Study of the safety, activity, and effect on the body of ASTX660 in people with advanced cancers.

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] - Neoplasms [C04]

Trial duration

1 Dec 2017 → 25 Nov 2025

Decision date (initial)

2024-09-23

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Taiho Oncology, Inc.

External identifiers

EU CT number

2024-516679-33-00

EudraCT number

2016-005039-34

ClinicalTrials.gov

NCT02503423

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

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

• Phase 1 (Complete): To assess safety, and to identify the maximum tolerated dose (MTD), the recommended Phase 2 dose (RP2D), and the recommended dosing regimen of ASTX660 (Completed).
• Phase 2: To assess preliminary efficacy, as determined by response rate in certain tumor types.
After Amendment 10 Objective: To monitor the safety of subjects ongoing in the study.

Secondary objectives 3

1. To determine the pharmacokinetic (PK) parameters of orally administred ASTX660 in humans.
2. To evaluate other efficacy parameters, such as duration of response (DOR) and progression-free survival (PFS)
3. To evaluate relevant pharmacodynamic (PD) targets and potential biomarkers of ASTX660 activity.

Conditions and MedDRA coding

Advanced Solid Tumors and Lymphomas that are metastatic or unresectable: Cohort#1:Recurrent/metastatic head and neck squamous cell carcinoma; #2:Relapsed/refractory diffuse large B-cell lymphoma; #3:Progressive, refractory or relapsed peripheral T-cell lymphoma; #4:Relapsed/refractory cutaneous T-cell lymphoma; #5: Other tumor types that may have sensitivity to ASTX660; # 6: Cervical carcinoma not responsive/relapsed after standard therapy

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Able to understand and comply with the protocol and study procedures, understand the risks involved in the study, and provide written informed consent before any study-specific procedure is performed.
2. Men and women 18 years of age or older.
3. Subjects with histologically or cytologically confirmed advanced solid tumors or lymphoma that is metastatic or unresectable, and for whom standard life-prolonging measures are not available. Specific tumor types that will be selected for study in Phase 2 are detailed in Section 4.1 (Table 3). a) For Phase 2 Cohort 3, subjects must have histologically confirmed PTCL (local pathology report) as defined by 2016 World Health Organization (WHO) classification. The following subtypes are eligible for the study: adult T-cell lymphoma/leukemia, extranodal natural killer (NK)/T-cell lymphoma nasal type, enteropathy-associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, hepatosplenic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, peripheral T-cell lymphoma not otherwise specified, angioimmunoblastic T-cell lymphoma, follicular T-cell lymphoma, nodal peripheral T-cell with T-follicular helper (THF) phenotype, and anaplastic large-cell lymphoma.
4. For Phase 2 Cohorts 3 and 4, subjects must have evidence of documented progressive disease and must have received at least two prior systemic therapies. a) Subjects with CD30-positive lymphoma must have received, be ineligible for, or intolerant to brentuximab vedotin, provided that brentuximab vedotin is locally approved and available. b) Subjects with mycosis fungoides or Sezary syndrome must have received, be ineligible, or intolerant to mogamulizumab, provided that mogamulizumab is locally approved and available.
5. In the Phase 2 portion of the protocol only, subjects must have measurable disease according to response criteria appropriate to their type of cancer a) For Phase 2 Cohort 3 (PTCL), measurable disease by contrast-enhanced diagnostic CT (at least 1 nodal lesion >1.5 cm or extranodal lesions >1.0 cm) is required.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
7. 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. c. Absolute neutrophil count (ANC): o Phase 1 and 2 (except subjects with known lymphoma, [i.e. Not applicable for Cohorts 3 or 4]): ≥1500 cells/mm3. o Phase 2 subjects with known lymphoma: ≥1000 cells/mm3 (≥750 cells/mm3 for subjects with lymphoma in bone marrow) (Administration of myeloid growth factors within 14 days prior to study entry are not allowed). d. Platelet count: o Phase 1 and 2 (except subjects with known lymphoma [i.e. Not applicable for Cohorts 3 or 4]): ≥100,000 cells/mm3. o Phase 2 subjects with known lymphoma: ≥50,000 cells/mm3 (≥25,000 cells/mm3 for subjects with lymphoma in bone marrow) (transfusion within 21 days prior to study entry are not allowed). e. Serum creatinine levels ≤1.5 × ULN, or calculated (by Cockcroft-Gault formula or other accepted formula) or measured creatinine clearance ≥ 50 mL/min. f. Amylase and lipase ≤ULN.
8. Women of child-bearing 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 child-bearing potential and men with female partners of childbearing potential must agree to practice 2 highly effective contraceptive measures of birth control (as described in the protocol) and must agree not to become pregnant or father a child while receiving treatment with study drug and for at least 3 months after completing treatment.
9. After Amendment 10: To continue to be eligible, enrolled subjects should be receiving benefit (in the opinion of the Investigator) from ASTX660.

Exclusion criteria 13

1. Hypersensitivity to ASTX660, excipients of the drug product, or other components of the study treatment regimen.
2. Poor medical risk because of systemic diseases (eg, active uncontrolled infections) in addition to the qualifying disease under study.
3. 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 ASTX660.
4. 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; <50%) on echocardiogram (ECHO) or multiplegated 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 3 months (90 days). d) History or presence of complete left bundle branch block, third-degree heart block, cardiac pacemaker or clinically significant arrhythmia. e) Concurrent treatment with any medication that prolongs QT interval and may induce torsades de pointes, and which cannot be discontinued at least 2 weeks before treatment with ASTX660. [Applies to Phase 1 only.] f) Personal history of long QTc syndrome or ventricular arrhythmias including ventricular bigeminy. g) Screening 12-lead ECG with measurable QTc interval (according to either Fridericia's or Bazett's correction) of ≥470 msec). h) Any other condition that, in the opinion of the investigator, could put the subject at increased cardiac risk.
5. 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.
6. Grade 2 or greater neuropathy. [Applies to Phase 1 ]. Grade 3 or greater neuropathy [Applies to Phase 2].
7. Known brain metastases, unless stable or previously treated.
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 subject to high risk of noncompliance with the protocol treatment or assessments.
9. Prior anticancer treatments or therapies within the indicated time window prior to first dose of study treatment (ASTX660), as follows: a) Cytotoxic chemotherapy or radiotherapy within 3 weeks prior (6 weeks if nitrosoureas). Palliative radiotherapy to a single lesion within 2 weeks prior. Any encountered treatment-related toxicities (excepting alopecia) must be stabilized or resolved to Grade 1 or less [Phase 1] or Grade 2 or less [Phase 2]. b) Skin directed treatments, including topicals and radiation within 2 weeks prior. c) Monoclonal antibodies within 4 weeks prior. Any encountered treatment-related toxicities must be stabilized or resolved to Grade 1 or less [Phase 1] or Grade 2 or less [Phase 2]. d) At least 6 weeks must have elapsed since 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. e) Small molecules or biologics (investigational or approved) within the longer of 2 weeks or 5 half-lives prior to study treatment. Any encountered treatment-related toxicities must be stabilized or resolved to Grade 1 or less [Phase 1] or Grade 2 or less [Phase 2].
10. Concurrent second malignancy currently requiring active therapy, except breast or prostate cancer stable on or responding to endocrine therapy or superficial bladder cancer [Phase 2].
11. Known central nervous system (CNS) lymphoma [Phase 2].
12. Patients with a history of allogenic transplant must not have ≥Grade 3 graft-versus-host disease (GVHD) or any clinically significant GVHD requiring systemic immunosuppression [Phase 2].
13. Systemic corticosteroids >20 mg prednisone equivalent (unless patient has been taking a continuous dose for >3 weeks prior to study entry and there is documented radiological progression) [Phase 2]. Stable dose of medium or low potency topical corticosteroids for at least 3 weeks prior to study entry are permitted [Phase 2].

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Incidence of SAEs.

Secondary endpoints 6

1. PK parameters of ASTX660, including area under the concentration-time curve (AUC), maximum concentration (Cmax), minimum concentration (Cmin), time to maximum concentration (Tmax), elimination half-life (t½), and other secondary PK parameters of ASTX660 if data permit; analysis of ASTX660 metabolites if applicable.
2. DOR, PFS, and overall survival (OS).
3. Percentage degradation of cIAP1 protein in PBMCs from baseline, in response to ASTX660 treatment. [applies to Phase 1 only].
4. Antitumor activity (ORR, DOR, and PFS) based on independent review committee (IRC) assessment: Phase 2 Cohort 3 Expansion using 2014 Lugano Classification with LYRIC criteria, and Phase 2 Cohort 4 Expansion using Global Response Score (skin, blood and node using Olsen classification and viscera using Lugano classification with LYRIC criteria.
5. Antitumor activity (DOR and PFS) based on investigator assessment using the Lugano classification with LYRIC criteria (Phase 2 Cohort 3 Expansion), and Phase 2 Cohort 4 Expansion using Global Response Score (skin, blood and node using Olsen classification] and viscera using Lugano classification with LYRIC criteria .
6. Antitumor activity (ORR, DOR, and PFS) based on IRC assessment using the Lugano classification alone (Phase 2 Cohort 3 Expansion).

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Taiho Oncology Inc.

Sponsor organisation

Taiho Oncology Inc.

Address

101 Carnegie Center Suite 101

City

Princeton

Postcode

08540-6231

Country

United States

Scientific contact point

Organisation

Taiho Oncology Inc.

Contact name

Harold Keer

Public contact point

Organisation

Taiho Oncology Inc.

Contact name

Harold Keer

Third parties 10

Locations

2 EU/EEA countries · 2 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 16 files

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

Application history

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