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Study of ASTX029 in Subjects With Advanced Solid Tumors

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ClinicalTrials.gov Identifier: NCT03520075
Recruitment Status : Recruiting
First Posted : May 9, 2018
Last Update Posted : June 11, 2019
Sponsor:
Information provided by (Responsible Party):
Astex Pharmaceuticals, Inc. ( Astex Pharmaceuticals )

Brief Summary:
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 or disease Intervention/treatment Phase
Solid Tumor, Adult Drug: ASTX029 Phase 1 Phase 2

Detailed Description:
ASTX029 is a synthetic small molecule inhibitor of extracellular signal-regulated kinases (ERKs) 1/2. ASTX029 has not been previously evaluated in human subjects. The Phase 1 portion of this study will assess safety and determine the maximum tolerated dose, the recommended Phase 2 dose (RP2D), and the recommended dosing regimen of ASTX029 administered orally. The Phase 2 portion will assess preliminary clinical activity in tumors characterized by gene aberrations in the mitogen-activated protein kinase (MAPK) signal pathway that may confer sensitivity to ASTX029.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 300 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1-2 Study of the Safety, Pharmacokinetics, and Activity of ASTX029 in Subjects With Advanced Solid Tumors
Actual Study Start Date : May 10, 2018
Estimated Primary Completion Date : August 1, 2021
Estimated Study Completion Date : January 14, 2022

Arm Intervention/treatment
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.

Drug: ASTX029
Described above

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.
Drug: ASTX029
Described above




Primary Outcome Measures :
  1. 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) ]
    Number of subjects with dose-limiting toxicities

  2. 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 ]
    Objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1


Secondary Outcome Measures :
  1. 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 ]
    1) Area under the time-concentration curve

  2. 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 ]
    2) Maximum plasma concentration

  3. 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 ]
    3) Minimum plasma concentration

  4. 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 ]
    4) Time to reach maximum concentration

  5. 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 ]
    5) Elimination half-life

  6. 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 ]
    6) Analysis of ASTX029 metabolites if applicable

  7. 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 ]
    Duration of response

  8. 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 ]
    Disease control rate

  9. 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 ]
    Progressive-free survival

  10. 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 ]
    Overall survival

  11. Target engagement in tumor tissues - pRSK [ Time Frame: Day 8 of Cycle 2 ]
    Inhibition of phosphorylated ribosomal s6 kinase protein in response to ASTX029 treatment in fresh tumor biopsies



Information from the National Library of Medicine

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

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03520075


Contacts
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Contact: Richard J Morishige, MS, RRT, RAC +1 925-560-2882 Richard.Morishige@astx.com
Contact: Deborah Harrington +1 925- 560-2895 Deborah.Harrington@astx.com

Locations
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United States, Connecticut
Smilow Cancer Hospital at Yale New Haven Recruiting
New Haven, Connecticut, United States, 06511
Contact: Nora Autuori    203-737-4833    nora.autuori@yale.edu   
Principal Investigator: Patricia LoRusso, DO, PhD         
United States, Maryland
The Sidney Kimmel Comprehensive Cancer Center Recruiting
Baltimore, Maryland, United States, 21205
Contact: Chelsea Miralles    410-955-9923    cmirall1@jhmi.edu   
Principal Investigator: Nilofer Azad, MD         
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Ryan Sullivan    617-724-4000    rsullivan7@mgh.harvard.edu   
Principal Investigator: Ryan Sullivan, MD         
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Loan Vuong    617-632-5485    loan_vuong@dfci.harvard.edu   
Principal Investigator: Geoffrey Shapiro, MD, PhD         
United States, Texas
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Anjali Raina    713-792-3238    ARaina@mdanderson.org   
Principal Investigator: Filip Janku, MD         
START - South Texas Accelerated Research Therapeutics, LLC Recruiting
San Antonio, Texas, United States, 78229
Contact: Carrie Choi       carrie.choi@startsa.com   
Contact: Karla Rivas    (210) 593-5934    karla.rivas@startsa.com   
Principal Investigator: Drew W Rasco, MD         
United States, Virginia
Virginia Cancer Specialists Recruiting
Fairfax, Virginia, United States, 22031
Contact: Frances Gatlin    703-208-9229    frances.gatlin@usoncology.com   
Principal Investigator: Alexander Spira, MD, PhD         
Sponsors and Collaborators
Astex Pharmaceuticals
Investigators
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Study Director: Roberta Ferraldeschi, MD, PhD Astex Pharmaceuticals

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Responsible Party: Astex Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03520075     History of Changes
Other Study ID Numbers: ASTX029-01
First Posted: May 9, 2018    Key Record Dates
Last Update Posted: June 11, 2019
Last Verified: June 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Astex Pharmaceuticals, Inc. ( Astex Pharmaceuticals ):
Neoplasms
Solid Tumors
Antineoplastic Agents
MAPK
ERK
Additional relevant MeSH terms:
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Neoplasms