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

Trial ID: 2022-500391-62-00
Protocol: ASTX660-03
Sponsor: Taiho Oncology Inc.

Trial statistics

science

test molecules

location_city

research sites

public

countries

medical_information

disease

person_search

investigators

handshake

vendors

Diseases & Conditions

T-cell lymphoma

Objectives

The primary objective of this study is to assess the **safety** and identify the recommended phase 2 dose (RP2D) of **tolinapant** in combination with oral **decitabine/cedazuridine** during Phase 1. In Phase 2, the study aims to evaluate the efficacy as determined by the overall response rate (ORR) in subjects with relapsed/refractory peripheral T-cell lymphoma (R/R PTCL). This is clinically relevant as it seeks to establish a safe and effective treatment regimen for a population with limited therapeutic options.

Secondary objectives include:

Phase 1: Assessing the safety and identifying the tolerated dosing of oral decitabine/cedazuridine alone.
Phase 1: Determining the pharmacokinetic (PK) parameters of both tolinapant and oral decitabine/cedazuridine.
Phase 2: Evaluating other efficacy parameters based on CT imaging and combined CT with positron emission tomography (PET) imaging assessments.
Phase 2: Assessing preliminary efficacy by ORR with the assessment for pseudo progression.
Phase 2: Evaluating anti-tumor responses based on PTCL subtypes.

Participants

The clinical trial involves a total of **80 participants** diagnosed with **relapsed/refractory peripheral T-cell lymphoma (R/R PTCL)**. The study population includes both male and female subjects, aged **18 years or older**, with an expected life expectancy of more than 12 weeks. Participants were selected based on their histologically confirmed diagnosis of R/R PTCL, as defined by the 2016 World Health Organization classification, and must have evidence of progressive disease with at least two prior systemic therapies. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2, and requires acceptable organ function as evidenced by specific laboratory data. The study population is characterized by a diverse range of T-cell lymphoma subtypes, and participants must have measurable disease by contrast-enhanced diagnostic CT. Both genders are included, and the trial considers vulnerable populations. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data.

Plans and Procedures

The clinical trial is designed as a **Phase 1-2, open-label study** to evaluate 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 (R/R PTCL). The trial aims to identify the recommended phase 2 dose (RP2D) of Tolinapant in combination with Decitabine/Cedazuridine during Phase 1, and to assess efficacy as determined by overall response rate (ORR) in Phase 2. The study is expected to conclude by August 17, 2026, with recruitment having commenced on January 31, 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease status, and organ function. The trial will include multiple follow-up visits to monitor treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and dose-limiting toxicities (DLTs) in Phase 1, as well as antitumor activity in Phase 2. The end-of-study visit will assess the overall response and gather final data on the safety and efficacy of the treatment regimen.

The expected length of participant involvement will vary depending on individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include the occurrence of unacceptable adverse events, disease progression, or withdrawal of consent by the participant. The trial will employ computerized tomography (CT) imaging as the primary modality for assessing antitumor activity, with response assessments performed by both the investigator and a blinded independent central radiologist.

Treatment

The clinical trial involves the administration of **ASTX727**, an experimental medication formulated as a **tablet**. This pharmaceutical product contains two active chemical substances: **decitabine** and **cedazuridine**. Decitabine, also known as 5-aza-2'-deoxycytidine, is a chemical compound with the molecular structure 4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)-s-triazin-2(1H)-one. Cedazuridine, chemically identified as (4R)-2'-deoxy-2',2'-difluoro-3,4,5,6-tetrahydrouridine, complements decitabine in this formulation. The route of administration for ASTX727 is **oral**, and the dosing schedule is determined based on the study protocol to assess safety and efficacy in subjects with relapsed/refractory peripheral T-cell lymphoma.

Another investigational product used in this study is **Tolinapant**, also known by its sponsor product code **ASTX660**. Tolinapant is provided in **capsule** form and contains the active substance **tolinapant lactate**. This chemical entity is also referred to by several synonyms, including ASTX660 lactate and AT29660AU. The molecular structure of tolinapant lactate is described as 1-{6-[(4-fluorophenyl)methyl]-5-(hydroxymethyl)-3,3-dimethyl-1H,2H,3H-pyrrolo[3,2-b]pyridin-1-yl}-2-[(2R,5R)-5-methyl-2-{[(3R)-3-methylmorpholin-4-yl]methyl}piperazin-1-yl]ethan-1-one, L-(+)-lactic acid salt. Tolinapant is also administered **orally**, and its dosing regimen is designed to evaluate its safety and pharmacokinetic profile when used in combination with ASTX727.

In this open-label study, the primary objective is to assess the safety and identify the recommended phase 2 dose of tolinapant in combination with oral decitabine/cedazuridine. The study also evaluates the efficacy of these treatments, as determined by the overall response rate in the target patient population. Participant compliance with the dosing schedule is monitored throughout the trial to ensure accurate assessment of the investigational treatments' effects.

Efficacy

The efficacy of the clinical trial will be assessed primarily during Phase 2, focusing on the **overall response rate (ORR)**. This will be evaluated using the 2014 Lugano Classification, with computerized tomography (CT) imaging serving as the primary modality for assessment. The ORR will be determined by the investigator, and response assessments will also be performed by a blinded independent central radiologist to ensure objectivity and accuracy.

Secondary efficacy endpoints in Phase 2 include the duration of response (DOR), complete response (CR), partial response (PR), progression-free survival (PFS), disease control rate (DCR), and overall survival (OS). These parameters will be assessed using the Lugano classification, incorporating both CT and PET imaging assessments. Additionally, anti-tumor activity will be evaluated based on the 2014 Lugano Classification with Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC), considering both pathology and molecular markers specific to peripheral T-cell lymphoma (PTCL) subtypes.

Data collection for these efficacy parameters will be conducted at specified intervals throughout the trial, with the schedule for imaging and assessments aligned with the trial protocol. The analysis will involve comparing the observed responses to the established criteria, ensuring a comprehensive evaluation of the treatment's efficacy in subjects with relapsed/refractory peripheral T-cell lymphoma.

Inclusion and Exclusion Criteria

check_circle

Inclusion Criteria

Able to understand and comply with the protocol and study procedures, understand the risks involved in the study, and provide legally effective informed consent before any study-specific procedure is performed.
Men or women 18 years of age or older.
Expected life expectancy of >12 weeks.
Subjects 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: a. Extranodal natural killer (NK)/T-cell lymphoma nasal type. b. Enteropathy-associated T-cell lymphoma. c. Monomorphic epitheliotropic intestinal T-cell lymphoma, d. Hepatosplenic T-cell lymphoma. e. Subcutaneous panniculitis-like T cell lymphoma. f. Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS). g. Angioimmunoblastic T cell lymphoma. h. Follicular peripheral T-cell lymphoma. i. Nodal peripheral T-cell with T-follicular helper (THF) phenotype. j. Anaplastic large-cell lymphoma (ALCL).
Subjects must have evidence of progressive disease and must have received at least two prior systemic therapies. Prior therapies encompass both initial and any subsequent systemic therapies, including autologous transplants.
Subjects must have measurable disease by contrast-enhanced diagnostic CT (at least 1 nodal lesion >1.5 cm or extranodal lesions >1.0 cm).
Subjects with CD30-positive disease must have received, be ineligible for, or intolerant to brentuximab vedotin, provided that brentuximab vedotin is locally approved and available. If an investigator determines, and the subject agrees through informed discussion and consent, that the subject will have a minimal likelihood of benefiting from brentuximab vedotin, this should be discussed with the medical monitor to confirm eligibility.
Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
Acceptable organ function, as evidenced by the following laboratory data: a. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.0×upper limit of normal (ULN). b. Total serum bilirubin ≤1.5×ULN. If a subject has a documented preexisting diagnosis of true Gilbert’s syndrome, AST and ALT must be normal, and total serum bilirubin must be ≤2.5×ULN. c. Absolute neutrophil count (ANC) ≥1000 cells/mm3 (≥750 cells/mm3 for subjects with lymphoma in bone marrow). d. Platelet count ≥50,000 cells/mm3 (≥25,000 cells/mm3 for subjects with lymphoma in bone marrow). Transfusion within 21 days before study entry is not allowed. e. Creatinine clearance ≥50 mL/min as estimated by Cockcroft-Gault formula. f. Amylase and lipase ≤1.2×ULN.
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. Women of childbearing potential must agree to practice 1 highly effective contraceptive measure of birth control (with a failure rate of <1% per year; preferably with low user dependency) during the study and for 6 months after the last dose of study treatment and must agree not to become pregnant for 6 months after completing treatment; men with female partners of childbearing potential must agree to use a condom and advise their partners to practice 1 highly effective contraceptive measure of birth control (user dependent or with low user dependency) during the study and for at least 3 months after completing treatment, and must agree not to father a child while receiving study treatment and for at least 3 months after completing treatment. See Section 10.2.7 for detailed contraceptive guidance.

cancel

Exclusion Criteria

Prior treatment with tolinapant or any hypomethylating agent.
Monoclonal antibody treatment for rheumatologic conditions within 4 weeks of study drug initiation
Concurrent second malignancy currently requiring active therapy, except breast or prostate cancer stable on or responding to endocrine therapy or superficial bladder cancer.
Any concurrent second malignancy that is metastatic.
Known central nervous system (CNS) lymphoma.
Patients with a history of allogeneic transplant are excluded from this study.
Autotransplant within 100 days of the first dose of the study drug(s).
Systemic corticosteroids >10mg prednisone equivalent within 7 days of the first dose of study drug(s).
Anti-T-cell directed therapy: a.Lymphotoxic agents (eg, anti-CD52) in the past 12 months. b.Inhibitory drugs (eg, calcineurin inhibitors) within 4 weeks of the first dose of study drug(s).
Use of a concomitant medication which is a moderate or strong CYP3A4 inhibitor/inducer within 2 weeks of the start of the study.
Use of any vaccine within 10 days of the first dose of the study drug(s).
Hypersensitivity to tolinapant or oral decitabine/cedazuridine, excipients of the drug product, or other components of the study treatment regimen.
Poor medical risk because of systemic diseases (eg, uncontrolled infections) in addition to the qualifying disease under study.
Life-threatening illness, significant organ system dysfunction, or other condition that,in the investigator’s opinion, could compromise subject safety or the integrity of the study outcomes, or interfere with the absorption or metabolism of tolinapant.
A history of, or at risk for, cardiac disease, as evidenced by 1 or more of the following conditions: a. Abnormal left ventricular ejection fraction (LVEF) of <50% on echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) .b. Congestive cardiac failure of Grade ≥3 severity according to New York Heart Association (NYHA) functional classification defined as subjects with marked limitation of activity and who are comfortable only at rest. c. Unstable cardiac disease including unstable angina or hypertension as defined by the need for overnight hospital admission within the last 90 days before screening. d. History or presence of complete left bundle branch block, third-degree heart block, cardiac pacemaker, or clinically significant arrhythmia. e. History of long QTc syndrome or ventricular arrhythmias including ventricular bigeminy. f. Screening 12-lead electrocardiogram (ECG) with measurable QTc interval of ≥470 msec (according to either Fridericia’s or Bazett’s correction). g. Any other condition that, in the opinion of the investigator, could put the subject at increased cardiac risk.
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.
Grade 3 or greater neuropathy.
Known significant mental illness or other conditions such as active alcohol or other substance abuse that, in the opinion of the investigator, predisposes the subject to high risk of noncompliance with the protocol treatment or assessments.
Prior anticancer treatments or therapies within the indicated time windowbefore first dose of study treatment (tolinapant), as follows:a.Cytotoxic chemotherapy or radiotherapy within 4 weeks prior. Palliative radiotherapy to a single lesion within 2 weeks prior. Any encountered treatment-related toxicities (excepting alopecia) must be stabilized or resolved to Grade 2 or less.b.Monoclonal antibodies within 4 weeks prior. Any encountered treatment-related toxicities must be stabilized or resolved to Grade 2 or less.c.At least 12 weeks must have elapsed since chimeric antigen receptor T-cell (CAR-T) infusion and subjects must have experienced disease progression, and not have residual circulating CAR-T cells in peripheral blood (based on local assessment). Any encountered treatment-related toxicities must have resolved to Grade ≤1.d.Small molecules or biologics (investigational or approved) within the longer of 3 weeks or 5 half-lives before study treatment. Any encountered treatment-related toxicities must be stabilized and resolved to Grade ≤2.
History of confirmed drug-induced myocarditis or clinically significant myocarditis or documented noninfectious pneumonitis/interstitial lung disease.
History of Stevens-Johnson syndrome or toxic epidermal necrolysis.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
France	Not Recruiting	31 Jan 2023	26
Hungary	Not Recruiting	31 Jan 2023	4
Italy	Not Recruiting	31 Jan 2023	17
Poland	Not Recruiting	31 Jan 2023	8
Spain	Not Recruiting	31 Jan 2023	22