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

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ClinicalTrials.gov Identifier: NCT04061421
Recruitment Status : Not yet recruiting
First Posted : August 19, 2019
Last Update Posted : December 18, 2019
Sponsor:
Collaborators:
Incyte Corporation
Theradex
Astex Pharmaceuticals, Inc.
Information provided by (Responsible Party):
Michael Savona, Vanderbilt-Ingram Cancer Center

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
MDS/MPN Drug: INCB053914 Drug: ASTX727 Drug: Itacitinib Drug: INCB059872 Phase 1 Phase 2

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 159 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Estimated Study Start Date : January 15, 2020
Estimated Primary Completion Date : April 2023
Estimated Study Completion Date : April 2024


Arm Intervention/treatment
Experimental: ASTX727 + itacitinib
ASTX727 and itacitinib will be taken by mouth
Drug: ASTX727
Taken by mouth daily during days 1-5 of every 28-day cycle.
Other Name: Fixed dose combination of cedazuridine (100mg) + oral decitabine (35mg)

Drug: Itacitinib
Taken by mouth daily during each 28-day cycle
Other Name: INCB039110

Experimental: ASTX727 + INCB053914
ASTX727 and INCB053914 will be taken by mouth
Drug: INCB053914
Taken by mouth twice daily during each 28-day cycle

Drug: ASTX727
Taken by mouth daily during days 1-5 of every 28-day cycle.
Other Name: Fixed dose combination of cedazuridine (100mg) + oral decitabine (35mg)

Experimental: ASTX727 + INCB059872
ASTX727 and INCB059872 will be taken by mouth
Drug: ASTX727
Taken by mouth daily during days 1-5 of every 28-day cycle.
Other Name: Fixed dose combination of cedazuridine (100mg) + oral decitabine (35mg)

Drug: INCB059872
Taken by mouth daily during each 28-day cycle




Primary Outcome Measures :
  1. Recommended phase 2 dose (phase 1) [ Time Frame: Up to 28 days ]
  2. Dose-limiting toxicity (phase 1) [ Time Frame: Up to 28 days ]
    Per CTCAE 5.0

  3. Overall response (phase 2) [ Time Frame: Up to 2 years ]
    As per Modified MDS/MPN IWG Proposed Response Criteria (Savona et al, Blood 2015)


Secondary Outcome Measures :
  1. Number of participants with treatment-related adverse events as assessed by CTCAE 5.0 [ Time Frame: Up to 28 days ]
  2. Morphologic bone marrow response [ Time Frame: Up to 2 years ]
  3. Effect of each treatment combination on patient survival [ Time Frame: Up to 2 years ]
    PFS

  4. Effect of each treatment combination on patient survival [ Time Frame: Up to 2 years ]
    OS

  5. Applicability of the proposed MDS/MPN IWG response criteria across multiple Arms of this study. [ Time Frame: Up to 2 years ]
    Validation of MDS/MPN IWG Proposed Response Criteria (Savona et al, Blood 2015)



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:

  • 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.

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): NCT04061421


Contacts
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Contact: Theradex Oncology US Inquiry 609.799.7580 info@theradex.com
Contact: Theradex Oncology EU Inquiry +44 (0)1293 510 319 enquiry@theradex.co.uk

Locations
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United States, Tennessee
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States, 37232
Contact: Vanderbilt-Ingram Service Information Program    800-811-8480    cip@vumc.org   
Principal Investigator: Michael Savona, MD         
Sponsors and Collaborators
Michael Savona
Incyte Corporation
Theradex
Astex Pharmaceuticals, Inc.
Investigators
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Study Chair: Michael Savona, MD Vanderbilt-Ingram Cancer Center
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Responsible Party: Michael Savona, Sponsor Investigator, Vanderbilt-Ingram Cancer Center
ClinicalTrials.gov Identifier: NCT04061421    
Other Study ID Numbers: VICC HEMP 1977
First Posted: August 19, 2019    Key Record Dates
Last Update Posted: December 18, 2019
Last Verified: December 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
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Myelodysplastic-Myeloproliferative Diseases
Undifferentiated Connective Tissue Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Bone Marrow Diseases
Hematologic Diseases
Decitabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors