A Study of Tolinapant in Combination With Oral Decitabine/Cedazuridine and Oral Decitabine/Cedazuridine Alone in Participants With Relapsed/Refractory Peripheral T-cell Lymphoma (R/R PTCL)

Phase 1

Active, not recruiting

• Conditions: Relapsed/Refractory Peripheral T-cell Lymphoma
• Interventions: Drug: Tolinapant; Drug: Decitabine + Cedazuridine

• Registration Number: NCT05403450
• Lead Sponsor: Taiho Oncology, Inc.

Brief Summary

The primary purpose of the study is to assess safety, and to identify the recommended phase 2 dose (RP2D) of tolinapant in combination with oral decitabine/cedazuridine in Phase 1 and to assess preliminary efficacy as determined by overall response rate (ORR) in Phase 2.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2022-05-23
• Study First Submitted QC: 2022-05-31
• Study First Posted: 2022-06-03
• Study Start: 2022-06-23
• Primary Completion: 2024-12-16
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-30
• Last Update Posted: 2025-05-02
• Study Completion: 2026-12-01

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 33

Inclusion Criteria

1. Participants with expected life expectancy of >12 weeks.

2. Participants must have histologically confirmed R/R PTCL (local pathology report) as defined by 2016 World Health Organization (WHO) classification. The following subtypes are eligible for the study:

   1. Extranodal natural killer (NK)/T-cell lymphoma nasal type.
   2. Enteropathy-associated T-cell lymphoma.
   3. Monomorphic epitheliotropic intestinal T-cell lymphoma.
   4. Hepatosplenic T-cell lymphoma.
   5. Subcutaneous panniculitis-like T-cell lymphoma.
   6. Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS).
   7. Angioimmunoblastic T-cell lymphoma.
   8. Follicular peripheral T-cell lymphoma.
   9. Nodal peripheral T-cell with T-follicular helper (THF) phenotype.
   10. Anaplastic large-cell lymphoma (ALCL).

3. Participants must have evidence of progressive disease and must have received at least two prior systemic therapies.

4. Participants must have measurable disease by contrast-enhanced diagnostic CT (at least 1 nodal lesion >1.5 centimeters (cm) or extranodal lesions >1.0 cm).

5. Participants with CD30-positive disease must have received, be ineligible for, or intolerant to brentuximab vedotin.

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

7. Acceptable organ function as per protocol.

8. Women of childbearing potential (according to recommendations of the Clinical Trial Facilitation Group [CTFG]) must not be pregnant or breastfeeding and must have a negative pregnancy test at screening.

Exclusion Criteria

1. Prior treatment with tolinapant or any hypomethylating agent.

2. Hypersensitivity to tolinapant or oral decitabine/cedazuridine, excipients of the drug product, or other components of the study treatment regimen.

3. Poor medical risk because of systemic diseases (e.g., uncontrolled infections) in addition to the qualifying disease under study.

4. Life-threatening illness, significant organ system dysfunction, or other condition that, in the investigator's opinion, could compromise participant safety or the integrity of the study outcomes, or interfere with the absorption or metabolism of tolinapant.

5. A history of, or at risk for, cardiac disease, as evidenced by 1 or more of the following conditions:

   1. Abnormal left ventricular ejection fraction.
   2. Congestive cardiac failure of Grade ≥3.
   3. Unstable cardiac disease.
   4. History or presence of complete left bundle branch block, third-degree heart block, cardiac pacemaker, or clinically significant arrhythmia.
   5. History of long QTc syndrome or ventricular arrhythmias including ventricular bigeminy.
   6. Screening 12-lead electrocardiogram (ECG) with measurable QTc interval of ≥470 milliseconds (msec) (according to either Fridericia's or Bazett's correction).
   7. Any other condition that, in the opinion of the investigator, could put the participant at increased cardiac risk.

6. Known history of human immunodeficiency virus (HIV) infection; or seropositive results consistent with active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection.

7. Grade 3 or greater neuropathy.

8. Known significant mental illness or other conditions such as active alcohol or other substance abuse that, in the opinion of the investigator, predisposes the participant to high risk of noncompliance with the protocol treatment or assessments.

9. Prior anticancer treatments or therapies within the indicated time window before first dose of study treatment (tolinapant), as follows:

   1. Cytotoxic chemotherapy or radiotherapy within 4 weeks prior.
   2. Monoclonal antibodies within 4 weeks prior.
   3. At least 12 weeks must have elapsed since chimeric antigen receptor T-cell (CAR-T) infusion.
   4. Small molecules or biologics (investigational or approved) within the longer of 3 weeks or 5 half-lives before study treatment.

10. Monoclonal antibody treatment for rheumatologic conditions within 4 weeks of study drug initiation.

11. Concurrent second malignancy currently requiring active therapy, except breast or prostate cancer stable on or responding to endocrine therapy or superficial bladder cancer.

12. Any concurrent second malignancy that is metastatic.

13. Known central nervous system (CNS) lymphoma.

14. Participants with a history of allogeneic transplant are excluded from this study.

15. Autotransplant within 100 days of the first dose of the study drug(s).

16. Systemic corticosteroids >10 mg prednisone equivalent within 7 days of the first dose of study drug(s).

17. Anti-T-cell directed therapy:

    1. Lymphotoxic agents (e.g., anti-CD52) in the past 12 months.
    2. Inhibitory drugs (e.g., calcineurin inhibitors) within 4 weeks of the first dose of study drug(s).

18. Use of a concomitant medication which is a moderate or strong CYP3A4 inhibitor/inducer within 2 weeks of the start of the study.

19. Use of any vaccine within 10 days of the first dose of the study drug(s).

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phases 1 and 2: Tolinapant + Oral Decitabine/Cedazuridine	Decitabine + Cedazuridine	Tolinapant, orally, once daily (QD) on Days 1 to 7 and 15 to 21 of each 28-day cycle in combination with oral decitabine/cedazuridine fixed-dose combination (FDC) tablet, QD on days determined by the Lead-in Phase during each 28-day cycle. The starting dose of tolinapant will be escalated stepwise in successive cohorts until the RP2D is determined. Based on RP2D and results determined from Phase 1 participants would receive tolinapant at the identified RP2D in combination with decitabine/cedazuridine, FDC tablet, orally, QD on days determined by the Lead-in Phase during each 28-day cycle in Phase 2.
Phase 1: Oral Decitabine/Cedazuridine	Decitabine + Cedazuridine	Decitabine/cedazuridine FDC tablet, orally, QD on days determined by the Lead-in Phase during each 28-day cycle.
Phases 1 and 2: Tolinapant + Oral Decitabine/Cedazuridine	Tolinapant	Tolinapant, orally, once daily (QD) on Days 1 to 7 and 15 to 21 of each 28-day cycle in combination with oral decitabine/cedazuridine fixed-dose combination (FDC) tablet, QD on days determined by the Lead-in Phase during each 28-day cycle. The starting dose of tolinapant will be escalated stepwise in successive cohorts until the RP2D is determined. Based on RP2D and results determined from Phase 1 participants would receive tolinapant at the identified RP2D in combination with decitabine/cedazuridine, FDC tablet, orally, QD on days determined by the Lead-in Phase during each 28-day cycle in Phase 2.

Primary Outcome Measures

Name	Time	Method
Phase 2: Antitumor Activity Assessed by Overall Response Rate (ORR) Based on 2014 Lugano Classification Using Computerized Tomography (CT) Imaging as the Primary Modality	Up to 54 months
Phase 1: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Dose Limiting Toxicities (DLTs)	Up to 54 months	This will be evaluated by looking at the number of participants with treatment-related adverse events, serious adverse events (SAEs), and dose-limiting toxicities (DLTs), which are medical problems severe enough to stop study doctors from increasing a treatment dose.

Secondary Outcome Measures

Name	Time	Method
Ph 1 & 2: t½: Apparent Elimination Half-Life	Up to 50 months
Phase 2: Percentage of Participants With Complete Response (CR) Based on the Lugano Classification Using CT Imaging as the Primary Modality	Up to 54 months
Ph 1 & 2: AUC: Area Under the Plasma Concentration-Time Curve	Up to 50 months
Phase 2: Percentage of Participants With Partial Response (PR) Based on the Lugano Classification Using CT Imaging as the Primary Modality	Up to 54 months
Phase 2: Percentage of Participants With Anti-Tumor Activity Based on PTCL Subtypes Anti-tumor activity in terms of ORR, DOR, DCR, CR, and PR will be evaluated based on PTCL subtypes (using both pathology and molecular markers).	Up to 54 months
Ph 1 & 2: Tmax: Time to Maximum Observed Plasma Concentration	Up to 50 months
Phase 2: Overall Survival (OS) Based on the Lugano Classification Using CT Imaging as the Primary Modality	Up to 54 months
Ph 1 & 2: Cmax: Maximum Observed Plasma Concentration	Up to 50 months
Phase 2: Duration of response (DOR) Based on the Lugano Classification Using CT Imaging as the Primary Modality	Up to 54 months
Phase 2: Disease Control Rate (DCR) Assessed as Percentage of Participants With Disease Control Based on the Lugano Classification Using CT Imaging as the Primary Modality	Up to 54 months
Phase 1: Number of Participants With TEAEs, SAEs and DLTs in the Oral Decitabine/Cedazuridine Arm	Up to 54 months
Ph 1 & 2: Cmin: Minimum Observed Plasma Concentration at Steady State	Up to 50 months
Phase 2: Progression-Free Survival (PFS) Based on the Lugano Classification Using CT Imaging as the Primary Modality	Up to 54 months
Phase 2: Percentage of Participants With Anti-Tumor Activity Based on Assessment Using 2014 Lugano Classification With Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC)	Up to 54 months	Anti-tumor activity in terms of ORR, DOR, CR, PR, and PFS will be evaluated based on assessment using 2014 Lugano Classification with LYRIC.
Phase 2: Percentage of Participants With DOR, CR, PR, PFS, DCR,and OS Based on the Lugano Classification Using CT Along With PET Imaging Assessments	Up to 54 months	Duration of response (DOR), complete response (CR), partial response (PR), progression-free survival (PFS), disease control rate (DCR)and overall survival (OS)

Trial Locations

Locations (46)

Institut Gustave Roussy; 🇫🇷 Villejuif, France

Institut Paoli-Calmettes; 🇫🇷 Marseille, France

Concord Hospital; 🇦🇺 Concord, New South Wales, Australia

Centre Antoine Lacassagne; 🇫🇷 Nice, France

City of Hope Site #151; 🇺🇸 Duarte, California, United States

University of Califonia, Los Angeles; 🇺🇸 Los Angeles, California, United States

Stanford University; 🇺🇸 Stanford, California, United States

University of Colorado Anschutz Medical Campus Site #118; 🇺🇸 Aurora, Colorado, United States

Yale Cancer Center Site #109; 🇺🇸 New Haven, Connecticut, United States

Moffitt Cancer Center Site #157; 🇺🇸 Tampa, Florida, United States

Winship Cancer Institute of Emory University; 🇺🇸 Atlanta, Georgia, United States

Johns Hopkins University; 🇺🇸 Baltimore, Maryland, United States

University of Michigan Rogel Cancer Center; 🇺🇸 Ann Arbor, Michigan, United States

Barbara Ann Karmanos Cancer Institute Site#159; 🇺🇸 Detroit, Michigan, United States

Rochester Skin Lymphoma Medical Group, PLLC Site #147; 🇺🇸 Fairport, New York, United States

University of Pennsylvania Site# 160; 🇺🇸 Philadelphia, Pennsylvania, United States

Monash Medical Center; 🇦🇺 Melbourne, Victoria, Australia

Centre Henri Becquerel; 🇫🇷 Rouen, Seine-Maritime, France

CHU Saint-Eloi Site#556; 🇫🇷 Montpellier, France

Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" - IRST; 🇮🇹 Meldola, Forli-Cesena, Italy

NYU Langone Laura and Isaac Perlmutter Cancer Center Site #153; 🇺🇸 New York, New York, United States

University of Virginia Comprehensive Cancer Center; 🇺🇸 Charlottesville, Virginia, United States

U.O.C. di Ematologia Pad. 8IRCCS Azienda OspedalieroUniversitaria di Bologna Site#651; 🇮🇹 Bologna, Italy

The University of Texas MD Anderson Cancer Center Site #101; 🇺🇸 Houston, Texas, United States

Fred Hutchinson Cancer Center; 🇺🇸 Seattle, Washington, United States

Linear Clinical Research Site #834; 🇦🇺 Nedlands, Australia

Hôpital Bretonneau; 🇫🇷 Tours, Indre-et-Loire, France

Institut Bergonié Site#553; 🇫🇷 Bordeaux, France

AP-HP Pitie Saltpetriere Site# 552; 🇫🇷 Paris, France

Ospedale Santa Maria delle Croci di Ravenna; 🇮🇹 Ravenna, Emilia-Romagna, Italy

Istituto Europeo di Oncologia Site#652; 🇮🇹 Milano, Italy

Azienda Socio Sanitaria Territoriale (ASST) degli Spedali Civili di Brescia Site#650; 🇮🇹 Brescia, Italy

Fondazione IRCCS San Gerardo dei Tintori Site #655; 🇮🇹 Monza, Italy

Wojewódzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii im. M. Kopernika w Łodzi; 🇵🇱 Lodz, Lodzkie, Poland

Narodowy Instytut Onkologii im. Marii Skłodowskiej-Curie - Państwowy Instytut Badawczy; 🇵🇱 Warsaw, Masovia, Poland

Hospital de la Santa Creu i Sant Pau; 🇪🇸 Barcelona, Catalonia, Spain

Hospital Universitario Fundación Jiménez Díaz Site #703; 🇪🇸 Madrid, Spain

Hospital Universitario 12 de Octubre Site#710; 🇪🇸 Madrid, Spain

Hospital Universitario Marqués de Valdecilla Site#711; 🇪🇸 Santander, Spain

Guy's and Saint Thomas' NHS Foundation Trust; 🇬🇧 London, England, United Kingdom

University College London Hospitals NHS Foundation Trust; 🇬🇧 London, England, United Kingdom

The Christie NHS Foundation Trust; 🇬🇧 Manchester, England, United Kingdom

Ośrodek Badań Klinicznych Wczesnych Faz - Uniwersyteckie Centrum Kliniczne w Gdańsku; 🇵🇱 Gdańsk, Pomerania, Poland

Institut Català d'Oncologia - Hospital Duran i Reynals (ICO L'Hospitalet); 🇪🇸 Barcelona, Catalonia, Spain

Hospital del Mar Site #704; 🇪🇸 Barcelona, Spain

Hospital Universitario Virgen del Rocío; 🇪🇸 Sevilla, Andalucía, Spain