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A Biomarker-Directed Phase 2 Trial of SY-1425 in Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome

NCT02807558

Description:

The purpose of this study is to determine the activity of SY-1425 in relapsed/refractory acute myeloid leukemia (AML) patients (SY-1425 administered as a monotherapy or in combination with azacitidine), relapsed/refractory higher-risk myelodysplastic syndrome (MDS) patients (SY-1425 administered as a monotherapy or in combination with daratumumab), newly diagnosed treatment naïve AML patients who are unlikely to tolerate standard intensive chemotherapy (SY-1425 administered as a monotherapy or in combination with azacitidine), or lower-risk myelodysplastic syndrome (MDS) patients (SY-1425 administered as a monotherapy).

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Biomarker-Directed Phase 2 Trial of SY-1425 in Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome
  • Official Title: A Biomarker-Directed Phase 2 Trial of SY-1425, a Selective Retinoic Acid Receptor Alpha Agonist, in Adult Patients With Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS)

Clinical Trial IDs

  • ORG STUDY ID: SY-1425-201
  • NCT ID: NCT02807558

Conditions

  • Acute Myeloid Leukemia
  • Myelodysplastic Syndrome

Interventions

DrugSynonymsArms
SY-1425 (tamibarotene)SY-1425 (tamibarotene)
azacitidineVidazaSY-1425 (tamibarotene) in combination with azacitidine
DaratumumabDarzalaxSY-1425 (tamibarotene) in combination with daratumumab

Purpose

The purpose of this study is to determine the activity of SY-1425 in relapsed/refractory acute myeloid leukemia (AML) patients, relapsed/refractory higher-risk myelodysplastic syndrome (MDS) patients (SY-1425 administered as a monotherapy or in combination with daratumumab), newly diagnosed treatment naïve AML patients who are unlikely to tolerate standard intensive chemotherapy (SY-1425 administered as a monotherapy or in combination with azacitidine), or lower-risk myelodysplastic syndrome (MDS) patients (SY-1425 administered as a monotherapy) who are positive for a RARA biomarker.

Detailed Description

      This is a phase 2, multi-center, open-label study exploring the activity of SY-1425 in
      patients with relapsed or refractory non-APL AML, relapsed or refractory higher-risk MDS,
      newly diagnosed treatment naïve AML, or transfusion dependent, lower-risk MDS. All patients
      must be positive for the RARA super-enhancer associated biomarker or RARA pathway biomarker
      at the time of the study screening evaluation. Patients will accrue to each of the five arms
      based on diagnosis, prior treatment, risk group, and investigator choice of treatment
      (SY-1425 single agent or in combination with azacitidine or daratumumab). SY-1425 will be
      administered at 6 mg/m2/day orally divided in two doses. SY-1425 will be given on a 28-day
      treatment cycle and dosing will be continuous. For those newly diagnosed treatment naïve AML
      patients receiving the combination of SY-1425 and azacitidine, azacitidine will be
      administered at 75 mg/m2/day IV or SC days 1-7, and SY-1425 will be administered at 6
      mg/m2/day orally divided in two doses days 8-28 on a 28-day treatment cycle. For those
      relapsed or refractory non-APL AML and relapsed or refractory higher-risk MDS patients
      receiving the combination of SY-1425 and daratumumab, SY-1425 daily dosing (dose level
      described above) will begin with a 7-day lead-in followed by continuous dosing on a 28-day
      treatment cycle. Daratumumab will be administered at a dose of 16 mg/kg starting on Cycle 1
      Day 1 weekly for 8 weeks (8 dose total), followed by dosing every 2 weeks for 16 weeks (8
      doses total), followed by dosing every 4 weeks.

      Dosing will continue unless: the patient experiences unacceptable toxicity, disease
      progression/relapse, pursues post-remission therapy other than SY-1425 (single agent or in
      combination with azacitidine or daratumumab), or the Investigator determines it is in the
      best interest of the patient to discontinue treatment. Newly diagnosed AML patients who
      achieve a CR/CRi or PR while on SY-1425 single agent treatment and then relapse, or who fail
      to achieve a CR/CRi or PR after completing at least 4 cycles of SY-1425 single agent
      treatment, are eligible to receive SY-1425 in combination with azacitidine.

      Lower-risk MDS patients will be withdrawn from the study at week 24 if they do not have at
      least a minor erythroid response. Lower-risk MDS patients who in the opinion of the
      investigator are receiving clinical benefit, but do not meet the minor erythroid response
      criteria can remain on study with sponsor approval. Lower-risk MDS patients who continue past
      week 24 will continue to receive treatment until erythroid relapse, disease progression, or
      unacceptable toxicity.

      An end of treatment visit will be conducted for all AML and higher-risk MDS patients within
      30 days of the last dose of study drug, but prior to the start of any subsequent therapies to
      monitor for safety and resolution of adverse events. For lower-risk MDS patients, the end of
      treatment visit will also be the end of study visit which will be conducted 30 days after the
      last dose of study drug. All AML and higher-risk MDS patients will be followed every three
      months for survival for up to 2 years and patients who are withdrawn prior to relapse will
      also follow-up for event free survival.
    

Trial Arms

NameTypeDescriptionInterventions
SY-1425 (tamibarotene)ExperimentalContinuous days 1-28 of a 28-day cycle of SY-1425 at 6mg/m2/day orally divided into twice a day dosing.
  • SY-1425 (tamibarotene)
SY-1425 (tamibarotene) in combination with azacitidineExperimentalSY-1425 days 8-28 of a 28-day cycle at 6mg/m2/day orally divided into twice a day dosing. Azacitidine 75 mg/m2/day IV or SC days 1-7 of a 28-day cycle in combination with SY-1425.
  • SY-1425 (tamibarotene)
  • azacitidine
SY-1425 (tamibarotene) in combination with daratumumabExperimentalSY-1425 during a 7-day lead-in and days 1-28 of a 28 day cycle at 6mg/m2/day orally divided into twice a day dosing. Daratumumab at 16 mg/kg/day IV starting on Cycle 1 Day 1 weekly for 8 weeks, followed by dosing every two weeks for 16 weeks, followed by dosing every 4 weeks in combination with SY-1425.
  • SY-1425 (tamibarotene)
  • Daratumumab

Eligibility Criteria

        Inclusion Criteria:

          1. Patients must be at least 18 years of age.

          2. Patients must have:

             a. Relapsed and/or refractory non-APL AML that has failed to achieve a complete
             remission (CR) or partial remission (PR) following standard induction therapy, or has
             relapsed after any duration of CR or PR i. Patients must have measurable disease with
             bone marrow blasts ≥5%at screening

             b. Relapsed and/or refractory higher-risk MDS (High / Very High Risk, as defined by
             the Revised International Prognostic Scoring System (IPSS-R)) that has failed to
             achieve a CR or PR, or any hematologic improvement (HI, per IWG 2006 criteria) after
             standard therapy with hypomethylating agents (e.g., azacitidine, decitabine), or has
             relapsed after any duration of CR or PR or HI i. Patients must have measurable disease
             with bone marrow blasts >5% at screening

             c. Newly diagnosed, treatment-naïve non-APL AML in patients who, at the time of study
             entry are unlikely to tolerate standard intensive chemotherapy due to age, performance
             status, or comorbidities based on at least one of the following criteria (Ferrara et
             al, 2013):

             i. Age ≥ 75 years old ii. Eastern Cooperative Oncology Group (ECOG) Performance Status
             (PS) of 3 iii. Cardiac history of congestive heart failure (CHF) or documented
             ejection fraction (EF) ≤ 50% iv. Pulmonary disease with DLCO ≤ 65% or FEVI ≤ 65% v.
             Creatinine clearance ≥ 30 mL/min to < 45 mL/min vi. Hepatic impairment with total
             bilirubin > 1.5 to ≤ 3.0 x upper limit of normal (ULN) vii. Any other comorbidity that
             the Investigator judges to be incompatible with intensive chemotherapy, and reviewed
             and approved by the Sponsor prior to enrollment

             d. Transfusion dependent lower-risk MDS without the del 5q abnormality, in patients
             refractory to erythropoietin treatment or unlikely to respond to erythropoietin
             treatment (EPO >500).

             i. Lower-risk MDS: Very Low /Low / Intermediate Risk, as defined by IPSS-R. ii.Red
             blood cell (RBC) transfusion dependent anemia defined as no eight consecutive weeks
             without RBC transfusions within the 16 weeks prior to study entry, or ≥4 RBC
             transfusions within the 8 weeks prior to study entry.

             iii.Refractory to or ineligible for ESAs is defined as RBC-Transfusion Dependence
             despite ESA treatment of ≥40,000 units/week recombinant human erythropoietin for 8
             weeks or an equivalent dose of darbepoetin (150 µg/week) or serum EPO level >500 mU/mL
             in patients not previously treated with ESAs.

          3. Patients must be positive for the RARA super-enhancer associated biomarker or RARA
             pathway associated biomarker at the time of study screening.

          4. Must be amenable to serial bone marrow aspirates and peripheral blood sampling during
             the study.

          5. ECOG Performance Status (PS) of 0, 1 or 2. For newly diagnosed AML patients < 75 years
             of age, ECOG 0-3; for ≥ 75 years of age, ECOG 0-2.

          6. Adequate organ function as defined by:

               1. Total bilirubin ≤ 1.5 x the upper limit of normal (ULN), unless suspected to have
                  Gilbert's disease. For newly diagnosed AML patients < 75 years of age, total
                  bilirubin ≤ 3 x ULN; for ≥ 75 years of age, total bilirubin ≤ 1.5 x ULN.

               2. ALT and AST ≤ 3 x ULN or ≤ 5 x ULN if documented liver infiltration with leukemia
                  cells

               3. Serum creatinine ≤ 2.0 x ULN or calculated creatinine clearance ≥ 45 mL/min based
                  on the Cockroft-Gault GFR estimation. For newly diagnosed AML patients < 75 years
                  of age, creatinine clearance ≥ 30 mL/min; for ≥ 75 years of age, creatinine
                  clearance ≥ 45 mL/min.

          7. Discontinued use of chemotherapy, radiation therapy, or growth factors for at least 2
             weeks prior to first study treatment, with the exception of hydroxyurea.

          8. No investigational agents within 2 weeks prior to first study treatment.

          9. No strong inducers of CYP3A4 (see Appendix 13.5) within 2 weeks prior to first study
             treatment.

         10. Resolved acute effects of any prior AML/MDS therapy to baseline or ≤ Grade 1 CTCAE
             severity.

         11. Serum/urine pregnancy test (for females of childbearing potential) that is negative at
             screening and immediately prior to initiation of treatment (first dose).

        Exclusion Criteria:

          1. Acute promyelocytic leukemia (APL, M3 subtype of AML) or patients with a t(9:22)
             cytogenetic translocation.

          2. Hyperleukocytosis (leukocytes ≥25 x 109/L) at study entry. These patients may be
             treated with hydroxyurea according to routine practice, and enroll in the study when
             the leukocyte count falls below 25 x 109/L.

          3. Patients known to be refractory to platelet or packed red cell transfusions per
             Institutional Guidelines, or a patient who refuses blood product support.

          4. Prior treatment with all-trans retinoic acid (ATRA) or systemic retinoid for the
             treatment of hematologic malignancy.

          5. SY-1425 and daratumumab combination only - Prior or concurrent exposure to daratumumab
             or other CD38 therapies5.

          6. SY-1425 and daratumumab combination only - Subject has either of the following:

               1. Known chronic obstructive pulmonary disease (COPD) with a forced expiratory
                  volume in 1 second (FEV1) <50% of predicted normal. Note that FEV1 testing is
                  required for subjects suspected of having COPD and subjects must be excluded if
                  FEV1 is <50% of predicted normal.

               2. Known moderate or severe persistent asthma within the past 2 years, or
                  uncontrolled asthma of any classification. Note that subjects who currently have
                  controlled intermittent asthma or controlled mild persistent asthma are allowed
                  to participate in the study.

          7. Patients with active malignancy (not including basal cell carcinoma, non-melanoma skin
             cancer, cervical carcinoma in situ, localized prostate cancer treated with hormone
             therapy). Patients with history of other cancers should be free of disease for at
             least 2 years.

          8. Patients with hypertriglyceridemia defined as >1000 mg/dL (CTCAE Grade 4).

          9. Patients with clinically significant cardiac disease including one of the following
             currently or in the previous 6 months: myocardial infarction, unstable cardiac
             function due to unstable angina or congestive heart failure, congenital long QT
             syndrome, torsades de pointes or significant ventricular arrhythmias .

         10. Patients with known active uncontrolled central nervous system (CNS) leukemia.

         11. Patients taking Vitamin A supplements (>10,000 IU/d) unless discontinued prior to
             first dose of study drug, or having hypervitaminosis A.

         12. Pregnant females; breastfeeding females; and males and females of childbearing
             potential not willing to use two highly effective methods of birth control, one being
             barrier method. Intrauterine Devices (IUD) and birth control pills are not barrier
             methods, but are highly effective especially when combined with a barrier method (e.g.
             latex condom or a diaphragm or cervical cap) while taking investigational product
             (SY-1425) and continuing contraception use for at least 90 days after the last dose of
             study drug. Men/women should not donate sperm or ova during this time frame.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR) in Relapsed/Refractory AML or Higher-Risk MDS patients treated with SY-1425 as a monotherapy.
Time Frame:Within 20 months
Safety Issue:
Description:Response to treatment assessed by the site investigators using International Working Group (IWG) response criteria

Secondary Outcome Measures

Measure:Event-free survival
Time Frame:Up to 30 months
Safety Issue:
Description:Time from first treatment until date of documentation of disease relapse following complete response/complete remission, or death, whichever comes first.
Measure:Relapse-free survival
Time Frame:Up to 30 months
Safety Issue:
Description:Time from first objective documentation of complete response/complete remission until the date of first objective documentation of disease relapse or death due to any cause, whichever occurs first.
Measure:Duration of response
Time Frame:Up to 20 months
Safety Issue:
Description:Time from first date of response (complete response/complete remission, partial response, or hematologic improvement) until date of relapse.
Measure:Overall survival
Time Frame:Up to 30 months
Safety Issue:
Description:Time from first treatment until death from any cause.
Measure:Hematologic Improvement
Time Frame:Within 20 months
Safety Issue:
Description:Hematologic response as measured by the site investigators using the modified International Working Group (IWG) response criteria
Measure:Proportion of patients requiring supportive measures
Time Frame:Up to 20 months
Safety Issue:
Description:Supportive measures secondary to cytopenias as measured by changes in transfusion rates, incidence and duration of use for growth factor support and antibiotics, and number of hospitalizations associated with febrile neutropenia and/or thrombocytopenic bleeding.
Measure:Number of patients with type, frequency, duration, and relatedness of adverse events.
Time Frame:Up to 20 months
Safety Issue:
Description:Includes changes in clinically significant clinical laboratory values, assessments of physical exams, vital signs, and electrocardiograms (ECGs).
Measure:Time to maximum plasma concentration (Tmax)
Time Frame:4 months
Safety Issue:
Description:
Measure:Peak Plasma Concentration (Cmax)
Time Frame:4 months
Safety Issue:
Description:
Measure:Trough plasma concentration (Cmin)
Time Frame:4 months
Safety Issue:
Description:
Measure:Area under the plasma concentration versus time curve (AUC)
Time Frame:4 months
Safety Issue:
Description:
Measure:Total body clearance from plasma (CL/F)
Time Frame:4 months
Safety Issue:
Description:
Measure:Terminal elimination half-life (t1/2)
Time Frame:4 months
Safety Issue:
Description:
Measure:Response Rate in patients who are positive for the RARA super-enhancer associated biomarker.
Time Frame:Within 20 months
Safety Issue:
Description:Response to treatment assessed by the site investigators using International Working Group (IWG) response criteria to determine overall response rate for AML and higher-risk MDS patients and transfusion-independence rate for lower-risk MDS patients
Measure:Response Rate in patients who are positive for the RARA pathway associated biomarker, and negative for the RARA super-enhancer associated biomarker
Time Frame:Within 20 months
Safety Issue:
Description:Response to treatment assessed by the site investigators using International Working Group (IWG) response criteria to determine overall response rate for AML and higher-risk MDS patients and transfusion-independence rate for lower-risk MDS patients
Measure:Overall Response Rate (ORR) in Relapsed/Refractory AML or Higher-Risk MDS patients treated with SY-1425 in combination with daratumumab
Time Frame:Within 20 months
Safety Issue:
Description:Response to treatment assessed by the site investigators using International Working Group (IWG) response criteria

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Syros Pharmaceuticals

Trial Keywords

  • AML
  • MDS

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