| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects with Wild-Type TP53 Advanced Solid Tumors |
|
| E.1.1.1 | Medical condition in easily understood language |
| Subjects with normal TP53 Advanced Solid Tumors |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065147 |
| E.1.2 | Term | Malignant solid tumor |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065252 |
| E.1.2 | Term | Solid tumor |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10027406 |
| E.1.2 | Term | Mesothelioma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10081431 |
| E.1.2 | Term | Uveal melanoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 2 (only phase 2 will be conducted in EU):
• To evaluate the clinical activity of ASTX295 at the RP2D in MPM; and other tumor type(s) based on emerging clinical and biomarker data |
|
| E.2.2 | Secondary objectives of the trial |
Phase 2 (only phase 2 will be conducted in EU):
• To characterize the safety profile of ASTX295.
• To determine the PK profile of ASTX295.
• To evaluate other parameters of clinical activity. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Participant must be 18 years of age or older, at the time of signing the informed consent.
2) Have histologically or cytologically confirmed advanced solid tumors that are metastatic or unresectable and are refractory or have relapsed after treatment with standard available therapies or for whom standard life-prolonging measures are not available.
a. Phase 1: any tumor type is eligible
b. Phase 2: eligible tumor types are as follows:
i) MPM (Cohort 1)
ii) Liposarcoma (WD, DD, or mix), intimal sarcoma, and other sarcomas with MDM2 amplification (Cohort 2)
iii) GBM and tumors with CDNK2A LOF excluding MPM, liposarcoma, intimal sarcoma, and UVM (Cohort 3)
iv) Tumors with BRCA1/2 or ATM deleterious mutations or with BAP1 LOF excluding MPM, liposarcoma, intimal sarcoma, and UVM (Cohort 4)
v) Uveal melanoma (Cohort 5)
vi) Any cancer type with MDM2 amplification excluding MPM, sarcoma, and UVM (Cohort 6)
3) Wild-type TP53 and other molecular feature requirements.
4) Have an Eastern Cooperative Oncology Group (ECOG) Performance status (PS) of 0 to 2.
5) Acceptable bone marrow function, as evidenced by the following laboratory data:
a. Absolute neutrophil count (ANC) ≥1500 cells/mm3
b. Platelet count ≥100,000 cells/mm3
c. Hemoglobin >9 g/dL
6) Adequate hepatic function as evidenced by:
a. Serum total bilirubin ≤1.5 × upper limit of normal (ULN).
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN (≤3 × ULN in the presence of liver metastases).
c. Serum creatinine ≤1.5 × ULN OR calculated creatinine clearance (by the standard Cockcroft-Gault formula) of ≥50 mL/min or measured glomerular filtration rate of ≥50 mL/min.
7) Participant can be male or female
a. Male participants:
Male participants are eligible to participate if they agree to the following during the treatment period and for at least 93 days (approximately 5 half-lives of ASTX295 [additional details can be found in the ASTX295 IB] plus 90 days) after the last dose of study treatment:
• Refrain from donating sperm.
PLUS either:
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent.
OR
• Must agree to use contraception/barrier as detailed below:
o Agree to use a male condom when having sexual intercourse with a woman of childbearing potential.
o Female partner should be advised of the benefit of using an additional highly effective contraceptive method (with a failure rate of <1% per year) as described in Appendix 2 (Section 10.2) as a condom may break or leak.
b. Female participants:
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
i) Is not a woman of childbearing potential (WOCBP)
OR
ii) Is a woman of childbearing potential and is using a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency, as described in Appendix 2 (Section 10.2 of the protocol) during the treatment period and for at least 93 days (approximately 5 half-lives of ASTX295 [additional details can be found in the ASTX295 IB] plus 90 days) after the last dose of study treatment and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study treatment.
iii) A woman of childbearing potential must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study treatment.
iv) The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
8) Capable of giving signed informed consent (as described in Appendix 1 [Section 10.1.3 of the protocol]), which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol, and willing to participate in the study.
9) In Phase 1b (dose expansion) of the protocol, subjects must have disease lesions that are amenable to biopsy and must agree and be able to undergo a pre- and on-treatment biopsy.
10) There is confirmed availability of sufficient tumor specimen either from archival formalin-fixed, paraffin embedded (FFPE) tissue or tissue obtained by a fresh biopsy for analyzing TP53 at a central laboratory.
11) Measurable disease according to appropriate criteria. |
|
| E.4 | Principal exclusion criteria |
1) Poor medical risk in the investigator’s opinion because of systemic diseases in addition to the cancer under study, for example, uncontrolled infections.
Confidential Information 34 Amendment 4, 21 March 2022
2) Life-threatening illness, significant organ system dysfunction, or other condition that, in the investigator’s opinion, could compromise subject safety, or the integrity of study outcomes, or interfere with the absorption or metabolism of ASTX295.
3) History of, or at risk for, cardiac disease, as evidenced by any of the following conditions:
a. Abnormal left ventricular ejection fraction (LVEF; <50%) on echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan at Screening.
b. Congestive cardiac failure of ≥Grade 3 severity according to New York Heart Association (NYHA) functional classification defined as patients 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 evidence at Screening of long QT interval corrected for heart rate (QTcF), ventricular arrhythmias including ventricular bigeminy, clinically significant bradyarrhythmias such as sick sinus syndrome, third-degree atrioventricular (AV) block, presence of cardiac pacemaker or defibrillator, or other clinically significant arrhythmias.
e. Screening 12-lead electrocardiogram (ECG) with measurable QTcF interval of ≥470 msec. (Fridericia’s formula should be used).
4) Known advanced human immunodeficiency virus (HIV) infection (including AIDS): clinical Stage ≥3 according to World Health Organization (WHO) classification (WHO 2007) and/or HIV-associated immunodeficiency (CD4 count less than 500 per mm3 of blood). Antiretroviral therapy (ART) is allowed (subjects should be on established ART for at least 4 weeks and have an HIV viral load less than 400 copies/mL prior to enrollment).
5) Known active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection (inactive hepatitis carrier status and subjects with laboratory evidence of no active replication on antivirals - viral load below limit of detection- will be permitted).
6) Known brain metastases, unless previously treated and clinically stable for at least 4 weeks with or without steroids.
7) Known significant mental illness or other conditions, such as active alcohol or other substance abuse that, in the opinion of the investigator, predispose the subject to high risk of noncompliance with the protocol treatment or assessments.
8) Prior anticancer treatments or therapies within the indicated time window prior to first dose of study treatment (ASTX295), as follows:
a. Cytotoxic chemotherapy within 3 weeks prior. Any encountered treatment-related toxicities (excepting alopecia) must be stabilized or resolved to ≤Grade 1.
b. Monoclonal antibodies, biologics, or immunotherapy within 4 weeks prior. Any encountered treatment-related toxicities must be stabilized or resolved to ≤Grade 1.
c. Molecularly targeted drug or other investigational drugs, with the potential for delayed toxicity, within 4 weeks of the first dose of study treatment or 5 half-lives (minimum 14 days), whichever is shorter. Any encountered treatment-related toxicities must be stabilized or resolved to ≤Grade 1.
d. Major surgery or radiation within 4 weeks prior to first dose (palliative radiotherapy to a single lesion within 2 weeks).
9) Prior treatment with MDM2 antagonist.
10) Inability to swallow oral medication or inability or unwillingness to comply with the administration requirements related to ASTX295.
11) Active malignancy other than the cancer under study (excludes low risk prostate cancer or early breast cancer with or without hormonal therapy, superficial, or surgically or locally controlled basal cell or squamous carcinoma of the skin, and superficial bladder cancer). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 2 Primary end points (only phase 2 will be conducted in EU):
• Cohort 1 (MPM): DCR is defined as the proportion of participants who have a CR, PR, or stable disease at Week 16 according to mRECIST 1.1 as assessed by the investigator.
• Cohorts 2, 3, 4, 5, and 6: ORR is defined as the proportion of participants whose best response is CR or PR according to RECIST 1.1 as assessed by the investigator. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
• Cohort 1 (MPM): DCR assessed at Week 16 according to mRECIST 1.1 by the investigator.
• Cohorts 2, 3, 4, 5, and 6: ORR assessed according to RECIST 1.1 by the investigator.
Disease response assessment (CT or MRI) performed at screening, Cycle 3 Day 1, Cycle 5 Day 1 (±7 days) and then every 3 cycles thereafter (±2 weeks) and at treatment termination visit. |
|
| E.5.2 | Secondary end point(s) |
Phase 2 secondary end points (only phase 2 will be conducted in EU):
• Incidence and severity of AEs including SAEs, as well as other safety assessments.
• ASTX295 plasma concentration profiles and PK parameters such as AUC, Cmax, Cmin, Tmax, and t½.
• PK parameters of ASTX295 metabolites if applicable.
• Progression free survival (PFS) is defined as the time from date of the first dose until the earliest date of disease progression, as assessed by the investigator, or death from any cause, whichever occurs first.
• Overall survival (OS) is defined as the time from the date of first dose to date of death due to any cause.
• ORR is defined as the proportion of participants whose best response is CR or PR according mRECIST 1.1 for MPM as assessed by the investigator.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
AE monitoring performed at each visit.
PK parameter analysis: Cycle 1 Day 1, Cycle 1 Day 2, Cycle 3 Day 1, Cycle 3 Day 2
Disease response assessment (CT or MRI) performed at screening, Cycle 3 Day 1, Cycle 5 Day 1 (±7 days) and then every 3 cycles thereafter (±2 weeks) and at treatment termination visit. |
|
| 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 | No |
| 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) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 29 |
| 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 |
| United States |
| France |
| Spain |
| Germany |
| Italy |
| United Kingdom |
|
| 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
|
The Phase 2 portion of the study will be considered complete when all subjects have died or withdrawn from the study or 1 year after the last subject receives their first dose.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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