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)

Relapsed/Refractory Peripheral T-cell Lymphoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05403450
• Other study ID #: ASTX660-03
• Secondary ID: 2021-005338-40
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: June 23, 2022
• Est. completion date: December 1, 2026

Study information

• Verified date: May 2024
• Source: Astex Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 132
• Est. completion date: December 1, 2026
• Est. primary completion date: December 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, T-Cell
• Lymphoma, T-Cell, Peripheral
• Relapsed/Refractory Peripheral T-cell Lymphoma

Intervention

Drug:
• Tolinapant
Capsule for oral administration
• Decitabine + Cedazuridine
Tablet for oral administration

Locations

Country	Name	City	State
Australia	Concord Hospital	Concord	New South Wales
Australia	Monash Medical Center	Melbourne	Victoria
Australia	Linear Clinical Research Site #834	Nedlands
France	Institut Bergonié Site#553	Bordeaux
France	Institut Paoli-Calmettes Site#561	Marseille
France	CHU Saint-Eloi Site#556	Montpellier
France	Centre de Lutte contre le Cancer - Centre Antoine Lacassagne Site#562	Nice
France	AP-HP Pitie Saltpetriere Site# 552	Paris
France	Centre Henri Becquerel	Rouen	Seine-Maritime
France	Hôpital Bretonneau	Tours	Indre-et-Loire
France	Institut Gustave Roussy Site#550	Villejuif
Italy	U.O.C. di Ematologia Pad. 8IRCCS Azienda OspedalieroUniversitaria di Bologna Site#651	Bologna
Italy	Azienda Socio Sanitaria Territoriale (ASST) degli Spedali Civili di Brescia Site#650	Brescia
Italy	Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" - IRST	Meldola	Forli-Cesena
Italy	Istituto Europeo di Oncologia Site#652	Milano
Italy	Fondazione IRCCS San Gerardo dei Tintori Site #655	Monza
Italy	Ospedale Santa Maria delle Croci di Ravenna	Ravenna	Emilia-Romagna
Poland	Osrodek Badan Klinicznych Wczesnych Faz - Uniwersyteckie Centrum Kliniczne w Gdansku	Gdansk	Pomerania
Poland	Wojewódzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii im. M. Kopernika w Lodzi	Lodz	Lodzkie
Poland	Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - Panstwowy Instytut Badawczy	Warsaw	Masovia
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona	Catalonia
Spain	Hospital del Mar Site #704	Barcelona
Spain	Institut Català d'Oncologia - Hospital Duran i Reynals (ICO L'Hospitalet)	Barcelona	Catalonia
Spain	Hospital Universitario 12 de Octubre Site#710	Madrid
Spain	Hospital Universitario Fundación Jiménez Díaz Site #703	Madrid
Spain	Hospital Universitario Marqués de Valdecilla Site#711	Santander
Spain	Hospital Universitario Virgen del Rocío	Sevilla	Andalucía
United Kingdom	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 States	University of Michigan Rogel Cancer Center	Ann Arbor	Michigan
United States	Winship Cancer Institute of Emory University	Atlanta	Georgia
United States	University of Colorado Anschutz Medical Campus Site #118	Aurora	Colorado
United States	Johns Hopkins University	Baltimore	Maryland
United States	University of Virginia Comprehensive Cancer Center	Charlottesville	Virginia
United States	Barbara Ann Karmanos Cancer Institute Site#159	Detroit	Michigan
United States	City of Hope Site #151	Duarte	California
United States	Rochester Skin Lymphoma Medical Group, PLLC Site #147	Fairport	New York
United States	The University of Texas MD Anderson Cancer Center Site #101	Houston	Texas
United States	University of Califonia, Los Angeles	Los Angeles	California
United States	Yale Cancer Center Site #109	New Haven	Connecticut
United States	NYU Langone Laura and Isaac Perlmutter Cancer Center Site #153	New York	New York
United States	University of Pennsylvania Site# 160	Philadelphia	Pennsylvania
United States	Fred Hutchinson Cancer Center	Seattle	Washington
United States	Stanford University	Stanford	California
United States	Moffitt Cancer Center Site #157	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Astex Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Australia,  France,  Italy,  Poland,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	Phase 1: Number of Participants With TEAEs, SAEs and DLTs in the Oral Decitabine/Cedazuridine Arm		Up to 54 months
Secondary	Ph 1 & 2: AUC: Area Under the Plasma Concentration-Time Curve		Up to 50 months
Secondary	Ph 1 & 2: Cmax: Maximum Observed Plasma Concentration		Up to 50 months
Secondary	Ph 1 & 2: Cmin: Minimum Observed Plasma Concentration at Steady State		Up to 50 months
Secondary	Ph 1 & 2: Tmax: Time to Maximum Observed Plasma Concentration		Up to 50 months
Secondary	Ph 1 & 2: t½: Apparent Elimination Half-Life		Up to 50 months
Secondary	Phase 2: Duration of response (DOR) Based on the Lugano Classification Using CT Imaging as the Primary Modality		Up to 54 months
Secondary	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
Secondary	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
Secondary	Phase 2: Progression-Free Survival (PFS) Based on the Lugano Classification Using CT Imaging as the Primary Modality		Up to 54 months
Secondary	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
Secondary	Phase 2: Overall Survival (OS) Based on the Lugano Classification Using CT Imaging as the Primary Modality		Up to 54 months
Secondary	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
Secondary	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
Secondary	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