness and potentially offer better outcomes for patients by attacking the cancer from multiple angles.

What evidence suggests that the combination treatment of azacytidine and romidepsin could be effective for Peripheral T-Cell Lymphoma?

Research has shown that using azacytidine and romidepsin together holds promise for treating Peripheral T-Cell Lymphoma (PTCL). Studies have found that 61% of patients responded to this combination, with 48% experiencing a complete response, meaning their cancer completely disappeared. This trial will evaluate the combination of azacytidine and romidepsin in one treatment arm. The other arm will involve the investigator's choice of treatments, which may include romidepsin alone or other options like belinostat, pralatrexate, or gemcitabine. Although azacytidine and romidepsin are not miracle cures, they offer hope for better results compared to some existing treatments. ^{1 3 4 6 7}

Who Is on the Research Team?

Enrica Marchi, MD

Principal Investigator

University of Virginia

Are You a Good Fit for This Trial?

Adults (18+) with Peripheral T-Cell Lymphoma that's come back or hasn't responded to treatment can join this trial. They should have tried no more than three treatments before, and if they've had a stem cell transplant, it counts as one line of therapy. Participants need good organ function, manageable heart conditions, not be HIV-positive or pregnant, and agree to use contraception.

Inclusion Criteria

Ability to understand and the willingness to sign a written informed consent document.

My T-cell lymphoma has returned or didn't respond to treatment after one therapy.

Absolute neutrophil count (ANC): ≥1000/mm3 (≥1000/dL); Platelets: > 75,000/mm3; Serum Creatinine:< 2 x ULN OR creatinine clearance >50 mL/min/for patients with creatinine levels above ULN; Bilirubin: ≤ 1.5 x ULN (except in patients with Gilbert's disease, where bilirubin to 4x ULN is allowed); AST and ALT: ≤ 2 x ULN OR ≤ 3 X ULN in presence of demonstrable liver involvement; Serum potassium: ≥ 3.8 mmol/L; Serum magnesium≥1.8 mg/dL.

Exclusion Criteria

My blood pressure is controlled and has been stable on medication for at least a month.

I have a genetic heart condition known as long QT syndrome.

I am not taking any medications that strongly affect liver enzymes.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either the combination of oral Azacytidine and Romidepsin or an investigator's choice of single-agent treatment

72 weeks

Multiple visits as per treatment cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

18 months

What Are the Treatments Tested in This Trial?

Interventions

• Azacytidine
• Romidepsin

Trial Overview The study is testing if combining two drugs—oral azacytidine and romidepsin—is better for treating PTCL compared to the standard single-agent therapies chosen by the investigator (belinostat, pralatrexate or gemcitabine). Patients will be randomly assigned to receive either the combination treatment or one of the standard therapies.

How Is the Trial Designed?

Group I: AZA and ROMI Experimental Treatment 2 Interventions

Oral Azacytidine (AZA) (300 mg daily on days 1-14) plus Romidepsin (ROMI) (14 mg/m2 as an intravenous infusion over 4 hours +/- 30 minutes on days 8, 15 and 22 of a 35-day cycle.

Group II: Investigator's Choice Active Control 4 Interventions

Investigator's choice to include: ROMI, 14 mg/m2 IV infusion on days 1, 8, and 15 of a 28 day cycle, belinostat,1000 mg/m2 IV infusion on days 1-5 every 21 days, pralatrexate, 30 mg/m2 IV push once weekly for 6 weeks of a 7-week treatment cycle, or gemcitabine, 1000 mg/m2 IV infusion on days 1, 8, and 15 of a 28-day cycle.

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

Approved in United States as Vidaza for:

• Myelodysplastic Syndrome
• Acute Myeloid Leukemia
• Juvenile Myelomonocytic Leukemia

Approved in European Union as Vidaza for:

• Myelodysplastic Syndrome
• Acute Myeloid Leukemia
• Juvenile Myelomonocytic Leukemia

Who Is Running the Clinical Trial?

University of Virginia

Lead Sponsor

Trials

802

Recruited

1,342,000+

Celgene

Industry Sponsor

Trials

649

Recruited

130,000+

Top Products

>- **Revlimid (lenalidomide)**: Multiple myeloma, myelodysplastic syndromes, and mantle cell lymphoma treatment. - **Pomalyst (pomalidomide)**: Relapsed/refractory multiple myeloma treatment. - **Otezla (apremilast)**: Psoriatic arthritis treatment. - **Thalomid (thalidomide)**: Erythema nodosum leprosum and multiple myeloma treatment.

Jay Backstrom

Celgene

Chief Medical Officer since 2016

MD

Mark Alles

Celgene

Chief Executive Officer since 2016

Bachelor's degree from Lock Haven University of Pennsylvania

Published Research Related to This Trial

In a study involving 37 patients with untreated peripheral T-cell lymphoma, romidepsin was found to be safely combined with CHOP therapy, with a recommended dose of 12 mg/m² established for further testing.

While the combination showed promise, it also resulted in significant side effects, including high rates of neutropenia and thrombocytopenia, indicating the need for careful monitoring and further randomized trials to assess its efficacy compared to CHOP alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of romidepsin with cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated patients with peripheral T-cell lymphoma: a non-randomised, phase 1b/2 study. Dupuis, J., Morschhauser, F., Ghesquières, H., et al.[2018]

In a study involving 15 patients with advanced metastatic osteogenic and Ewing's sarcoma, treatment with 5-azacytidine showed no significant antitumor activity, indicating it may not be an effective option for these types of cancer.

The treatment was associated with major toxicities, primarily hematologic and gastrointestinal, highlighting safety concerns despite the lack of efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of 5-azacytidine in sarcomas of bone. Srinivasan, U., Reaman, GH., Poplack, DG., et al.[2019]

In a study involving rhesus monkeys, arabinosyl-5-azacytidine (AAC) showed no clinically significant toxicity after various intravenous infusion durations, indicating a favorable safety profile for this treatment.

The pharmacokinetics of AAC revealed rapid plasma elimination with a complex decay pattern, and the drug demonstrated limited penetration into cerebrospinal fluid (CSF), which may inform future human studies on dosing and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical pharmacology of arabinosyl-5-azacytidine in nonhuman primates. Heideman, RL., Balis, FM., McCully, C., et al.[2014]

The ROMAZA trial established that the maximum tolerated dose of the combination therapy of romidepsin (ROM) and azacitidine (AZA) for treating acute myeloid leukaemia (AML) is ROM 12 mg/m2 on Days 8 and 15, along with AZA 75 mg/m2 for a 7/28 day cycle.

Out of 38 patients treated at this maximum tolerated dose, 23.7% achieved a response by Cycle 6, with 7 patients reaching complete remission and 2 achieving partial response, indicating the potential efficacy of this combination therapy in AML patients who cannot undergo intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination romidepsin and azacitidine therapy is well tolerated and clinically active in adults with high-risk acute myeloid leukaemia ineligible for intensive chemotherapy. Loke, J., Metzner, M., Boucher, R., et al.[2022]

In a Phase I trial involving 27 adult patients with refractory cancer, 1-beta-D-arabinofuranosyl-5-azacytosine (ara-AC) showed dose-limiting toxicities, primarily reversible granulocytopenia and thrombocytopenia, with significant side effects observed at a dose rate of 1.96 mg/m2/h.

Despite the toxicity, minor clinical responses were noted in several patients, leading to a recommended dose of 2.0 mg/m2/h for future Phase II studies, indicating potential efficacy in treating certain types of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I and pharmacokinetic study of arabinofuranosyl-5-azacytosine (fazarabine, NSC 281272). Surbone, A., Ford, H., Kelley, JA., et al.[2014]

5-Azacytidine has shown a 36% overall response rate and 20% complete remission in patients with acute myelogenous leukemia (AML) who have previously been treated, indicating its potential effectiveness in this specific cancer.

While the drug has dose-limiting toxicities such as nausea, vomiting, and leukopenia, it has low incidence of thrombocytopenia and varying degrees of hepatic toxicity, suggesting that its safety profile needs careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

5-Azacytidine. A new anticancer drug with effectiveness in acute myelogenous leukemia. Von Hoff, DD., Slavik, M., Muggia, FM.[2019]

Romidepsin, a histone deacetylase inhibitor, has shown considerable activity and good tolerability in patients with peripheral T-cell lymphoma (PTCL), which is known for poor outcomes with conventional chemotherapy.

The promising results from two large Phase II trials with romidepsin suggest that it could be a foundation for developing combination therapies and exploring other drugs with similar mechanisms for treating T-cell lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Romidepsin for peripheral T-cell lymphoma. Khot, A., Dickinson, M., Prince, HM.[2014]

A total of 26 new 5-azacytidine analogues were synthesized and tested for their ability to inhibit the growth of human leukemia HL-60 cells, with one compound (ribofuranosyl S-nucleoside 3a) showing similar effectiveness to the original 5-azacytidine.

Modifications to the 5-azacytidine structure, such as adding a methyl group or changing the sugar type, generally reduced antiproliferative activity, but some analogues improved differentiation of leukemia cells when combined with all-trans retinoic acid.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis and antiproliferative activities of 5-azacytidine analogues in human leukemia cells. Guo, G., Li, G., Liu, D., et al.[2021]

The study demonstrated that the DNA methyltransferase inhibitor azacytidine (aza) can be safely administered at a dose of 50 mg/m2 twice a week in combination with lenalidomide and dexamethasone for patients with relapsed and/or refractory multiple myeloma, showing tolerability with manageable side effects.

Although the overall response rate was relatively low at 22%, the treatment may help reactivate pathways that allow some patients to overcome resistance to lenalidomide, particularly in those with lower levels of the enzyme that inactivates aza, suggesting a need for further optimization and patient selection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DNA methylation inhibition in myeloma: Experience from a phase 1b study of low-dose continuous azacitidine in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. Khouri, J., Faiman, BM., Grabowski, D., et al.[2022]

Romidepsin, an antitumor drug that inhibits histone deacetylase (HDAC), showed a treatment response rate of 42.5% in a phase II study involving 40 Japanese patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).

The safety profile of romidepsin was deemed acceptable, with common severe side effects including lymphopenia (74%), neutropenia (54%), and leukocytopenia (46%), leading to its approval for PTCL treatment in Japan in July 2017.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Romidepsin (Istodax&#174; for intravenous injection 10&#8197;mg): pharmacokinetics, pharmacodynamics and clinical study outcome]. Ro, T., Nakayama, N., Achiwa, H., et al.[2018]

In a randomized phase III study involving 421 patients with untreated peripheral T-cell lymphoma (PTCL), the combination of romidepsin and CHOP (Ro-CHOP) did not significantly improve progression-free survival (PFS) or overall survival compared to CHOP alone.

The Ro-CHOP treatment resulted in a higher incidence of severe side effects, such as thrombocytopenia and neutropenia, indicating that while romidepsin was added to the regimen, it did not provide a meaningful benefit and increased the risk of adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Romidepsin Plus CHOP Versus CHOP in Patients With Previously Untreated Peripheral T-Cell Lymphoma: Results of the Ro-CHOP Phase III Study (Conducted by LYSA). Bachy, E., Camus, V., Thieblemont, C., et al.[2023]

In a phase 1 study involving 31 patients with advanced lymphoid malignancies, the combination of oral 5-azacytidine and romidepsin was found to be significantly more effective in treating peripheral T-cell lymphomas (PTCL), achieving a 73% overall response rate compared to only 10% in non-T-cell lymphomas.

The maximum tolerated dose was established at 300 mg of 5-azacytidine and 14 mg/m2 of romidepsin, with dose-limiting toxicities including severe thrombocytopenia and neutropenia, but no treatment-related deaths were reported, indicating a manageable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral 5-azacytidine and romidepsin exhibit marked activity in patients with PTCL: a multicenter phase 1 study. O'Connor, OA., Falchi, L., Lue, JK., et al.[2021]

5-Azacytidine is more effective against L1210 leukemia in mice when given by injection rather than orally, but its oral effectiveness can be significantly improved.

When 5-azacytidine is combined with tetrahydrouridine, a drug that inhibits a specific enzyme, the oral administration of 5-azacytidine achieves blood levels comparable to those seen with injections, resulting in similar therapeutic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhancement by tetrahydrouridine (NSC-112907) of the oral activity of 5-azacytidine (NSC-102816) in L1210 leukemic mice. Neil, GL., Moxley, TE., Kuentzel, SL., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10368677/

Real-world experience of combined treatment with azacitidine ... A phase 2 study of aza/romi in patients with PTCL demonstrated an overall response rate (ORR) and complete response rate (CRR) of 61% and 48%, respectively, ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33171487/

Combined oral 5-azacytidine and romidepsin are highly ... We found oral 5-azacytidine and romidepsin to be safe and effective, with lineage-selective activity among patients with relapsed/refractory (R/R) PTCL.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04747236

Randomized Phase IIB Trial of Oral Azacytidine Plus ... ... azacytidine is safe and effective in patients with Peripheral T-Cell Lymphoma (PTCL). This study will compare the experimental combination treatment of ...

4. actr.amegroups.org actr.amegroups.org/article/view/9959/html

Romidepsin in peripheral T-cell lymphomas: current updates ... These treatments frequently yield unsatisfactory results, with a 5-year overall survival (OS) rate of around 30% (2,3). For patients younger than 65 years, ...

5. frontiersin.org frontiersin.org/journals/hematology/articles/10.3389/frhem.2025.1638236/pdf

Real-world data of azacitidine for relapsed/refractory nodal ... Azacitidine may be a suitable treatment option for some patients with r/r nodal T-follicular helper cell lymphoma. KEYWORDS azacitidine, PTCL, ...

6. ashpublications.org ashpublications.org/bloodadvances/article/7/14/3760/494491/Real-world-experience-of-combined-treatment-with

Real-world experience of combined treatment with azacitidine ... A phase 1 study of oral azacitidine and romidepsin (aza/romi) demonstrated higher efficacy in patients with PTCL than in patients with B-cell lymphomas.

7. sciencedirect.com sciencedirect.com/science/article/pii/S0006497121008612

Combined oral 5-azacytidine and romidepsin are highly ... We found oral 5-azacytidine and romidepsin to be safe and effective, with lineage-selective activity among patients with relapsed/refractory (R/R) PTCL.