Clinical trial NCT03975387: Study of ASTX295 in Patients With Solid Tumors With Wild-Type p53
Official title: Phase 1/2 Open-Label Study of the Safety, Pharmacokinetics, and Preliminary Activity of ASTX295 in Subjects With Wild-Type TP53 Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Solid Tumor
Keywords: solid tumor
mesothelioma
TP53
Lead sponsor: Taiho Oncology, Inc.
Sponsor class: INDUSTRY
First posted: 2019-06-05
Enrollment: 106
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Study ASTX295-01 is a first in human Phase 1/2 open-label study of the safety, pharmacokinetics, and preliminary activity of ASTX295 in participants with wild-type TP53 advanced solid tumors. Phase 1 is a dose escalation and dose expansion study design. Sponsor made the strategic decision to not pursue the Phase 2 part of the study.


Eligibility criteria: Inclusion Criteria:

Age

1. Participant must be 18 years of age or older, at the time of signing the informed consent.

   Type of Participant and Disease Characteristics
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.

   1. Phase 1: any tumor type is eligible
   2. Phase 2: eligible tumor types as follows: malignant pleural mesothelioma (MPM) (Cohort 1); Liposarcoma (well-differentiated (WD) , de- differentiated (DD), or mix), intimal sarcoma, and other sarcomas with human murine double minute 2 (MDM2) amplification (Cohort 2); Glioblastoma multiforme (GBM) and tumors with CDNK2A loss of function (LOF) excluding MPM, liposarcoma, intimal sarcoma, and uveal melanoma (UVM) (Cohort 3); any solid tumors with molecular feature that may confer sensitivity to ASTX295 (Cohort 4); Uveal melanoma (Cohort 5); Any cancer type with MDM2 amplification excluding MPM, sarcoma, and UVM(Cohort 6).
3. Documented 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:

   1. Absolute neutrophil count (ANC) ≥1500 cells/mm3
   2. Platelet count ≥100,000 cells/mm3
   3. Hemoglobin \>9 g/dL
6. Adequate hepatic function as evidenced by:

   1. Serum total bilirubin ≤1.5 × upper limit of normal (ULN).
   2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN (≤ 3 ULN in the presence of liver metastases).
   3. 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.

   Sex
7. Participant can be male or female

   Informed Consent
8. Capable of giving signed informed consent, 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.

   Participants are eligible to be included in Phase 1 Part B of the study only if all of the following additional criteria apply:
9. In Phase 1 Part B (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.

   Participants are eligible to be included in Phase 2 of the study only if all of the following additional criteria apply:
10. Have 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 as per protocol.

Exclusion Criteria:

Medical Conditions

1. Poor medical risk in the investigator's opinion because of systemic diseases in addition to the cancer under study, for example, uncontrolled infections.
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:

   1. Abnormal left ventricular ejection fraction.
   2. Congestive cardiac failure of ≥Grade 3.
   3. Unstable cardiac disease.
   4. History or evidence at Screening of long QT interval corrected for heart rate (QTcF), ventricular arrhythmias, clinically significant bradyarrhythmias, third-degree atrioventricular (AV) block, presence of cardiac pacemaker or defibrillator, or other clinically significant arrhythmias.
   5. 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 WHO classification and/or HIV-associated immunodeficiency.
5. Known active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection (Inactive Hepatitis Carrier 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.

   Prior/Concomitant Therapy
8. Prior anticancer treatments or therapies within the indicated time window prior to first dose of study treatment (ASTX295), as follows:

   1. Cytotoxic chemotherapy within 3 weeks prior. Any encountered treatment-related toxicities (excepting alopecia) must be stabilized or resolved to ≤Grade 1.
   2. Monoclonal antibodies, biologics, or immunotherapy within 4 weeks prior. Any encountered treatment-related toxicities must be stabilized or resolved to ≤Grade 1.
   3. Molecularly targeted drug or other investigational drugs, without 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.
   4. 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.

    Participants are excluded from the Phase 2 part of the study if any of the following additional criteria apply:
11. Active malignancy other than the cancer under study (excludes low risk prostate cancer or early breast cancer with or without hormonal therapy, basal cell carcinoma of the skin and superficial bladder cancer).

Primary outcomes:
measure: Phase 1a: Safety and tolerability of ASTX295 including determination of maximum tolerated dose (MTD), and/or recommended dose for expansion (RDE) to Phase 1b
timeFrame: From the date of the first dose until 30 days after discontinuation of study treatment
measure: Phase 1b: Recommended Phase 2 dose (RP2D) and regimen of ASTX295 to proceed to Phase 2
timeFrame: From the date of the first dose until 30 days after discontinuation of study treatment, an average of 6 months to 1 year
measure: Phase 2: Disease control rate (DCR) in Cohort 1
timeFrame: From the date of the first dose until Week 16
measure: Phase 2: Overall response rate (ORR) in Cohorts 2, 3, 4, 5, and 6
timeFrame: From the date of the first dose until study treatment discontinuation, an average of 6 months to 1 year
Secondary outcomes:
measure: Phase 1: Preliminary clinical activity of ASTX295 as assessed by disease control rate (DCR)
timeFrame: From the date of the first dose until Week 16
measure: Phase 1: Preliminary clinical activity as assessed by objective response rate (ORR) of ASTX295
timeFrame: From the date of the first dose until study treatment discontinuation, an average of 6 months to 1 year
measure: Phase 2: Safety profile of ASTX295
timeFrame: From the date of the first dose until 30 days after discontinuation of study treatment, an average of 6 months to 1 year
measure: Phase 2: Progression free survival (PFS)
timeFrame: Up to approximately 1 year
measure: Phase 2: Overall survival (OS)
timeFrame: Up to approximately 1 year
measure: Phase 2: Overall response rate (ORR) in Cohort 1
timeFrame: From the date of the first dose until study treatment discontinuation, an average of 6 months to 1 year
measure: Pharmacokinetic (PK) profile of ASTX295 (area under the curve [AUC])
timeFrame: Blood will be collected during Cycles 1 and 2 in Phase 1, Cycles 1 and 3 in Phase 2 (each cycle is 28 days)
measure: Pharmacokinetic (PK) profile of ASTX295 (minimum concentration [Cmin])
timeFrame: Blood will be collected during Cycles 1 and 2 in Phase 1, Cycles 1 and 3 in Phase 2 (each cycle is 28 days)
measure: Pharmacokinetic (PK) profile of ASTX295 (maximum concentration [Cmax])
timeFrame: Blood will be collected during Cycles 1 and 2 in Phase 1, Cycles 1 and 3 in Phase 2 (each cycle is 28 days)
measure: Pharmacokinetic (PK) profile of ASTX295 (time to reach maximum concentration [Tmax])
timeFrame: Blood will be collected during Cycles 1 and 2 in Phase 1, Cycles 1 and 3 in Phase 2 (each cycle is 28 days)
measure: Pharmacokinetic (PK) profile of ASTX295 (elimination half-life [t½])
timeFrame: Blood will be collected during Cycles 1 and 2 in Phase 1, Cycles 1 and 3 in Phase 2 (each cycle is 28 days)
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center Site#114
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center Site #105
state: California
city: Newport Beach
country: United States
facility: Hoag Hospital Site#110
state: California
city: Iowa City
country: United States
facility: Holden Comprehensive Cancer Center Site#108
state: Iowa
city: Ann Arbor
country: United States
facility: University of Michigan Rogel Cancer Center Site#109
state: Michigan
city: Saint Paul
country: United States
facility: Regions Cancer Center Site #115
state: Minnesota
city: New York
country: United States
facility: Columbia University Irving Medical Center - Herbert Irving Pavilion Site#104
state: New York
city: Philadelphia
country: United States
facility: University of Pennsylvania-Abramson Cancer Center Site#113
state: Pennsylvania
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center Site #102
state: Texas
city: San Antonio
country: United States
facility: NEXT Oncology Site #101
state: Texas
city: Fairfax
country: United States
facility: Virgnia Cancer Specialists Site #103
state: Virginia
Study officials:
References: