A Study of Tolinapant in Combination with Oral Decitabine/Cedazuridine and Oral Decitabine/Cedazuridine Alone in Subjects with R/R PTCL

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Taiho Oncology Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20], Diseases [C] - Neoplasms [C04], Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

19 Jan 2023 → ongoing

Decision date (initial)

2022-11-24

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Astex Pharmaceuticals, Inc.

External identifiers

EU CT number

2022-500391-62-00

ClinicalTrials.gov

NCT05403450

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Pharmacodynamic, Pharmacokinetic, Dose response

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

Secondary objectives 6

1. Phase 1: To assess safety and to identify the tolerated dosing of oral decitabine/cedazuridine alone in this population.
2. Phase 1: To determine the pharmacokinetic (PK) parameters of both tolinapant and oral decitabine/cedazuridine
3. Phase 2: To evaluate other efficacy parameters, based on CT imaging.
4. Phase 2: To evaluate other efficacy parameters, based on CT combined with positron emission tomography (PET) imaging assessments.
5. Phase 2: To assess preliminary efficacy by ORR with the assessment for pseudo progression.
6. Phase 2: To evaluate anti-tumor responses based on PTCL subtypes.

Conditions and MedDRA coding

Subjects with relapsed/refractory peripheral T-cell lymphoma (R/R PTCL)

Study design 1 period

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. 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.
2. Men or women 18 years of age or older.
3. Expected life expectancy of >12 weeks.
4. 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).
5. 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.
6. Subjects must have measurable disease by contrast-enhanced diagnostic CT (at least 1 nodal lesion >1.5 cm or extranodal lesions >1.0 cm).
7. 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.
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
9. 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.
10. 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.

Exclusion criteria 21

1. Prior treatment with tolinapant or any hypomethylating agent.
2. Monoclonal antibody treatment for rheumatologic conditions within 4 weeks of study drug initiation
3. Concurrent second malignancy currently requiring active therapy, except breast or prostate cancer stable on or responding to endocrine therapy or superficial bladder cancer.
4. Any concurrent second malignancy that is metastatic.
5. Known central nervous system (CNS) lymphoma.
6. Patients with a history of allogeneic transplant are excluded from this study.
7. Autotransplant within 100 days of the first dose of the study drug(s).
8. Systemic corticosteroids >10mg prednisone equivalent within 7 days of the first dose of study drug(s).
9. 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).
10. Use of a concomitant medication which is a moderate or strong CYP3A4 inhibitor/inducer within 2 weeks of the start of the study.
11. Use of any vaccine within 10 days of the first dose of the study drug(s).
12. Hypersensitivity to tolinapant or oral decitabine/cedazuridine, excipients of the drug product, or other components of the study treatment regimen.
13. Poor medical risk because of systemic diseases (eg, uncontrolled infections) in addition to the qualifying disease under study.
14. 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.
15. 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.
16. 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.
17. Grade 3 or greater neuropathy.
18. 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.
19. 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.
20. History of confirmed drug-induced myocarditis or clinically significant myocarditis or documented noninfectious pneumonitis/interstitial lung disease.
21. History of Stevens-Johnson syndrome or toxic epidermal necrolysis.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Phase 1: Incidence and severity of treatment-emergent adverse events (TEAEs) including serious adverse events (SAEs) and dose limiting toxicities (DLTs).
2. Phase 2: Antitumor activity assessed by ORR using 2014 Lugano Classification (Cheson et al 2014; Cheson 2015) using computerized tomography (CT) imaging as the primary modality as assessed by the investigator.

Secondary endpoints 5

1. Phase 1: Oral decitabine/cedazuridine alone arm: Incidence and severity of TEAEs including SAEs and DLTs.
2. Phase 1 and Phase 2: PK parameters of tolinapant and oral decitabine/cedazuridine, as well as oral decitabine/cedazuridine alone, including area under the concentration-time curve (AUC), maximum observed concentration (Cmax), minimum observed concentration at steady state (Cmin), time to maximum observed concentration (Tmax), apparent elimination half life (t½), and other secondary PK parameters.
3. Phase 2: Duration of response (DOR), complete response (CR), partial response (PR), progression-free survival (PFS), disease control rate (DCR) and overall survival (OS) using the Lugano classification (Cheson et al 2014 and Cheson 2015) using CT imaging as the primary modality. - DOR, CR, PR, PFS, DCR, and OS using the Lugano classification (Cheson et al 2014 and Cheson 2015) using CT along with PET imaging assessments.
4. Phase 2: Anti-tumor activity (ORR, DOR, CR, PR, and PFS) based on assessment using 2014 Lugano Classification with Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) (Cheson et al 2016). - Anti-tumor activity (ORR, DOR, DCR, CR, and PR) based on PTCL subtypes (using both pathology and molecular markers).
5. Phase 2: Response assessments performed by both the investigator and blinded independent central radiologist.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Taiho Oncology Inc.

Sponsor organisation

Taiho Oncology Inc.

Address

101 Carnegie Center Suite 300

City

Princeton

Postcode

08540-6231

Country

United States

Scientific contact point

Organisation

Taiho Oncology Inc.

Contact name

Volker Wacheck

Public contact point

Organisation

Taiho Oncology Inc.

Contact name

Volker Wacheck

Third parties 5

Locations

5 EU/EEA countries · 29 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 45 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

11 submissions — initial application plus substantial / non-substantial modifications