Clinical Trial - NCT03520075

Study of ASTX029 in Subjects With Advanced Solid Tumors

Recruiting

Sponsor: Astex Pharmaceuticals

Collaborators:

Information provided by (Responsible party): Sponsor

ClinicalTrials.gov Identifier: NCT03520075

Protocol Info

Short Description: Phase 1/2 ASTX029 in Advanced Solid Tumors
Long Description: A Phase 1-2 Study of the Safety, Pharmacokinetics, and Activity of ASTX029 in Subjects With Advanced Solid Tumors
MGH Status: Open
Sponsor: Astex Therapeutics Limited
Disease Program: Phase I

Next Steps


If you are interested in this protocol or in other treatment options at Massachusetts General Hospital, please Request a Consultation.




Purpose

This study is a first-in-human, open-label, multicenter, Phase 1-2 study to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity of ASTX029 administered orally to subjects with advanced solid malignancies who are not candidates for approved or available therapies.
Condition Title Intervention Phase
Solid Tumor, Adult ASTX029 Phase 1/Phase 2
Study Type Interventional
Official Title A Phase 1-2 Study of the Safety, Pharmacokinetics, and Activity of ASTX029 in Subjects With Advanced Solid Tumors

Primary Outcome Measures

Safety (Phase 1) - Dose-limiting toxicities including incidence of Treatment-Emergent Adverse Events [Time Frame: End of each dosing cycle (Day 21 of 21-day cycle)] [Designated as safety issue: ]

Efficacy (Phase 2) - Response Evaluation Criteria in Solid Tumors using RECIST v1.1 [Time Frame: Baseline to measured progressive disease or start of new anticancer therapy, through study completion, an average of 6 months to 1 year] [Designated as safety issue: ]


Secondary Outcome Measures

Pharmacokinetic profile of ASTX029 - AUC [Time Frame: Day 1 and 2 of Cycle 1 and Cycle 2 for Regimen 1, and Day 1, 2, 14, and 15 of Cycle 1 for Regimen 2] [Designated as safety issue: ]

Pharmacokinetic profile of ASTX029 - Cmax [Time Frame: Day 1 and 2 of Cycle 1 and Cycle 2 for Regimen 1, and Day 1, 2, 14, and 15 of Cycle 1 for Regimen 2] [Designated as safety issue: ]

Pharmacokinetic profile of ASTX029 - Cmin [Time Frame: Day 1 and 2 of Cycle 1 and Cycle 2 for Regimen 1, and Day 1, 2, 14, and 15 of Cycle 1 for Regimen 2] [Designated as safety issue: ]

Pharmacokinetic profile of ASTX029 - Tmax [Time Frame: Day 1 and 2 of Cycle 1 and Cycle 2 for Regimen 1, and Day 1, 2, 14, and 15 of Cycle 1 for Regimen 2] [Designated as safety issue: ]

Pharmacokinetic profile of ASTX029 - Half-life [Time Frame: Day 1 and 2 of Cycle 1 and Cycle 2 for Regimen 1, and Day 1, 2, 14, and 15 of Cycle 1 for Regimen 2] [Designated as safety issue: ]

Pharmacokinetic profile of ASTX029 - Metabolites [Time Frame: Day 1 and 2 of Cycle 1 and Cycle 2 for Regimen 1, and Day 1, 2, 14, and 15 of Cycle 1 for Regimen 2] [Designated as safety issue: ]

Efficacy - DOR [Time Frame: Baseline to measured progressive disease or start of new anticancer therapy, through study completion, an average of 6 months to 1 year] [Designated as safety issue: ]

Efficacy - DCR [Time Frame: Baseline to measured progressive disease or start of new anticancer therapy, through study completion, an average of 6 months to 1 year] [Designated as safety issue: ]

Efficacy - PFS [Time Frame: Baseline to measured progressive disease or start of new anticancer therapy, through study completion, an average of 6 months to 1 year] [Designated as safety issue: ]

Efficacy - OS [Time Frame: Baseline to measured progressive disease or start of new anticancer therapy, through study completion, an average of 6 months to 1 year] [Designated as safety issue: ]

Target engagement in tumor tissues - pRSK [Time Frame: Day 8 of Cycle 2] [Designated as safety issue: ]

Estimated Enrollment: 300
Study Start Date: May 2018
Estimated Study Completion Date: January 2022
Estimated Primary Completion Date: August 2021
Arms Assigned Interventions

Experimental:Phase 1 Regimen 1

Dose escalation and expansion: Regimen 1: ASTX029 orally once a day for 21 days of each 21-day cycle.
Drug:ASTX029
Described above

Experimental:Phase 1 Regimen 2

Dose escalation and expansion: Regimen 2: ASTX029 orally once a day for 14 days of each 21-day cycle.

Experimental:Phase 2

ASTX029 at the RP2D of the selected dosing regimen identified in Phase 1 to subjects with tumors characterized by gene aberrations in the MAPK signal pathway that may confer sensitivity to ASTX029.

Eligibility

Ages Eligible for Study: N/A-N/A

Genders Eligible for Study: All

Accepts Healthly Volunteers: No

Inclusion Criteria:

Subjects must fulfill all of the following inclusion criteria.

1. Able to understand and comply with study procedures, understand the risks involved in the study, and provide written informed consent before any study-specific procedure is performed.

2. Men or women 18 years of age or older.

3. Subjects with histologically or cytologically confirmed advanced solid tumors that are metastatic or unresectable, who are refractory or have relapsed after treatment with available therapies or for whom standard life-prolonging measures or approved therapies are not available. In Phase 1 Part B (except in the potential food-effect cohort) and in the Phase 2 portion of the protocol, subjects must also have documented gene alterations in the MAPK pathway as detailed in the protocol.

4. In Phase 1 Part B (except in the potential food-effect cohort) of the protocol, subjects must have disease lesions that are amenable to biopsy.

5. In the Phase 2 portion of the protocol, subjects must have measurable disease according to RECIST v1.1.

6. Eastern Cooperative Oncology Group performance status 0 to 2.

7. Acceptable organ function as evidenced by the following laboratory data:

1. Aspartate aminotransferase and alanine aminotransferase ≤2×upper limit of normal (ULN) or ≤3 ULN in the presence of liver metastases.

2. Total serum bilirubin ≤1.5×ULN.

3. Absolute neutrophil count ≥1500 cells/mm3.

4. Platelet count ≥100,000 cells/mm3.

5. Calculated creatinine clearance (by the standard Cockcroft Gault formula) of ≥50 mL/min or glomerular filtration rate of ≥50 mL/min.

8. Women of child-bearing potential (according to recommendations of the Clinical Trial Facilitation Group as detailed in the protocol) 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 child-bearing potential must agree to practice 2 highly effective contraceptive measures (as described in the protocol) during the study and for at least 3 months after completing treatment and must agree not to become pregnant or father a child while receiving study treatment and for at least 3 months after completing treatment.

Exclusion Criteria:

1. Hypersensitivity to ASTX029 or excipients of the drug product.

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

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 study outcomes or interfere with the absorption or metabolism of ASTX029.

4. Prior anticancer treatments or therapies within the indicated time window prior to first dose of study treatment (ASTX029), as follows:

1. Cytotoxic chemotherapy or radiotherapy within 3 weeks prior and any encountered treatment-related toxicities (excepting alopecia) not stabilized or resolved to ≤Grade 1.

2. Monoclonal antibodies within 4 weeks prior and any encountered treatment-related toxicities not resolved to ≤Grade 1.

3. Molecularly targeted drug or 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.

5. Prior treatment with ERK inhibitors.

6. History of, or at risk for, cardiac disease, as evidenced by 1 or more of the following conditions:

1. Abnormal left ventricular ejection fraction (<50%) on echocardiogram or multiple-gated acquisition scan.

2. Congestive cardiac failure of ≥Grade 3 severity according to New York Heart Association functional classification defined as patients with marked limitation of activity and who are comfortable only at rest.

3. Unstable cardiac disease including unstable angina or hypertension as defined by the need for overnight hospital admission within the last 3 months (90 days).

4. History or evidence of long QT interval corrected for heart rate (QTc), ventricular arrhythmias including ventricular bigeminy, complete left bundle branch block, clinically significant bradyarrhythmias such as sick sinus syndrome, second- and third-degree atrioventricular block, presence of cardiac pacemaker or defibrillator, or other significant arrhythmias.

5. Screening 12-lead electrocardiogram with measurable QTc interval of ≥470 msec. (Fridericia's formula should be used to calculate the QTc interval throughout the study.)

7. Known history of human immunodeficiency virus infection or seropositive results consistent with active hepatitis B virus or active hepatitis C virus infection.

8. Known brain metastases, unless previously treated and stable for at least 3 months with or without steroids.

9. 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.

10. History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) including:

1. Presence of predisposing factors to RVO or CSR (eg, uncontrolled glaucoma or ocular hypertension, uncontrolled diabetes mellitus) or

2. Visible retinal pathology as assessed by ophthalmic examination at screening that is considered a risk factor for RVO or CSR such as:

  • Evidence of optic disc cupping or
  • Evidence of new visual field defects on automated perimetry or
  • Intraocular pressure >21 mmHg as measured by tonography.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT03520075

Locations

  • United States, Connecticut
    • Smilow Cancer Hospital at Yale New Haven New Haven, Connecticut, United States, 06511
  • United States, Maryland
    • The Sidney Kimmel Comprehensive Cancer Center Baltimore, Maryland, United States, 21205
  • United States, Massachusetts
    • Massachusetts General Hospital Boston, Massachusetts, United States, 02114
    • Dana Farber Cancer Institute Boston, Massachusetts, United States, 02215
  • United States, Texas
    • MD Anderson Cancer Center Houston, Texas, United States, 77030
    • START - South Texas Accelerated Research Therapeutics, LLC San Antonio, Texas, United States, 78229
  • United States, Virginia
    • Virginia Cancer Specialists Fairfax, Virginia, United States, 22031

Sponsors and Collaborators

Astex Pharmaceuticals

More Information

No publications provided

Responsible Party: Sponsor
ClinicalTrials.gov Identifier: NCT03520075
Other Study ID Numbers:
Study First Received:
Last Updated:
Health Authority:

Keywords provided by Astex Pharmaceuticals:

Neoplasms

Solid Tumors

Antineoplastic Agents

MAPK

ERK

Next Steps


If you are interested in this protocol or in other treatment options at Massachusetts General Hospital, please Request a Consultation.







ClinicalTrials.gov processed this data on July 18, 2019