Clinical Trials /

A Basket Study of Novel Therapy for Untreated MDS/MPN and Relapsed/Refractory Overlap Syndromes (ABNL-MARRO)

NCT04061421

Description:

ABNL-MARRO (A Basket study of Novel therapy for untreated MDS/MPN and Relapsed/Refractory Overlap Syndromes) is an international European-American cooperation providing the framework for collaborative studies to advance treatment of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) and explore clinical-pathologic markers of disease severity, prognosis and treatment response. ABNL MARRO 001 (AM-001) is an Open label, randomized phase 1/2 study within the framework of the ABNL-MARRO that will test novel treatment combinations in MDS/MPN. Each Arm of AM-001 will test an active myeloid target compound in combination with ASTX727, an oral drug combining fixed doses of the DNA methyltransferase inhibitor (DNMTi) decitabine and the cytidine deaminase inhibitor E7727, also known as cedazuridine in a single tablet.

Related Conditions:
  • Myelodysplastic/Myeloproliferative Neoplasm
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Basket Study of Novel Therapy for Untreated MDS/MPN and Relapsed/Refractory Overlap Syndromes (ABNL-MARRO)
  • Official Title: ABNL-MARRO (A Basket Study of Novel Therapy for Untreated MDS/MPN and Relapsed/Refractory Overlap Syndromes) - The ABNL-MARRO 001 Study: A Randomized Phase 1/2 Study of Active Myeloid Target Compound Combinations in MDS/MPN

Clinical Trial IDs

  • ORG STUDY ID: VICC HEMP 1977
  • NCT ID: NCT04061421

Conditions

  • MDS/MPN

Interventions

DrugSynonymsArms
INCB053914ASTX727 + INCB053914
ASTX727Fixed dose combination of cedazuridine (100mg) + oral decitabine (35mg)ASTX727 + itacitinib
ItacitinibINCB039110ASTX727 + itacitinib
INCB059872ASTX727 + INCB059872

Purpose

ABNL-MARRO (A Basket study of Novel therapy for untreated MDS/MPN and Relapsed/Refractory Overlap Syndromes) is an international European-American cooperation providing the framework for collaborative studies to advance treatment of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) and explore clinical-pathologic markers of disease severity, prognosis and treatment response. ABNL MARRO 001 (AM-001) is an Open label, randomized phase 1/2 study within the framework of the ABNL-MARRO that will test novel treatment combinations in MDS/MPN. Each Arm of AM-001 will test an active myeloid target compound in combination with ASTX727, an oral drug combining fixed doses of the DNA methyltransferase inhibitor (DNMTi) decitabine and the cytidine deaminase inhibitor E7727, also known as cedazuridine in a single tablet.

Detailed Description

      AM-001 is the first clinical study to be conducted within the infrastructure of ABNL MARRO in
      conjunction with the MDS/MPN IWG. AM-001 will include three treatment Arms. Each Arm tests
      ASTX727 in combination with a novel targeted agent. Additional Arms may be added as new
      treatment compounds/alternative treatment combinations complete safety testing in Phase 1
      studies in myeloid diseases.

      Current Arms of AM-001 include: Arm 1: ASTX727 + itacitinib (INCB039110; JAK1 inhibitor); Arm
      2: ASTX727 + INCB053914 (Pan-PIM inhibitor); Arm 3: ASTX727 + INCB059872 (LSD1 inhibitor)

      Primary Objective Phase 1:

      - Characterize the dose-limiting toxicities (DLTs) of each novel oral targeted agent in
      combination with oral ASTX727 in order to determine the recommended phase 2 dose (RP2D) and
      schedule.

      Primary Objective Phase 2:

      - To test whether the overall response to each novel ASTX727 combination therapy in MDS/MPN
      patients is sufficiently high to warrant further investigation in more definitive trials.

      Secondary Objectives:

        -  To expand the safety analysis of each treatment combination in MDS/MPN patients.

        -  To assess the morphologic bone marrow response in MDS/MPN patients treated on each Arm
           of the study.

        -  To estimate the effect of each treatment combination on patient survival

        -  To test the applicability of the proposed MDS/MPN IWG response criteria across multiple
           Arms of this study.

      Tertiary/Exploratory objectives:

        -  To investigate genetic biomarkers of response in MDS/MPN.

        -  To characterize molecular responses to individual treatments.

        -  To evaluate synergistic effects of hypomethylation by ASTX727 and specific pathway
           blockade by study compounds.

        -  To explore the use of automated quantification of spleen volume from CT exams as a
           measure of clinical benefit

        -  To test and/or validate diagnostic algorithms and prognostic indices for MDS/MPN
           patients

        -  To investigate the correlation of patient reported outcomes with disease severity and/or
           treatment response
    

Trial Arms

NameTypeDescriptionInterventions
ASTX727 + itacitinibExperimentalASTX727 and itacitinib will be taken by mouth
  • ASTX727
  • Itacitinib
ASTX727 + INCB053914ExperimentalASTX727 and INCB053914 will be taken by mouth
  • INCB053914
  • ASTX727
ASTX727 + INCB059872ExperimentalASTX727 and INCB059872 will be taken by mouth
  • ASTX727
  • INCB059872

Eligibility Criteria

        Inclusion Criteria:

          -  Must be ≥ 18 years of age at the time of signing the Informed Consent Form (ICF); must
             voluntarily sign an ICF; and must be willing and able to meet all study requirements.

          -  Must have morphologically confirmed diagnosis of MDS/MPN, excluding JMML, in
             accordancewith WHO (2016) diagnostic criteria.

          -  Treatment-naïve patients (patients who have had no prior disease-modifying therapy)
             may enroll in any AM-001 Arm that is open to accrual in phase 1 or phase 2.
             Treatment-naïve patients may have received recombinant erythropoietin, danazol,
             hydroxyurea or anagrelide, which are not considered to be disease-modifying therapy
             for the purpose of this study.

          -  After an appropriate wash-out period, patients who have failed (or were intolerant to)
             prior therapy with a regimen(s) containing a DNMTi may enroll in any Arm in phase 1b
             or any Arm which has met the criterion of the first Simon's Stage and are open to
             accrual in the second Simon's Stage in phase 2. Except in the first stage of the phase
             2, there are no limits on number of prior therapies if the patient meets all other
             eligibility criteria. Previously treated patients include:

               -  Patients treated with DNMTi therapy prior to enrollment in AM-001 who failed to
                  achieve a complete remission, per the MDS/MPN IWG response criteria, after at
                  least 4 cycles of DNMTi therapy

               -  ;Patients enrolled in AM-001, or patients treated off-study with a regimen
                  containing a DNMTi, who have definitive disease progression as defined in the
                  protocol after at least 2 cycles of the prior therapy—this includes patients who
                  fail to achieve a response with clearly progressive disease and patients who
                  achieve an initial response who then lose that response;

               -  Patients enrolled in AM-001 who have stable disease as best response at the
                  second response evaluation after 6 cycles of the prior AM-001 therapy;

               -  Patients treated on AM-001 who had and recovered from an adverse event that
                  precludes further therapy on that Arm; after recovery from a toxicity that is
                  likely to be related to ASTX727, enrollment in another AM-001 may occur provided
                  that dose modifications are made as appropriate.

          -  Must be willing to undergo bone marrow biopsy with aspiration during screening and
             bone marrow aspiration with tissue collection for disease assessment and correlative
             studies periodically throughout the trial.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.

          -  Life expectancy of at least 3 months, as assessed by the treating physician.

          -  For previously treated patients, recovery to ≤ Grade 1 or baseline of any toxicities
             due to prior systemic treatments, excluding alopecia.

          -  Must have adequate hepatic and renal function during screening as demonstrated by:

               -  ALT (SGPT) and AST (SGOT) ≤ 3x the institutional upper limit of normal (ULN);

               -  Total bilirubin ≤ 1.5x ULN or ≤ 2x ULN, if upon judgment of the treating
                  investigator the elevated bilirubin is due to extramedullary hematopoiesis
                  related to the underlying MDS/MPN or to Gilbert's disease;

               -  Creatinine < 1.5x ULN or estimated creatinine clearance (eCCR) >/=40
                  ml/min/1.73m2 Patients must have eCCR >/= 60ml/min/1.73m2 to enter into the
                  INCB59872 arm. eCCR may be calculated using the standard institutional formula.
                  The estimation tool/formula employed and result must be declared in the case
                  report form (CRF).

        Exclusion Criteria:

          -  Patients should be excluded from any treatment Arm that includes a novel targeted
             agent to which they ave had previous exposure. Novel targeted agents in this study
             include itacitinib (INCB039110), INCB053914, and INCB059872. Patients who have had
             prior exposure to ASTX727 therapy are not excluded, provided they meet all other
             eligibility criteria.

          -  Prior receipt of any investigational study drug, including treatment on any prior
             AM-001 Arm, within 30 days or 5 half-lives (whichever is longer) before receiving the
             first dose of study drug in an Arm of AM-001, except if approved by the medical
             monitor.

          -  Prior receipt of any systemic antineoplastic therapy, including but not limited to
             prior DNMTi therapy, standard induction or cytotoxic chemotherapy (excluding
             hydroxyurea), or approved targeted agent within 21 days or 5 half-lives (whichever is
             longer) before receiving the first dose of study drug in an Arm of AM-001.

          -  Known hypersensitivity to decitabine.

          -  Transformation to acute myeloid leukemia (e.g. >20% myeloid blasts in bone marrow or
             >20% circulating blasts in peripheral blood).

          -  Organ transplant recipients including allogeneic hematopoietic stem cell transplant
             (HSCT).

          -  History of clinically significant or uncontrolled cardiac disease, including recent
             history (within 6 months) of unstable angina, acute myocardial infarction, New York
             Heart Association Class III or IV congestive heart failure, or clinically significant
             arrhythmia. Patients with history of atrial tachycardia and/or bradycardia that is
             well-controlled with medical management and/or pacemaker for at least 1 month before
             the first dose of study drug will be allowed.

          -  History of abnormal EKG or presence of abnormal screening EKG that, in the
             investigator's opinion, is clinically significant and contraindicated for clinical
             study. Corrected QT interval (QTc), as corrected by Fredericia, on screening EKG >500
             milliseconds is excluded, unless there is concomitant right bundle branch block (RBBB)
             or concomitant left bundle branch block (LBBB) with a pacemaker.

          -  Any known contraindications to the use of ASTX727.

          -  Any sign of active and clinically significant bleeding.

          -  Other active malignancy, not including localized non-melanoma skin cancer, cervical
             carcinoma in situ, breast ductal carcinoma in situ of the breast, or localized
             prostate cancer controlled with hormone therapy. Patients with history of other
             cancers should be free of disease without ongoing anti-neoplastic therapy for at least
             2 years.

          -  Receipt of wide-field radiotherapy (including therapeutic radioisotopes) ≤ 28 days or
             limited field radiation for palliation ≤ 14 days prior to starting study medications;
             or has not recovered from side effects of such therapy.

          -  Patients who require continuation of a prohibited concomitant medication for which no
             alternative therapy or allowable substitute is available.

          -  Active, uncontrolled infection. Patients with infection that is under control with
             active treatment are eligible.

          -  Major surgery requiring general anesthesia within 4 weeks prior to starting study
             treatment.(Placement of a central line or port-a-catheter is acceptable within this
             time frame and does not exclude the patient.)

          -  Women who are pregnant or lactating.

          -  Subjects who expect to conceive or father children within the projected duration of
             the study and/or who are unwilling to use highly effective methods of contraception
             throughout the duration of the study, starting with the screening visit through the
             end of treatment visit. For women of child-bearing potential (WOCBP), a negative urine
             pregnancy test at screening and immediately prior to initiating treatment on any
             AM-001 treatment Arm (Cycle 1 Day 1) is required.

          -  Any concurrent serious or unstable medical or psychiatric condition that in the
             investigator's opinion would jeopardize the patient's ability to provide informed
             consent or to comply with the protocol.

          -  Any psychological, familial, geographical or sociological condition that in the
             investigator's opinion would jeopardize the patient's ability to comply with the
             protocol.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended phase 2 dose (phase 1)
Time Frame:Up to 28 days
Safety Issue:
Description:Per CTCAE 5.0

Secondary Outcome Measures

Measure:Number of participants with treatment-related adverse events as assessed by CTCAE 5.0
Time Frame:Up to 28 days
Safety Issue:
Description:
Measure:Morphologic bone marrow response
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Effect of each treatment combination on patient survival
Time Frame:Up to 2 years
Safety Issue:
Description:PFS
Measure:Effect of each treatment combination on patient survival
Time Frame:Up to 2 years
Safety Issue:
Description:OS
Measure:Applicability of the proposed MDS/MPN IWG response criteria across multiple Arms of this study.
Time Frame:Up to 2 years
Safety Issue:
Description:Validation of MDS/MPN IWG Proposed Response Criteria (Savona et al, Blood 2015)

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Michael Savona

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