What side effects are associated with this type of intervention?

Common treatments for Peripheral T-Cell Lymphoma (PTCL) similar to Romidepsin (an HDAC inhibitor) and Oral Azacytidine (a DNA methyltransferase inhibitor) include single-agent therapies like belinostat, pralatrexate, and gemcitabine. The known side effects of these treatments often include hematologic toxicities such as neutropenia, thrombocytopenia, and anemia. Non-hematologic side effects can include fatigue, nausea, vomiting, diarrhea, and infections. Specific to HDAC inhibitors like Romidepsin, additional side effects may include cardiac arrhythmias and electrolyte imbalances. DNA methyltransferase inhibitors like Azacytidine can also cause injection site reactions and gastrointestinal disturbances.

What prior FDA approvals exist?

For the treatment of Peripheral T-Cell Lymphoma (PTCL), the FDA has approved several drugs, including Romidepsin, an HDAC inhibitor, and Belinostat, another HDAC inhibitor. These drugs work by inhibiting histone deacetylases, which can help induce cancer cell death. Additionally, Pralatrexate, a folate analog metabolic inhibitor, has been approved for PTCL. While Azacytidine, a DNA methyltransferase inhibitor, is not specifically approved for PTCL, it is used in related hematologic malignancies and is being studied in combination with Romidepsin for potential efficacy in PTCL.

What other types of research exist?

Promising novel alternatives for PTCL treatment in 2024 include: 1) Chimeric Antigen Receptor (CAR) T-cell therapies, which are being explored for their potential to target specific cancer cells. 2) Bispecific T-cell engagers (BiTEs), such as those targeting CD3 and other tumor-specific antigens. 3) Novel agents targeting specific mutations or pathways, such as farnesyltransferase inhibitors for HRAS mutant PTCL. 4) Combination therapies involving immune checkpoint inhibitors like pembrolizumab with other agents. These alternatives are in various stages of clinical trials and show potential for improved outcomes in PTCL patients.

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Anti-metabolites

Azacytidine + Romidepsin for Peripheral T-Cell Lymphoma (PTCL Trial)

Phase 2

Recruiting

Led By Enrica Marchi, MD

Research Sponsored by University of Virginia

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Age ≥18 years.

Patients must have histologically confirmed relapsed or refractory peripheral T-cell lymphoma as defined by 2016 WHO criteria (Section 13.7), who have progressed following one line of prior systemic therapy.

Must not have

Congenital long QT syndrome

Diagnosis of patch/plaque stage mycosis fungoides

Timeline

Screening 3 weeks

Treatment Varies

Follow Up from time of informed consent until 90 days after the last day of study treatment for all adverse events or anytime for serious adverse events considered related to the study intervention, through study completion, an average of 18 months.

Awards & highlights

Summary

This trial is testing if a combination of two drugs, romidepsin and azacytidine, is safe and effective for patients with aggressive Peripheral T-Cell Lymphoma that hasn't responded to other treatments. The goal is to see if this combination works better than using just one drug alone. Romidepsin is approved for certain types of T-cell lymphoma and has shown positive results in various T-cell cancers.

Who is the study for?

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.

What is being tested?

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.

What are the potential side effects?

Possible side effects include nausea, vomiting, fatigue, low blood counts leading to increased infection risk or bleeding problems. There may also be liver issues indicated by abnormal tests results and potential heart rhythm problems.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am 18 years old or older.

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

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I have anaplastic large cell lymphoma and have been treated with brentuximab vedotin.

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I can take care of myself but might not be able to do heavy physical work.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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

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I have been diagnosed with early-stage mycosis fungoides.

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My cancer has spread to my brain or spinal cord.

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I am not on medications that greatly affect my heart's rhythm.

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My steroid medication dose is not stable or is above 10 mg/day of prednisone.

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I do not have any serious illnesses that would stop me from following the study's requirements.

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I have a history of serious gut conditions that could affect drug absorption or increase risk of stomach side effects.

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I have an enlarged or stiff heart from previous treatments or other reasons.

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I am on medication for an irregular heartbeat, not including beta-blockers.

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I am currently breastfeeding.

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I do not have active Hepatitis A, B, or C.

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My ECG showed signs of heart issues, and I may need further tests to check for heart disease.

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I have heart failure classified as moderate to severe, or my heart's pumping ability is significantly reduced.

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I have a history of serious heart rhythm problems.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ from time of informed consent until 90 days after the last day of study treatment for all adverse events or anytime for serious adverse events considered related to the study intervention, through study completion, an average of 18 months.

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~from time of informed consent until 90 days after the last day of study treatment for all adverse events or anytime for serious adverse events considered related to the study intervention, through study completion, an average of 18 months.

This trial's timeline: 3 weeks for screening, Varies for treatment, and from time of informed consent until 90 days after the last day of study treatment for all adverse events or anytime for serious adverse events considered related to the study intervention, through study completion, an average of 18 months. for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Progression free survival

Secondary study objectives

Complete response rate

Duration of response rate

Frequency of adverse events

+3 more

Side effects data

From 2018 Phase 2 trial • 16 Patients • NCT02196857

31%

Febrile Neutropenia

31%

Lung Infection

25%

Hypotnesion

25%

Diarrhea

25%

Fatigue

13%

Urinary Tract Infection

13%

Laryngeal Inflammation

13%

Nausea

13%

Pain

13%

Colitis

13%

Dyspnea

13%

Dyspena

Facial Pain/Dental

Fever

Infection

Intestine Obstruction

Intracranial Hemorrhage

Laryngeal Hemorrhage

Syncope

Tremor

Arthritis

Hypercalcemia

Cough

Rash

Vomiting

Watery eye

Acute Heart Failure

Acute Kidney failure

Acute Respiratory Failure

Cardiac Triponin Increase

Cellulitis

Dehydration

Thrombocytopenia

generalized edema

Seizure

Sepsis

Skin Infection

Stroke

Dizziness

Edema

Hemorrhage

Hyperglycemia

100%

80%

60%

40%

20%

Study treatment Arm

Azacytidine + Sorafenib

Trial Design

2Treatment groups

Experimental Treatment

Active Control

Group I: AZA and ROMIExperimental Treatment2 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 ChoiceActive Control4 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.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Azacytidine

2008

Completed Phase 2

~140

Romidepsin

2011

Completed Phase 2

~790

0 / 18Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Romidepsin, a histone deacetylase (HDAC) inhibitor, works by blocking the activity of HDAC enzymes, leading to an accumulation of acetylated histones and other proteins. This results in altered gene expression, cell cycle arrest, and apoptosis of cancer cells. Oral Azacytidine, a DNA methyltransferase inhibitor, incorporates into DNA and RNA, leading to hypomethylation of DNA and reactivation of tumor suppressor genes. This can inhibit cancer cell growth and induce cell death. These mechanisms are crucial for PTCL patients as they target the epigenetic modifications that often drive the malignancy, offering a therapeutic approach that can potentially improve outcomes in this aggressive cancer.