Study of ASTX295 in Patients With Solid Tumors With Wild-Type p53

• ClinicalTrials.gov Identifier: NCT03975387
• Recruitment Status: Recruiting
• First Posted: June 5, 2019
• Last Update Posted: November 22, 2022
• Sponsor: Astex Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Astex Pharmaceuticals, Inc.

Study Description

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 subjects with wild-type TP53 advanced solid tumors. Phase 1 is a dose escalation and dose expansion study design followed by a Phase 2 study.

Condition or disease	Intervention/treatment	Phase
Solid Tumor	Drug: ASTX295	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 250 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: July 11, 2019
• Estimated Primary Completion Date: June 22, 2025
• Estimated Study Completion Date: August 27, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: ASTX295	Drug: ASTX295; ASTX295 orally for 28-day cycle continuous or on an intermittent dosing schedule.

Outcome Measures

Primary Outcome Measures :

1. Phase 1a: Safety and tolerability of ASTX295 including determination of maximum tolerated dose (MTD), and/or recommended dose for expansion (RDE) to Phase 1b [ Time Frame: From the date of the first dose until 30 days after discontinuation of study treatment ]
2. Phase 1b: Recommended Phase 2 dose (RP2D) and regimen of ASTX295 to proceed to Phase 2 [ Time Frame: From the date of the first dose until 30 days after discontinuation of study treatment, an average of 6 months to 1 year ]
   The RP2D will be based on incidence and severity of AEs, including SAEs and will be determined by the data and safety review committee (DSRC)
3. Phase 2: Disease control rate (DCR) in Cohort 1 [ Time Frame: From the date of the first dose until Week 16 ]
   DCR will be calculated in Cohort 1 as the number of subjects whose response at Week 16 is CR, partial response (PR), or stable disease, divided by the total number of subjects evaluable for DCR analysis.
4. Phase 2: Overall response rate (ORR) in Cohorts 2, 3, 4, 5, and 6 [ Time Frame: From the date of the first dose until study treatment discontinuation, an average of 6 months to 1 year ]
   ORR in Cohorts 2, 3, 4, 5, and 6 will be calculated as the number of subjects whose best response is CR or PR, divided by the total number of subjects evaluable for ORR analysis.

Secondary Outcome Measures :

1. Phase 1: Preliminary clinical activity of ASTX295 as assessed by disease control rate (DCR) [ Time Frame: From the date of the first dose until Week 16 ]
   DCR will be calculated as the number of subjects whose response at Week 16 is CR, PR, or stable disease, divided by the total number of subjects evaluable for DCR analysis
2. Phase 1: Preliminary clinical activity as assessed by objective response rate (ORR) of ASTX295 [ Time Frame: From the date of the first dose until study treatment discontinuation, an average of 6 months to 1 year ]
   ORR will be calculated as the number of subjects whose best response is CR or PR, divided by the total number of subjects evaluable for ORR analysis
3. Phase 2: Safety profile of ASTX295 [ Time Frame: From the date of the first dose until 30 days after discontinuation of study treatment, an average of 6 months to 1 year ]
   Incidence and severity of adverse events (AEs) including serious adverse events (SAEs)
4. Phase 2: Progression free survival (PFS) [ Time Frame: Up to approximately 1 year ]
   PFS is defined as the time from date of the first dose until the earliest date of disease progression or death from any cause, whichever comes first
5. Phase 2: Overall survival (OS) [ Time Frame: Up to approximately 1 year ]
   OS is defined as the time from the date of first dose to date of death due to any cause
6. Phase 2: Overall response rate (ORR) in Cohort 1 [ Time Frame: From the date of the first dose until study treatment discontinuation, an average of 6 months to 1 year ]
   ORR in Cohort 1 will be calculated as the number of subjects whose best response is CR or PR, divided by the total number of subjects evaluable for ORR analysis.
7. Pharmacokinetic (PK) profile of ASTX295 (area under the curve [AUC]) [ Time Frame: Blood will be collected during Cycles 1 and 2 in Phase 1, Cycles 1 and 3 in Phase 2 (each cycle is 28 days) ]
8. Pharmacokinetic (PK) profile of ASTX295 (minimum concentration [Cmin]) [ Time Frame: Blood will be collected during Cycles 1 and 2 in Phase 1, Cycles 1 and 3 in Phase 2 (each cycle is 28 days) ]
9. Pharmacokinetic (PK) profile of ASTX295 (maximum concentration [Cmax]) [ Time Frame: Blood will be collected during Cycles 1 and 2 in Phase 1, Cycles 1 and 3 in Phase 2 (each cycle is 28 days) ]
10. Pharmacokinetic (PK) profile of ASTX295 (time to reach maximum concentration [Tmax]) [ Time Frame: Blood will be collected during Cycles 1 and 2 in Phase 1, Cycles 1 and 3 in Phase 2 (each cycle is 28 days) ]
11. Pharmacokinetic (PK) profile of ASTX295 (elimination half-life [t½]) [ Time Frame: Blood will be collected during Cycles 1 and 2 in Phase 1, Cycles 1 and 3 in Phase 2 (each cycle is 28 days) ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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).

Contacts and Locations

Contacts

Contact: Astex Pharmaceuticals; 925-560-0100; clinicaltrials@astx.com

Locations

United States, California

City of Hope Comprehensive Cancer Center; Recruiting

Duarte, California, United States, 91010

Contact magulnik@coh.org

Cedars-Sinai Medical Center; Recruiting

Los Angeles, California, United States, 90048

Contact: Paulina Linares 310-423-1108 paulina.linares@cshs.org

Hoag Hospital; Recruiting

Newport Beach, California, United States, 92663

Contact: Rosie Blancas rosie.blancas1@hoag.org

United States, Iowa

Holden Comprehensive Cancer Center; Recruiting

Iowa City, Iowa, United States, 52242

Contact jennifer-adams@uiowa.edu

United States, Michigan

University of Michigan Rogel Cancer Center; Not yet recruiting

Ann Arbor, Michigan, United States, 48109

Contact: Becky Tilley 734-232-0798 trebekah@umich.edu

United States, New York

Columbia University Irving Medical Center - Herbert Irving Pavilion; Recruiting

New York, New York, United States, 10032

Contact: Robert Garofano rfg2115@columbia.edu

United States, Pennsylvania

University of Pennsylvania-Abramson Cancer Center; Recruiting

Philadelphia, Pennsylvania, United States, 19104

Contact: Pavit Singh pavit.singh@pennmedicine.upenn.edu

United States, Texas

The University of Texas MD Anderson Cancer Center; Recruiting

Houston, Texas, United States, 77030

Contact: Puja =Aggarwal, MS, PhD paggarwal1@mdanderson.org

NEXT Oncology; Recruiting

San Antonio, Texas, United States, 78229

Contact: Cynthia De Leon 210-580-9521 cdeleon@nextoncology.com

Contact: Jordan Georg jgeorg@nextoncology.com

United States, Virginia

Virgnia Cancer Specialists; Recruiting

Fairfax, Virginia, United States, 22031

Contact: Kay Scott kay.scott@usoncology.com

Sponsors and Collaborators

Astex Pharmaceuticals, Inc.

More Information

• Responsible Party: Astex Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT03975387
• Other Study ID Numbers: ASTX295-01; 2021-005033-16 ( EudraCT Number )
• First Posted: June 5, 2019
• Last Update Posted: November 22, 2022
• Last Verified: November 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Astex Pharmaceuticals, Inc.:

solid tumor; mesothelioma; TP53

Additional relevant MeSH terms:

Neoplasms