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)

A Phase 1-2, Open-Label Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Activity of Tolinapant in Combination With Oral Decitabine/Cedazuridine and Oral Decitabine/Cedazuridine Alone in Subjects With Relapsed/Refractory Peripheral T-cell Lymphoma

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.

As no safe and tolerable dosing for the combination of tolinapant and decitabine/cedazuridine was identified based on protocol defined criteria, Sponsor decided to halt recruitment and to not conduct Phase 2 of the study.

Study Overview

• Status: Active, not recruiting
• Conditions: Relapsed/Refractory Peripheral T-cell Lymphoma
• Intervention / Treatment: Drug: Tolinapant; Drug: Decitabine + Cedazuridine

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Nedlands, Australia, 6009
    • Linear Clinical Research Site #834
  • New South Wales
    • Concord, New South Wales, Australia, 2139
      • Concord Hospital
  • Victoria
    • Melbourne, Victoria, Australia, 3168
      • Monash Medical Center
• France
  • Bordeaux, France, 33000
    • Institut Bergonié Site#553
  • Marseille, France, 13009
    • Institut Paoli-Calmettes
  • Montpellier, France, 34295
    • CHU Saint-Eloi Site#556
  • Nice, France, 06189
    • Centre Antoine Lacassagne
  • Paris, France, 75013
    • AP-HP Pitie Saltpetriere Site# 552
  • Villejuif, France, 94805
    • Institut Gustave Roussy
  • Indre-et-Loire
    • Tours, Indre-et-Loire, France, 37000
      • Hopital Bretonneau
  • Seine-Maritime
    • Rouen, Seine-Maritime, France, 76038
      • Centre Henri Becquerel
• Italy
  • Bologna, Italy, 40138
    • U.O.C. di Ematologia Pad. 8IRCCS Azienda OspedalieroUniversitaria di Bologna Site#651
  • Brescia, Italy, 25123
    • Azienda Socio Sanitaria Territoriale (ASST) degli Spedali Civili di Brescia Site#650
  • Milan, Italy, 20141
    • Istituto Europeo di Oncologia Site#652
  • Monza, Italy, 20900
    • Fondazione IRCCS San Gerardo dei Tintori Site #655
  • Emilia-Romagna
    • Ravenna, Emilia-Romagna, Italy, 48121
      • Ospedale Santa Maria delle Croci di Ravenna
  • Forli-Cesena
    • Meldola, Forli-Cesena, Italy, 47014
      • Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" - IRST
• Poland
  • Masovia
    • Warsaw, Masovia, Poland, 02-781
      • Narodowy Instytut Onkologii im. Marii Skłodowskiej-Curie - Państwowy Instytut Badawczy
  • Pomeranian Voivodeship
    • Gdansk, Pomeranian Voivodeship, Poland, 80-214
      • Ośrodek Badań Klinicznych Wczesnych Faz - Uniwersyteckie Centrum Kliniczne w Gdańsku
  • Łódź Voivodeship
    • Lodz, Łódź Voivodeship, Poland, 93-513
      • Wojewódzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii im. M. Kopernika w Łodzi
• Spain
  • Barcelona, Spain, 08003
    • Hospital del Mar Site #704
  • Madrid, Spain, 28040
    • Hospital Universitario Fundación Jiménez Díaz Site #703
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre Site#710
  • Santander, Spain, 39008
    • Hospital Universitario Marqués de Valdecilla Site#711
  • Andalusia
    • Seville, Andalusia, Spain, 41013
      • Hospital Universitario Virgen del Rocio
  • Catalonia
    • Barcelona, Catalonia, Spain, 8025
      • Hospital De La Santa Creu I Sant Pau
    • Barcelona, Catalonia, Spain, 8908
      • Institut Català d'Oncologia - Hospital Duran i Reynals (ICO L'Hospitalet)
• United Kingdom
  • England
    • London, England, United Kingdom, SE1 9Rt
      • Guy's and Saint Thomas' NHS Foundation Trust
    • London, England, United Kingdom, W1T 7HA
      • University College London Hospitals NHS Foundation Trust
    • Manchester, England, United Kingdom, M20 4BX
      • The Christie NHS Foundation Trust
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope Site #151
    • Los Angeles, California, United States, 90095
      • University of Califonia, Los Angeles
    • Stanford, California, United States, 94305
      • Stanford University
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Anschutz Medical Campus Site #118
  • Connecticut
    • New Haven, Connecticut, United States, 06511
      • Yale Cancer Center Site #109
  • Florida
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center Site #157
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute of Emory University
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Rogel Cancer Center
    • Detroit, Michigan, United States, 48201
      • Barbara Ann Karmanos Cancer Institute Site#159
  • New York
    • Fairport, New York, United States, 14450
      • Rochester Skin Lymphoma Medical Group, PLLC Site #147
    • New York, New York, United States, 10016
      • NYU Langone Laura and Isaac Perlmutter Cancer Center Site #153
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Site# 160
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas MD Anderson Cancer Center Site #101
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Comprehensive Cancer Center
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phases 1 and 2: Tolinapant + Oral 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.	Drug: Tolinapant; Capsule for oral administration; Other Names: ASTX660; Drug: Decitabine + Cedazuridine; Tablet for oral administration; Other Names: ASTX727
Experimental: Phase 1: Oral Decitabine/Cedazuridine; Decitabine/cedazuridine FDC tablet, orally, QD on days determined by the Lead-in Phase during each 28-day cycle.	Drug: Decitabine + Cedazuridine; Tablet for oral administration; Other Names: ASTX727

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Dose Limiting Toxicities (DLTs)	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.	Up to 54 months
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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: Number of Participants With TEAEs, SAEs and DLTs in the Oral Decitabine/Cedazuridine Arm		Up to 54 months
Ph 1 & 2: AUC: Area Under the Plasma Concentration-Time Curve		Up to 50 months
Ph 1 & 2: Cmax: Maximum Observed Plasma Concentration		Up to 50 months
Ph 1 & 2: Cmin: Minimum Observed Plasma Concentration at Steady State		Up to 50 months
Ph 1 & 2: Tmax: Time to Maximum Observed Plasma Concentration		Up to 50 months
Ph 1 & 2: t½: Apparent Elimination Half-Life		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: Percentage of Participants With Complete Response (CR) Based on the Lugano Classification Using CT Imaging as the Primary Modality		Up to 54 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: Progression-Free Survival (PFS) 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 2: Overall Survival (OS) Based on the Lugano Classification Using CT Imaging as the Primary Modality		Up to 54 months
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	Duration of response (DOR), complete response (CR), partial response (PR), progression-free survival (PFS), disease control rate (DCR)and overall survival (OS)	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)	Anti-tumor activity in terms of ORR, DOR, CR, PR, and PFS will be evaluated based on assessment using 2014 Lugano Classification with LYRIC.	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

Collaborators and Investigators

• Sponsor: Taiho Oncology, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): February 22, 2023
• Primary Completion (Actual): December 16, 2024
• Study Completion (Estimated): March 31, 2026

Study Registration Dates

• First Submitted: May 23, 2022
• First Submitted That Met QC Criteria: May 31, 2022
• First Posted (Actual): June 3, 2022

Study Record Updates

• Last Update Posted (Actual): February 23, 2026
• Last Update Submitted That Met QC Criteria: February 19, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Non-Hodgkin Lymphoma
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma; Lymphoma, T-Cell; Hemic and Lymphatic Diseases; Lymphoma, Non-Hodgkin; Lymphoma, T-Cell, Peripheral; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; decitabine and cedazuridine drug combination; ASTX-660
• Other Study ID Numbers: ASTX660-03; 2021-005338-40 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No