Randomized Phase IIB Trial of Oral Azacytidine Plus Romidepsin Versus Investigator's Choice in PTCL

NCT ID: NCT04747236

Last Updated: 2026-01-21

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 50 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-02-19
• Study Completion Date: 2030-06-02

Brief Summary

The purpose of this study is to find out whether the combination treatment of romidepsin and oral azacytidine is safe and effective in patients with Peripheral T-Cell Lymphoma (PTCL). This study will compare the experimental combination treatment of romidepsin and oral azacytidine to single agent drugs already determined effective in patients with PTCL. For the purposes of this study, the single agent drugs already used to treat lymphoma are called investigator's choice (IC), meaning the investigator will choose which one of these drugs to administer. The IC drug options include romidepsin, belinostat, pralatrexate or gemcitabine given alone. Funding Source: FDA OOPD.

Detailed Description

Peripheral T-Cell Lymphoma (PTCL) is a rare and heterogeneous group of non-Hodgkin lymphoma (NHL) originating from mature (or post-thymic or 'peripheral') T- lymphocytes and NK cells. They are considered very aggressive and are often resistant to conventional chemotherapy.

This study employs a stratified randomization with equal allocation within strata of patients to receive oral 5-azacytidine (AZA) plus romidepsin (ROMI) versus pre-specified investigator choice (ROMI, belinostat, pralatrexate or gemcitabine), for the treatment of relapsed or refractory (R/R) PTCL. The dose and schedule of AZA/ROMI has been determined from a phase I clinical trial of the combination. The primary objective of this study is to estimate the progression free survival (PFS) among patients receiving the combination compared to single agent of choice.

Conditions

PTCL

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

AZA and ROMI

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 Type: EXPERIMENTAL

Azacytidine

Intervention Type: DRUG

Azacytidine, 300 mg po daily on Days 1-14

Romidepsin

Intervention Type: DRUG

Romidepsin, 14 mg/m2 as an intravenous infusion over 4 hours on Days 8, 15, and 22 of a 35-day cycle

Investigator's Choice

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.

Group Type: ACTIVE_COMPARATOR

Romidepsin

Intervention Type: DRUG

Romidepsin, 14 mg/m2 as an intravenous infusion over 4 hours on Days 8, 15, and 22 of a 35-day cycle

Belinostat

Intervention Type: DRUG

Belinostat, 1000 mg/m2 as an intravenous infusion over 30 minutes on Days 1-5 every 21 days.

Pralatrexate

Intervention Type: DRUG

Pralatrexate, 30 mg/m2 as an intravenous infusion over a 3-5 minute push once weekly for 6 weeks of a 7 week treatment cycle.

Gemcitabine

Intervention Type: DRUG

Gemcitabine, 1000 mg/m2 as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of a 28 day cycle.

Interventions

Azacytidine

Azacytidine, 300 mg po daily on Days 1-14

Intervention Type: DRUG

Romidepsin

Romidepsin, 14 mg/m2 as an intravenous infusion over 4 hours on Days 8, 15, and 22 of a 35-day cycle

Intervention Type: DRUG

Belinostat

Belinostat, 1000 mg/m2 as an intravenous infusion over 30 minutes on Days 1-5 every 21 days.

Intervention Type: DRUG

Pralatrexate

Pralatrexate, 30 mg/m2 as an intravenous infusion over a 3-5 minute push once weekly for 6 weeks of a 7 week treatment cycle.

Intervention Type: DRUG

Gemcitabine

Gemcitabine, 1000 mg/m2 as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of a 28 day cycle.

Intervention Type: DRUG

Other Intervention Names

Vidaza; Istodax; Beleodaq; Folotyn; Gemzar

Eligibility Criteria

Inclusion Criteria

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

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.

1. Patients are required to have no more than 3 lines of prior therapy (with cytoreductive therapy [ex ICE, DHAP, etc.] followed by autologous stem cell transplant counting as one line of therapy). Patients are eligible if they have relapsed after prior autologous or allogeneic stem cell transplant.

2. Patients with anaplastic large cell lymphoma are required to have received brentuximab vedotin (Bv) prior to study enrollment.

3. Measurable Disease as defined in Section 8.1.3.1.

4. Age ≥18 years.

5. ECOG performance status ≤2

6. Patients must have adequate organ and marrow function as defined below:

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.

7. Negative urine or serum pregnancy test for females of childbearing potential

8. All females of childbearing potential and male subjects must agree to use an effective method of contraception (see section 5.4 for more details)

9. Be willing and able to provide written consent or assent for the trial.

• Any cardiac arrhythmia requiring an anti-arrhythmic medication (excluding stable doses of beta-blockers)

Exclusion Criteria

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Diagnosis of patch/plaque stage mycosis fungoides

2. Prior Therapy: Prior exposure to any hypomethylating agent or any histone deacetylase inhibitor (ex: romidepsin, chidamide, belinostat, or vorinostat); exposure to chemotherapy or radiotherapy within 2 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier.

3. Systemic steroids that have not been stabilized to the equivalent of ≤10 mg/day prednisone prior to the start of the study drugs.

4. No other concurrent investigational agents are allowed within 2 weeks of enrollment.

5. Known central nervous system metastases, including lymphomatous meningitis

6. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

7. Nursing women

8. Other active concurrent malignancy (except non-melanoma skin cancer, carcinoma in situ of the cervix, or carcinoma in situ of the breast (DCIS or LCIS). If there is a history of prior malignancy, the patient must be disease-free for ≥ 3-years. Patients whose lymphoma has transformed from a less aggressive histology remain eligible.

9. Patients known to be Human Immunodeficiency Virus (HIV)-positive.

10. Patients with active Hepatitis A, hepatitis B, or hepatitis C infection.

11. Concomitant use of CYP3A4 inhibitors (see Section 13.3)

12. History of inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis), celiac disease (ie, sprue), prior gastrectomy or upper bowel removal, or any other gastrointestinal disorder or defect that would interfere with the absorption, distribution, metabolism or excretion of the study drug and/or predispose the subject to an increased risk of gastrointestinal toxicity

13. Abnormal coagulation parameters (PT >15 seconds, PTT>40 seconds, and/or INR >1.5) unless related to ongoing anticoagulation treatment required by the patient.

14. Known or suspected hypersensitivity to azacitidine (or any excipients in the formulation) or mannitol.

15. Any known cardiac abnormalities such as:

• Congenital long QT syndrome
• QTc interval ≥ 500 millisecond (using the Fridericia formula)
• Patients taking drugs leading to significant QT prolongation (See Section 13.2)
• Myocardial infarction within 6 months of C1D1. [Subjects with a history of myocardial infarction between 6 and 12 months prior to C1D1 who are asymptomatic and have had a negative cardiac risk assessment (treadmill stress test, nuclear medicine stress test, or stress echocardiogram) since the event, may participate];
• Other significant ECG abnormalities including 2nd degree atrio-ventricular (AV) block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50 beats/min);
• Symptomatic coronary artery disease (CAD), e.g., angina Canadian Class II-IV (see Section 13.4) In any patient in whom there is doubt, the patient should have a stress imaging study and, if abnormal, angiography to define whether or not CAD is present;
• An ECG recorded at screening showing evidence of cardiac ischemia (ST depression of ≥2 mm, measured from isoelectric line to the ST segment). If in any doubt, the patient should have a stress imaging study and, if abnormal, angiography to define whether or not CAD is present;
• Congestive heart failure (CHF) that meets New York Heart Association (NYHA) Class II to IV definitions (see Section 13.5) and/or ejection fraction <40% by MUGA scan or <50% by echocardiogram and/or MRI;
• A known history of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), Torsade de Pointes, or cardiac arrest;
• Hypertrophic cardiomegaly or restrictive cardiomyopathy from prior treatment or other causes;

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Celgene

INDUSTRY

Sponsor Role: collaborator

University of Virginia

OTHER

Sponsor Role: lead

Responsible Party

Craig A Portell, MD

Professor of Medicine, Section Head for Hem Malignancies

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Craig Portell, MD

Role: PRINCIPAL_INVESTIGATOR

University of Virginia

Locations

VA Long Beach Health Care System

Long Beach, California, United States

Site Status: RECRUITING

Yale Cancer Center

New Haven, Connecticut, United States

Site Status: RECRUITING

Icahn School of Medicine at Mount Sinai

New York, New York, United States

Site Status: RECRUITING

Duke University

Durham, North Carolina, United States

Site Status: RECRUITING

The Ohio State University

Columbus, Ohio, United States

Site Status: NOT_YET_RECRUITING

University of Virginia

Charlottesville, Virginia, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Craig Portell, MD

Role: CONTACT

cp4ys@uvahealth.org

434-924-9637

Marian Abdelmalek, MS

Role: CONTACT

mka6s@uvahealth.org

434-924-8827

Facility Contacts

Helen MA, MD

Role: primary

helen.ma@va.gov

562-826-8000 ext. 1-3906

Pankaj Gupta, MD

Role: backup

pankaj.gupta@va.gov

562-826-8000 ext. 1-2243

Francesca Montanari, MD

Role: primary

francesca.montanari@yale.edu

475-241-1338

Kylie Boyhen

Role: backup

kylie.boyhen@yale.edu

203-752-7835

Suchitra Sundaram, MD

Role: primary

suchitra.sundaram@mssm.edu

212-824-7377

Martine van Voorthuysen

Role: backup

martine.VanVoorthuysen@mssm.edu

646-745-6092

Jie Wang, MD

Role: primary

jie.wang416@duke.edu

919-684-8964

Juliana Turner

Role: backup

julianna.turner@duke.edu

Jonathan Brammer, MD

Role: primary

Jonathan.Brammer@osumc.edu

Marian Abdelmalek, MS

Role: primary

mka6s@uvahealth.org

434-924-8827

References

Wang K, Shen Y, Hu C, Xu F, Wang Q, Gao Y, Zhou L. Population Pharmacokinetics and Exposure-Response Analysis of Serplulimab in Small Cell Lung Cancer Patients. Clin Transl Sci. 2025 Sep;18(9):e70322. doi: 10.1111/cts.70322.

Reference Type: DERIVED

PMID: 40932107 (View on PubMed)

Other Identifiers

FD-R-006814-01

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

PTCL-001

Identifier Type: -

Identifier Source: org_study_id