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Clinical Trial
. 2022 Sep 24;22(1):1013.
doi: 10.1186/s12885-022-10073-w.

The ABNL-MARRO 001 study: a phase 1-2 study of randomly allocated active myeloid target compound combinations in MDS/MPN overlap syndromes

Tamara K Moyo  1   2 , Jason H Mendler  3 , Raphael Itzykson  4 , Ashwin Kishtagari  1 , Eric Solary  5 , Adam C Seegmiller  1 , Aaron T Gerds  6 , Gregory D Ayers  1 , Amy E Dezern  7 , Aziz Nazha  6 , Peter Valent  8   9 , Arjan A van de Loosdrecht  10 , Francesco Onida  11 , Lisa Pleyer  12   13 , Blanca Xicoy Cirici  14 , Raoul Tibes  15 , Klaus Geissler  16 , Rami S Komrokji  17 , Jing Zhang  18 , Ulrich Germing  19 , David P Steensma  20 , Daniel H Wiseman  21 , Michael Pfeilstöecker  22 , Chiara Elena  23 , Nicholas C P Cross  24 , Jean-Jacques Kiladjian  25 , Michael Luebbert  26 , Ruben A Mesa  27 , Guillermo Montalban-Bravo  28 , Guillermo F Sanz  29 , Uwe Platzbecker  30 , Mrinal M Patnaik  31 , Eric Padron  17 , Valeria Santini  32 , Pierre Fenaux  4 , Michael R Savona  33 ; MDS/MPN International Working Group
Affiliations
Clinical Trial

The ABNL-MARRO 001 study: a phase 1-2 study of randomly allocated active myeloid target compound combinations in MDS/MPN overlap syndromes

Tamara K Moyo et al. BMC Cancer. .

Abstract

Background: Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) comprise several rare hematologic malignancies with shared concomitant dysplastic and proliferative clinicopathologic features of bone marrow failure and propensity of acute leukemic transformation, and have significant impact on patient quality of life. The only approved disease-modifying therapies for any of the MDS/MPN are DNA methyltransferase inhibitors (DNMTi) for patients with dysplastic CMML, and still, outcomes are generally poor, making this an important area of unmet clinical need. Due to both the rarity and the heterogeneous nature of MDS/MPN, they have been challenging to study in dedicated prospective studies. Thus, refining first-line treatment strategies has been difficult, and optimal salvage treatments following DNMTi failure have also not been rigorously studied. ABNL-MARRO (A Basket study of Novel therapy for untreated MDS/MPN and Relapsed/Refractory Overlap Syndromes) is an international cooperation that leverages the expertise of the MDS/MPN International Working Group (IWG) and provides the framework for collaborative studies to advance treatment of MDS/MPN and to explore clinical and pathologic markers of disease severity, prognosis, and treatment response.

Methods: ABNL MARRO 001 (AM-001) is an open label, randomly allocated phase 1/2 study that will test novel treatment combinations in MDS/MPNs, beginning with the novel targeted agent itacitinib, a selective JAK1 inhibitor, combined with ASTX727, a fixed dose oral combination of the DNMTi decitabine and the cytidine deaminase inhibitor cedazuridine to improve decitabine bioavailability.

Discussion: Beyond the primary objectives of the study to evaluate the safety and efficacy of novel treatment combinations in MDS/MPN, the study will (i) Establish the ABNL MARRO infrastructure for future prospective studies, (ii) Forge innovative scientific research that will improve our understanding of pathogenetic mechanisms of disease, and (iii) Inform the clinical application of diagnostic criteria, risk stratification and prognostication tools, as well as response assessments in this heterogeneous patient population.

Trial registration: This trial was registered with ClinicalTrials.gov on August 19, 2019 (Registration No. NCT04061421).

Keywords: ABNL MARRO; ASTX727; Itacitinib; MDS/MPN; Phase 1b/2.

PubMed Disclaimer

Conflict of interest statement

Tamara K. Moyo:

None

Jason Mendler:

None

Raphaël Itzykson:

Research Funding Janssen Novartis, Abbvie

Honoraria: Abbvie, Amgen, Astellas, BMS/Celgene, Daiichi-Sankyo, Jazz, Karyopharm, Servier

Consulting: Abbvie, Amgen, Novartis, Otsuka Pharma, Jazz Pharmaceuticals, Karyopharm, StemLine.

Ashwin Kishtagari:

None

Eric Solary:

Advisor: Stemline therapeutics.

Adam Seegmiller:

None

Aaron T. Gerds:

Consulting/Advisory: Celgene (Bristol-Myers Squibb), Pfizer, Kartos Therapeutics, CTI Biopharma, Promedior.

Research funding: Roche, Celgene (Bristol-Myers Squibb), Incyte, Imago Biosciences.

Gregory D. Ayers:

None

Amy E. DeZern:

Consulting honoraria from Abbie, Taiho, Novartis.

Aziz Nazha:

Amazon (own stocks).

Speaker Bureau: Incyte Corporation, Novartis.

Data monitoring committee: MEI Pharma.

Advisory Board / Consulting (pharmaceutical/biotechnology): Karyopharma, Abbvie, Daiichi Sankyo.

Peter Valent:

COI—study related: no.

COI—unrelated to this study: P.V. received honoraria from Celgene/BMS, Novartis, AOP Orphan Pharmaceuticals, Pfizer, and Incyte.

Arjan A. van de Loosdrecht:

None

Francesco Onida:

None.

Lisa Pleyer:

Honoraria from AbbVie, Agios, Bristol Myers Squibb (BMS), Celgene, Inflection Point Biomedical Advisors, and Novartis.

Blanca Xicoy Cirici:

None

Raoul Tibes:

Employment: AstraZeneca.

Klaus Geissler:

Speaker and Consultancy Honoraria: Abbvie, Celgene, Novartis.

Rami S. Komrokji:

Speaker bureau: JAZZ, BMS.

Honoraria/consulting: Jazz, BMS, Geron, Abbvie, Acceleron, Novartis.

Jing Zhang:

None

Ulrich Germing:

Speakers Honoraria: Celgene, Jazz, Novartis, Janssen.

Institutional Research Support: Celgene, Novartis.

David P. Steensma:

Employment: Novartis.

Daniel H. Wiseman:

Research funding: Astex.

Speaker/consultancy honoraria: Novartis, StemLine, Takeda, Celgene.

Michael Pfeilstoecker:

Speaker and Consultancy Honoraria: Abbvie, Astellas, Takeda, Celgene, and Novartis.

Chiara Elena:

Advisory boards for Novartis, Pfizer, Gilead.

Nicholas C.P. Cross:

Novartis: consultancy and research support; Incyte: consultancy.

Jean-Jacques Kiladjian:

Novartis, Celgene, Abbvie, AOP Orphan: advisory boards.

Michael Lübbert:

Research Support: Janssen, Cheplapharm, TEVA.

Travel Support: Janssen.

Ruben Mesa:

Consultant: Novartis, Sierra Oncology, La Jolla, Samus.

Research Support – Incyte, CTI, Celgene, Abbvie, Imago.

Guillermo Montelban-Bravo:

None

Guillermo F. Sanz:

Honoraria: Celgene.

Consulting or Advisory Role: Roche, Novartis, Takeda, Boehringer Ingelheim, Abbvie, Helsinn Healthcare, Amgen, Celgene, Janssen.

Uwe Platzbecker:

Received honoraria and research funding from Celgene, Janssen, Jazz, Novartis and Amgen.

Mrinal M. Patnaik:

Advisory board for Kura Oncology and Stem Line therapeutics.

Eric Padron:

Research funding: Kura Oncology, Incyte Corporation, and BMS, and serves as a consultant for Taiho Oncology and Blueprint Medicines.

Valeria Santini:

Honoraria: Celgene/Bristol-Myers Squibb, Novartis, Janssen-Cilag.

Consulting or Advisory Role: Celgene/Bristol-Myers Squibb, Novartis, Menarini, Takeda, Pfizer, Geron, Gilead Sciences.

Research Funding: Celgene.

Travel, Accommodations, Expenses: Janssen-Cilag, Celgene.

Pierre Fenaux:

Research support, as GFM chairperson, from AbbVie, Celgene, Janssen, Novartis.

Michael R. Savona:

Research funding from ALX Oncology, Astex, Incyte, Takeda and TG Therapuetics; consults or serves on advisory or DSMB for AbbVie, BMS, Forma, Geron, Karyopharm, Novartis, Ryvu, Sierra Oncology, Taiho, Takeda, TG Therapeutics; and has equity in Karyopharm and Ryvu.

Figures

Fig. 1
Fig. 1
Study Design. Once the RP2D and schedule has been determined for a given treatment in the phase 1b, that treatment arm may enter phase 2, which will follow a Simon Two-Stage design. Stage 1 of the phase 2 will include treatment-naïve MDS/MPN patients only. If sufficient efficacy is demonstrated in treatment-naïve patients to proceed to Stage 2 of the phase 2, then patients who have failed or were intolerant to DNMTi-containing regimens, including treatment on other AM-001 arms or prior to enrolling in the study, will also be included. Eligible patients will be randomly allocated to AM-001 arms that are actively accruing and to which they have not had prior exposure. In Stage 2, patients will be stratified based on treatment status (e.g. treatment-naïve vs relapsed/refractory/intolerant)
See this image and copyright information in PMC

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