Clinical Trials /

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

NCT04021368

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: SEL120 in Patients With Acute Myeloid Leukemia or High-risk Myelodysplastic Syndrome
  • Official Title: A Phase Ib Study of SEL120 in Patients With Acute Myeloid Leukemia or High-risk Myelodysplastic Syndrome

Clinical Trial IDs

  • ORG STUDY ID: CLI120-001
  • NCT ID: NCT04021368

Conditions

  • Acute Myeloid Leukemia
  • High-risk Myelodysplastic Syndrome

Interventions

DrugSynonymsArms
SEL120SEL120

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
SEL120ExperimentalThe 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.
  • SEL120

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended dose (RD)
Time Frame:Up to 18 months
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:The Maximum Observed Concentration (C[max])
Time Frame:Up to 18 months
Safety Issue:
Description:Pharmacokinetic profile of SEL120 will be characterized using the Maximum Observed Concentration (C[max]).
Measure:The Terminal Half-life (t[1/2])
Time Frame:Up to 18 months
Safety Issue:
Description:Pharmacokinetic profile of SEL120 will be characterized using the Terminal Half-life (t[1/2]).
Measure:The Area Under the Curve (AUC)
Time Frame:Up to 18 months
Safety Issue:
Description:Pharmacokinetic profile of SEL120 will be characterized using the Area Under the Curve (AUC).
Measure:The Volume of Distribution at Steady State (Vss)
Time Frame:Up to 18 months
Safety Issue:
Description:Pharmacokinetic profile of SEL120 will be characterized using the Volume of Distribution at Steady State (Vss).
Measure:Anti-leukemic activity
Time Frame:Up to 18 months
Safety Issue:
Description:Anti-leukemic activity will be assessed by AML or MDS Response Criteria (Döhner et al., 2017, or Cheson et al., 2006, respectively).

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Selvita S.A.

Trial Keywords

  • Acute Myeloid Leukemia
  • Myelodysplastic Syndrome
  • CDK8/19 Inhibitor
  • SEL120
  • Clinical Trial, Phase Ib

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