E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced Solid Tumors and Lymphomas that are metastatic or unresectable: cohort 1:Recurrent/metastatic head and neck squamous cell carcinoma; cohort 2:Relapsed or refractory diffuse large B-cell lymphoma; cohort 3:Progressive or relapsed peripheral T-cell lymphoma; cohort 4:Relapsed or refractory cutaneous T-cell lymphoma; cohort 5: Other tumor types that may have sensitivity to ASTX660: cohort 6: Cervical carcinoma not responsive or relapsed after standard therapy |
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E.1.1.1 | Medical condition in easily understood language |
multiple tumour types (solid and liquid) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10012818 |
E.1.2 | Term | Diffuse large B-cell lymphoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10011677 |
E.1.2 | Term | Cutaneous T-cell lymphoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067821 |
E.1.2 | Term | Head and neck cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008229 |
E.1.2 | Term | Cervical cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10034623 |
E.1.2 | Term | Peripheral T-cell lymphoma unspecified |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• Phase 1: 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. |
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E.2.2 | Secondary objectives of the trial |
• To determine the pharmacokinetic (PK) parameters of orally administered ASTX660 in humans.
• To evaluate other efficacy parameters, such as duration of response and progression-free survival.
• To evaluate relevant pharmacodynamic (PD) targets and potential biomarkers of ASTX660 activity. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects must fulfill all of the following inclusion criteria.
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.
4. Subjects must have measurable disease according to RECIST v1.1, or evaluable disease that can be reliably and consistently followed.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
6. 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 (except subjects with known lymphoma): ≥1500 cells/mm3.
o subjects with known lymphoma: ≥1000 cells/mm3 (≥750 cells/mm3 for subjects with lymphoma in bone marrow).
d. Platelet count:
o (except subjects with known lymphoma): ≥100,000 cells/mm3.
o subjects with known lymphoma: ≥50,000 cells/mm3 (≥25,000 cells/mm3 for subjects with lymphoma in bone marrow).
e. Serum creatinine levels ≤1.5 × ULN, or calculated (by Cockcroft-Gault formula or other accepted formula) or measured creatinine clearance ≥50 mL/min.
7. Women of child-bearing potential must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women of child-bearing potential and all men with female partners of child-bearing potential must be practicing 2 medically acceptable methods of birth control and must not become pregnant or father a child while receiving treatment with study drug and for at least 3 months after completing treatment |
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E.4 | Principal exclusion criteria |
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). [Applies to Phase 1 only; ECHO/MUGA scans are not performed in Phase 2.]
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, heart block, cardiac pacemaker or 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).
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 only.]
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:
• Cytotoxic chemotherapy or radiotherapy within 3 weeks prior and any encountered treatment-related toxicities (excepting alopecia) not resolved to Grade 1 or less [Phase 1] or Grade 2 or less [Phase 2].
• Monoclonal antibodies within 4 weeks prior and any encountered treatment-related toxicities not resolved to Grade 1 or less [Phase 1] or Grade 2 or less [Phase 2].
• Investigational drugs (small molecules or biologics) within the longer of 2 weeks or 5 half-lives prior to study treatment and any encountered treatment-related toxicities not resolved to Grade 1 or less [Phase 1] or Grade 2 or less [Phase 2]. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Endpoint(s)
All tumor types except CTCL: Antitumor activity assessed by objective response rate (ORR) and disease control rate (DCR) according to RECIST v1.1 criteria. CTCL response will be by RECIST v1.1, along with the modified Severity-Weighted Assessment Tool (mSWAT) and blood assessment, as appropriate. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Every 2 months for the first 6 months (6 cycles), and then every 3 months hereafter until clinical and/or radiographic disease progression, or death, or the subject
withdraws consent |
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E.5.2 | Secondary end point(s) |
Secondary Endpoint(s)
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. Duration of response and progression-free survival.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.At specified study visits, blood samples for PK will be collected predose for assessment of ASTX660 concentration in plasma. In addition, serial samples will be collected predose and at several specified time points after dosing on C1D1 and C1D7
2.Every 2 months for the first 6 months (6 cycles), and then every 3 months hereafter until clinical and/or radiographic disease progression, or death, or the subject
withdraws consent
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
France |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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6 months from last subject treatment visit |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |