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SEL120 in Patients With Acute Myeloid Leukemia or High-risk Myelodysplastic Syndrome

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ClinicalTrials.gov Identifier: NCT04021368
Recruitment Status : Recruiting
First Posted : July 16, 2019
Last Update Posted : July 19, 2019
Sponsor:
Collaborator:
ICON plc
Information provided by (Responsible Party):
Selvita S.A.

Brief Summary:
This first-in-human study will evaluate SEL120, a novel small molecule CDK8/19 inhibitor, in patients with Acute Myeloid Leukemia (AML) or High-risk Myelodysplastic Syndrome (HR-MDS), in terms of selection of the recommended dose for further clinical development and assessment of safety, tolerability, preliminary anti-leukemic activity, as well as pharmacokinetic and pharmacodynamic profiles.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia High-risk Myelodysplastic Syndrome Drug: SEL120 Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 68 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase Ib Study of SEL120 in Patients With Acute Myeloid Leukemia or High-risk Myelodysplastic Syndrome
Actual Study Start Date : July 15, 2019
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2020


Arm Intervention/treatment
Experimental: SEL120
The first part of the study consists of dose-escalation cohorts where patients will receive ascending doses of SEL120 to determine the recommended dose (RD) for further clinical development. The second part of the study is an enrichment cohort where additional 6 to 20 patients will be treated with SEL120 to support the evaluation of the RD.
Drug: SEL120
SEL120 will be administered as a single oral dose every other day (q.a.d.) for a total of 7 doses i.e. on Days 1, 3, 5, 7, 9, 11 and 13, in a 3-week treatment cycle.




Primary Outcome Measures :
  1. Recommended dose (RD) [ Time Frame: Up to 18 months ]
    The RD will be determined using all available data, which will include dose limiting toxicities (DLTs) and other toxicities, signs of anti-leukemic activity, pharmacokinetic and pharmacodynamic characteristics.

  2. Incidence of Adverse Events (Safety and Tolerability) [ Time Frame: Up to 18 months ]
    Safety and tolerability profile will be assessed by Common Terminology Criteria for Adverse Events v5.0 and summarized by type, frequency, and severity of adverse events.


Secondary Outcome Measures :
  1. The Maximum Observed Concentration (C[max]) [ Time Frame: Up to 18 months ]
    Pharmacokinetic profile of SEL120 will be characterized using the Maximum Observed Concentration (C[max]).

  2. The Terminal Half-life (t[1/2]) [ Time Frame: Up to 18 months ]
    Pharmacokinetic profile of SEL120 will be characterized using the Terminal Half-life (t[1/2]).

  3. The Area Under the Curve (AUC) [ Time Frame: Up to 18 months ]
    Pharmacokinetic profile of SEL120 will be characterized using the Area Under the Curve (AUC).

  4. The Volume of Distribution at Steady State (Vss) [ Time Frame: Up to 18 months ]
    Pharmacokinetic profile of SEL120 will be characterized using the Volume of Distribution at Steady State (Vss).

  5. Anti-leukemic activity [ Time Frame: Up to 18 months ]
    Anti-leukemic activity will be assessed by AML or MDS Response Criteria (Döhner et al., 2017, or Cheson et al., 2006, respectively).


Other Outcome Measures:
  1. AML surface markers [ Time Frame: Up to 18 months ]
    Pharmacodynamic profile of SEL120 will be characterized using immunophenotyping of AML surface markers by exploratory assay.

  2. Phosphorylated protein levels in AML blasts [ Time Frame: Up to 18 months ]
    Pharmacodynamic profile of SEL120 will be characterized using phosphorylated protein levels in AML blasts by exploratory immunoassay.

  3. Transcriptomic profile changes in AML blasts [ Time Frame: Up to 18 months ]
    Pharmacodynamic profile of SEL120 will be characterized using transcriptomic profile changes in AML blasts by exploratory next generation sequencing.

  4. Genetic profile changes in AML blasts [ Time Frame: Up to 18 months ]
    Pharmacodynamic profile of SEL120 will be characterized using genetic profile changes in AML blasts by next generation sequencing.



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:

All the following criteria must be met for a patient to be eligible for the study:

  1. Written informed consent provided prior to any study-related procedure.
  2. Age ≥18 years.
  3. AML diagnosis according to the 2016 World Health Organisation (WHO) classification (Arber et al. 2016) with relapsed or refractory disease who have received no more than 3 prior lines of therapy and with no available therapy; or Myelodysplastic Syndrome (MDS) diagnosis according to the 2016 WHO classification (Arber et al. 2016) with high-risk disease per the Revised International Prognostic Scoring System and with relapsed or refractory disease, who have received no more than 3 prior lines of therapy and with no available therapy.
  4. Eastern Cooperative Oncology Group (ECOG) performance score of 0-2.
  5. Patients must have been off anti-cancer treatment for 2 weeks or 5 half-lives, whichever is longer. Note: Hydroxyurea is exempted if used to reduce total white blood cell (WBC) count (see below); radiation must have been completed at least 4 weeks prior to first dose of study drug.
  6. Patients must have recovered from the toxic effects of previous treatments to at least Grade 1, for neurotoxicity or alopecia to Grade 2.
  7. Clinical laboratory parameters as follows:

    1. Peripheral white blood cell (WBC) count, no upper limit at Screening, but must be <10x10^9/L on Day 1 prior to first dose of study drug. Note: Patients with excessive blasts may be treated with hydroxyurea until 2 days prior to first dose of study drug to reduce WBC;
    2. Platelet count >10,000/µL;
    3. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3x the upper limit of normal (ULN);
    4. Total bilirubin ≤1.5x ULN; and
    5. Creatinine clearance ≥60 mL/min (Cockcroft-Gault formula).
  8. Adequate cardiac function confirmed by left ventricular ejection fraction ≥40% as per echocardiography.
  9. Life expectancy of at least 12 weeks.
  10. For females of childbearing potential (FCBP), a negative pregnancy test must be confirmed before enrolment. FCBP must commit to using two medically accepted forms of effective contraception during study participation and until 90 days after the last dose of study drug. Note: Where oral contraceptives are considered, please contact the Medical Monitor. Females must also refrain from donating blood during the same time-period.
  11. For males, an effective barrier method of contraception must be used during study participation until 90 days after the last dose of study drug, if the patient is sexually active with a FCBP. Males must also refrain from donating blood or sperm during the same time-period.
  12. Investigator considers the patient to be suitable for participation in the clinical study by assessing that they:

    • Understand the requirements of the clinical study and can give informed consent;
    • Can comply with study medication dosing requirements and all study-related procedures and evaluations; and
    • Are not considered to be potentially unreliable and/or not cooperative.

Exclusion Criteria:

Any of the following will exclude a patient from enrolment:

  1. Active central nervous system (CNS) leukemia.
  2. Previous treatment with CDK8-targeted therapy.
  3. Patients who have undergone major surgery within 28 days prior to first dose of study drug.
  4. Hematopoietic stem cell transplant within 120 days prior to first dose of study drug.
  5. Active Grade 2-4 acute graft versus host disease (GVHD), active moderate-to-severe chronic GVHD, or requirement for systemic immunosuppressive medications for GVHD.
  6. Evidence of ongoing and uncontrolled systemic bacterial, fungal, or viral infection.
  7. Known seropositivity or history of active viral infection with human immunodeficiency virus (HIV).
  8. Ongoing significant liver disease such as cirrhosis, drug-induced liver injury, active hepatitis or chronic persistent hepatitis B and/or C.
  9. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of SEL120 (e.g. active inflammatory bowel disease, ulcerative disease, malabsorption syndrome, short bowel syndrome, uncontrolled nausea, vomiting or diarrhea).
  10. Ongoing drug-induced pneumonitis.
  11. Concurrent participation in another investigational clinical trial.
  12. Taking any medications, herbal supplements or other substances (including smoking) that are known to be strong inhibitors or inducers of CYP1A2 or that can prolong Q wave to T wave (QT) interval and/or cause torsade de pointes within less than 2 weeks or 5 half-lives, whichever is shorter, prior to first dose of study drug.
  13. Significant cardiac dysfunction defined as myocardial infarction within 12 months of first dose of study drug, New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled dysrhythmias, or poorly controlled angina.
  14. Personal or family history of serious ventricular arrhythmia, or QT interval corrected for heart rate (QTc) ≥450 ms (Bazett's formula).
  15. Any other prior or current medical condition, intercurrent illness, surgical history, physical or electrocardiogram (ECG) findings, laboratory abnormalities, or extenuating circumstance (e.g. alcohol or drug addiction) that, in the Investigator's opinion, could jeopardize patient safety or interfere with the objectives of the study.
  16. Prior history of malignancies other than AML or MDS, unless the patient has been free of the disease for 5 years or more prior to Screening. Exceptions to the ≥5-year time limit include history of the following:

    1. basal cell carcinoma of the skin;
    2. non-metastatic squamous cell carcinoma of the skin;
    3. carcinoma in situ of the cervix;
    4. carcinoma in situ of the breast;
    5. carcinoma in situ of the bladder; and
    6. incidental histological finding of prostate cancer (Tumor/Node/Metastasis [TNM] stage of T1a or T1b).
  17. Pregnant or breast-feeding females.

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): NCT04021368


Contacts
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Contact: Head of Clinical Operations +48 123453272 clinicaltrials@selvita.com

Locations
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United States, Tennessee
Tennessee Oncology Recruiting
Nashville, Tennessee, United States, 37203
Contact: William Donnellan, MD         
Sponsors and Collaborators
Selvita S.A.
ICON plc

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Responsible Party: Selvita S.A.
ClinicalTrials.gov Identifier: NCT04021368     History of Changes
Other Study ID Numbers: CLI120-001
First Posted: July 16, 2019    Key Record Dates
Last Update Posted: July 19, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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 Selvita S.A.:
Acute Myeloid Leukemia
Myelodysplastic Syndrome
CDK8/19 Inhibitor
SEL120
Clinical Trial, Phase Ib
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Preleukemia
Myelodysplastic Syndromes
Syndrome
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions