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    DRUG:

    Amnolake (tamibarotene)

    i
    Other names: SY-1425, INNO 507, RR 110, TM‑411, TOS-80T, Z-208, OMS0728, AM‑80, OP-09, NSC-608000
    Company:
    Nippon Shinyaku, Ohara Pharma, RaQualia, Syros, Zeria Pharma
    Drug class:
    RARα agonist
    3ms
    SELECT-AML-1: Tamibarotene Plus Venetoclax/Azacitidine in Participants With Newly Diagnosed AML (clinicaltrials.gov)
    P2, N=95, Active, not recruiting, Syros Pharmaceuticals | Recruiting --> Active, not recruiting
    Enrollment closed • Combination therapy
    |
    Venclexta (venetoclax) • azacitidine • Amnolake (tamibarotene)
    7ms
    Synergistic Effects of the RARalpha Agonist Tamibarotene and the Menin Inhibitor Revumenib in Acute Myeloid Leukemia Cells with KMT2A Rearrangement or NPM1 Mutation. (PubMed, Cancers (Basel))
    The impact of revumenib on KMT2Ar or NPM1c AML cells was significantly enhanced when combined with tamibarotene, demonstrating synergistic differentiation or apoptosis initiation. These findings propose promising strategies for relapsed/refractory AML patients with defined molecular characteristics.
    Journal
    |
    NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A) • RARA (Retinoic Acid Receptor Alpha) • CDK6 (Cyclin-dependent kinase 6) • CEBPA (CCAAT Enhancer Binding Protein Alpha)
    |
    NPM1 mutation • KMT2A rearrangement • MLL rearrangement
    |
    revumenib (SNDX-5613) • Amnolake (tamibarotene)
    8ms
    A Case of Relapsed/Refractory CD56-Positive Acute Promyelocytic Leukemia, in Which Complete Molecular Remission Was Achieved Following Combination Therapy with Venetoclax and Azacitidine. (PubMed, Gan To Kagaku Ryoho)
    In August Year X-1, she developed molecular relapse and was started on tamibarotene(Am80). She died of gastrointestinal hemorrhage. This is considered a valuable case for accumulating information on the treatment of CD56-positive APL resistant to ATRA and ATO.
    Journal • Combination therapy
    |
    RARA (Retinoic Acid Receptor Alpha) • NCAM1 (Neural cell adhesion molecule 1)
    |
    NCAM1 positive
    |
    Venclexta (venetoclax) • azacitidine • Amnolake (tamibarotene)
    9ms
    SY-1425-202: Tamibarotene Plus Venetoclax/Azacitidine in Participants With Newly Diagnosed AML (clinicaltrials.gov)
    P2, N=95, Recruiting, Syros Pharmaceuticals | Trial completion date: Apr 2024 --> Apr 2028 | Trial primary completion date: Apr 2024 --> Apr 2028
    Trial completion date • Trial primary completion date • Combination therapy
    |
    RARA positive
    |
    Venclexta (venetoclax) • azacitidine • Amnolake (tamibarotene)
    9ms
    SELECT MDS-1: Tamibarotene Plus Azacitidine in Participants With Newly Diagnosed RARA-positive Higher-Risk Myelodysplastic Syndrome (clinicaltrials.gov)
    P3, N=550, Recruiting, Syros Pharmaceuticals | Trial primary completion date: Dec 2023 --> Nov 2024
    Trial primary completion date
    |
    RARA positive
    |
    azacitidine • Amnolake (tamibarotene)
    10ms
    A Biomarker-Directed Phase 2 Trial of Tamibarotene (SY-1425) in Participants With Acute Myeloid Leukemia or Myelodysplastic Syndrome (clinicaltrials.gov)
    P2, N=155, Completed, Syros Pharmaceuticals | Active, not recruiting --> Completed
    Trial completion
    |
    azacitidine • Darzalex (daratumumab) • Amnolake (tamibarotene)
    1year
    Phase I/II Study of SY-1425 (Tamibarotene) in Combination With Azacitidine and Venetoclax for Patients With Chronic Myelomonocytic Leukemia (clinicaltrials.gov)
    P1/2, N=0, Withdrawn, M.D. Anderson Cancer Center | Not yet recruiting --> Withdrawn
    Trial withdrawal • Combination therapy
    |
    Venclexta (venetoclax) • azacitidine • Amnolake (tamibarotene)
    1year
    Phase I/II Study of SY-1425 (Tamibarotene) in Combination With Azacitidine and Venetoclax for Patients With Chronic Myelomonocytic Leukemia (clinicaltrials.gov)
    P1/2, N=52, Not yet recruiting, M.D. Anderson Cancer Center
    New P1/2 trial • Combination therapy
    |
    Venclexta (venetoclax) • azacitidine • Amnolake (tamibarotene)
    over1year
    Use of tamibarotene, a potent and selective RARα agonist, in combination with azacitidine in patients with relapsed and refractory AML with RARA gene overexpression. (PubMed, Leuk Lymphoma)
    In 21 response-evaluable patients, the complete remission/complete remission with incomplete hematologic recovery (CR/CRi) rate was 19%, and median time to initial CR/CRi was 1.2 months. The favorable safety profile and preliminary clinical activity support the development of combination therapies with tamibarotene in myeloid malignancies with RARA overexpression.
    Journal • Combination therapy
    |
    RARA (Retinoic Acid Receptor Alpha)
    |
    RARA overexpression
    |
    azacitidine • Amnolake (tamibarotene)
    over1year
    The Promise of Retinoids in the Treatment of Cancer: Neither Burnt Out Nor Fading Away. (PubMed, Cancers (Basel))
    Since the introduction of all-trans retinoic acid (ATRA), acute promyelocytic leukemia (APL) has become a highly curable malignancy, especially in combination with arsenic trioxide (ATO)...Furthermore, recent super-enhancer (SE) analysis has identified a novel AML subgroup characterized by high expression of RARα through strong SE levels in the gene locus and increased sensitivity to tamibarotene. Combined with a hypomethylating agent, synthetic retinoids have shown synergistic anti-leukemic effects in non-APL AML preclinical models and are now being studied in phase II and III clinical trials.
    Review • Journal
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    RARA (Retinoic Acid Receptor Alpha) • CYP26A1 (Cytochrome P450 Family 26 Subfamily A Member 1)
    |
    Vesanoid (tretinoin) • arsenic trioxide • Amnolake (tamibarotene)
    over1year
    Tamibarotene targets heparin-binding protein for attenuating lung injury in sepsis. (PubMed, Allergol Immunopathol (Madr))
    These findings demonstrated that tamibarotene lessens sepsis-induced lung injury, and the effect could be exerted by targeting HBP and thereby deregulating the NF-κB signaling pathway.
    Journal
    |
    IL6 (Interleukin 6) • TNFA (Tumor Necrosis Factor-Alpha) • IL17A (Interleukin 17A) • IL1B (Interleukin 1, beta)
    |
    Amnolake (tamibarotene)
    over1year
    Acyclic retinoid peretinoin reduces hemorrhage-associated brain injury in vitro and in vivo. (PubMed, Eur J Pharmacol)
    On the other hand, nuclear factor-κB (NF-κB) inhibitors such as pyrrolidine dithiocarbamate (50 μM) and Bay11-7082 (10 μM) prevented thrombin-induced shrinkage of the striatal region...We also found that daily administration of peretinoin reduced histopathological injury and alleviated motor deficits in a mouse model of intracerebral hemorrhage. These results indicate that NR1B agonists including peretinoin may serve as a therapeutic option for hemorrhagic brain injury.
    Preclinical • Journal
    |
    Amnolake (tamibarotene) • Bay11-7082 • peretinoin (K-333)
    over1year
    AML AND MDS WITH RARA OVEREXPRESSION: MOLECULAR AND CLINICAL FEATURES OF PATIENTS ENROLLED IN A PHASE 2 TRIAL EVALUATING TAMIBAROTENE-BASED THERAPY (EHA 2023)
    AML and MDS with RARA overexpression present with molecular features similar to those described in published datasets. Notably, SRSF2 was the most common mutation in the ND older unfit AML cohort, consistent withpublished series. While the small number of RARA -positive MDS patients precludes definitive characterization of molecular profiles, data in AML patients suggest that RARA overexpression may be agnostic to known molecular features.
    P2 data • Clinical
    |
    TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • ETV6 (ETS Variant Transcription Factor 6) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • RARA (Retinoic Acid Receptor Alpha) • SRSF2 (Serine and arginine rich splicing factor 2) • BCOR (BCL6 Corepressor) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • STAG2 (Stromal Antigen 2)
    |
    SRSF2 mutation • U2AF1 mutation • RARA overexpression • RARA positive
    |
    Oncomine Myeloid Assay GX
    |
    Venclexta (venetoclax) • azacitidine • Amnolake (tamibarotene)
    over1year
    RARA-positive AML is a Novel Patient Subset with an Actionable Target for Treatment with SY-1425, an Oral, Selective RARα Antagonist (IASL 2023)
    No abstract available
    Clinical
    |
    RARA (Retinoic Acid Receptor Alpha)
    |
    RARA positive
    |
    Amnolake (tamibarotene)
    almost2years
    Targeting RARA Overexpression with Tamibarotene, a Potent and Selective RARα Agonist, is a Novel Approach in AML. (PubMed, Blood Adv)
    The combination of oral tamibarotene plus azacitidine was evaluated in a Phase 2 clinical study in 51 newly diagnosed unfit AML patients identified as RARA-positive (N = 22) or RARA-negative (N = 29) for RARA mRNA overexpression in peripheral blasts with a blood-based biomarker test. These results support further evaluation of tamibarotene-based treatment strategies in AML and MDS patients with RARA overexpression to provide a targeted approach with the goal of improving patient outcomes. This trial is registered at www.clinicaltrials.gov as NCT02807558.
    Journal
    |
    RARA (Retinoic Acid Receptor Alpha)
    |
    RARA overexpression • RARA positive
    |
    azacitidine • Amnolake (tamibarotene)
    2years
    Initial Results from SELECT-AML-1, a Phase 2 Study of Tamibarotene in Combination with Venetoclax and Azacitidine in RARA-Positive Newly Diagnosed AML Patients Ineligible for Standard Induction Chemotherapy (ASH 2022)
    The triplet demonstrated an initial safety profile similar to ven/aza. Data from the safety lead-in will inform triplet dosing for the randomized portion of the study.
    Clinical • P2 data • Combination therapy
    |
    IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • RUNX1 (RUNX Family Transcription Factor 1) • RARA (Retinoic Acid Receptor Alpha) • SRSF2 (Serine and arginine rich splicing factor 2) • BCOR (BCL6 Corepressor) • CSF3R (Colony Stimulating Factor 3 Receptor)
    |
    IDH2 mutation • SRSF2 mutation • RARA overexpression • RARA positive
    |
    Venclexta (venetoclax) • azacitidine • Amnolake (tamibarotene)
    2years
    AML-108 SELECT-AML-1 Trial in Progress: A Phase 2 Study of Tamibarotene in Combination With Venetoclax and Azacitidine in Previously Untreated Adult Patients Selected for RARA-Positive AML who are Ineligible for Standard Induction Therapy. (PubMed, Clin Lymphoma Myeloma Leuk)
    U.S. and France.
    Clinical • P2 data • Clinical Trial,Phase II • Journal • Combination therapy
    |
    RARA (Retinoic Acid Receptor Alpha)
    |
    RARA positive
    |
    Venclexta (venetoclax) • azacitidine • Amnolake (tamibarotene)
    2years
    MDS-110 SELECT-MDS-1 Trial in Progress: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of Tamibarotene/Azacitidine Versus Placebo/Azacitidine in Newly Diagnosed Adult Patients Selected for RARA-Positive Higher-Risk MDS. (PubMed, Clin Lymphoma Myeloma Leuk)
    Azacitidine will be administered at 75 mg/m IV/SC daily on days 1-7 (or 1-5, 8-9) followed by tamibarotene/placebo at 6 mg BID orally on days 8-28 of each 28-day cycle. Response is assessed per the modified IWG MDS criteria (Cheson 2006).
    Clinical • P3 data • Clinical Trial,Phase III • Journal
    |
    RARA (Retinoic Acid Receptor Alpha)
    |
    RARA overexpression • RARA positive
    |
    azacitidine • Amnolake (tamibarotene)
    over2years
    A RANDOMIZED, DOUBLE-BLIND, PHASE 3 STUDY OF TAMIBAROTENE/AZACITIDINE VERSUS PLACEBO/AZACITIDINE IN NEWLY DIAGNOSED ADULT PATIENTS SELECTED FOR RARA-POSITIVE HR-MDS (SELECT-MDS-1) (EHA 2022)
    Results Approximately 190 patients will be randomized 2:1 and stratified by IPSS-R risk group and geographic region, providing 90% power to detect the difference in CR rates between the experimental and control arms, respectively, with one-sided alpha of 0.025. Conclusion The SELECT-MDS-1 trial opened to enrollment in February 2021, recruitment is ongoing, with sites located in North America, Israel, and Europe (NCT04797780).
    Clinical • P3 data
    |
    RARA (Retinoic Acid Receptor Alpha)
    |
    RARA overexpression • RARA positive
    |
    azacitidine • Amnolake (tamibarotene)
    over2years
    TAMIBAROTENE IN COMBINATION WITH VENETOCLAX AND AZACITIDINE IN PREVIOUSLY UNTREATED ADULT PATIENTS SELECTED FOR RARA-POSITIVE AML WHO ARE INELIGIBLE FOR STANDARD INDUCTION THERAPY (SELECT AML-1) (EHA 2022)
    Results Response rates and 95% exact binomial confidence intervals will be calculated by treatment group. Conclusion The SELECT AML-1 trial ( NCT04905407) opened in July 2021 with ongoing enrollment.
    Clinical • Combination therapy
    |
    RARA (Retinoic Acid Receptor Alpha)
    |
    RARA overexpression • RARA positive
    |
    Venclexta (venetoclax) • azacitidine • Amnolake (tamibarotene)
    3years
    Defining the Transcriptional Control of Pediatric AML Highlights RARA as a Super-Enhancer Regulated Druggable Dependency. (PubMed, Blood Adv)
    Tamibarotene prolonged 13 survival and suppressed the leukemia burden of a RARA SE-positive pAML patient-14 derived xenograft (PDX) mouse model compared to a RARA SE-negative PDX. Our work 15 demonstrates that examining chromatin regulation can identify new, druggable 16 dependencies in pAML and provides rationale for a pediatric tamibarotene trial in children 17 with RARA-high AML.
    Clinical • Journal
    |
    KMT2A (Lysine Methyltransferase 2A) • RARA (Retinoic Acid Receptor Alpha)
    |
    MLL rearrangement
    |
    Amnolake (tamibarotene)
    4years
    [VIRTUAL] Selection of RARA-Positive Newly Diagnosed Unfit AML Patients with Elevated RARA Gene Expression Enriches for Features Associated with Primary Resistance to Venetoclax and Clinical Response to SY‑1425, a Potent and Selective RARα Agonist, Plus Azacitidine (ASH 2020)
    Introduction: Super-enhancer (SE) mapping in non-APL AML patient (pt) blasts identified RARα as a novel therapeutic target in approximately 30% of pts, who have elevated RARA gene expression. In ND unfit AML, RARA+ pts, including those with clinical responses to SY-1425 plus Aza, are enriched for monocytic features associated with resistance to Ven. SY-1425 plus Aza shows potential as a novel targeted regimen for the treatment of RARA+ ND unfit AML and warrants further development in this genomically defined subset of AML pts who may be resistant to upfront SOC therapy with Ven.
    Clinical • IO biomarker
    |
    KIT (KIT proto-oncogene, receptor tyrosine kinase) • MCL1 (Myeloid cell leukemia 1) • CD34 (CD34 molecule)
    |
    BCL2 expression • KIT expression
    |
    Venclexta (venetoclax) • azacitidine • Amnolake (tamibarotene)
    4years
    Therapy-related acute promyelocytic leukemia developing during chemotherapy for thymic carcinoma (PubMed, Rinsho Ketsueki)
    He had a history of thymic carcinoma, which had been treated with carboplatin in combination with either paclitaxel or amrubicin...Administration of tegafur/gimeracil/oteracil (TS-1) was initiated, which resulted in tumor size reduction and a partial response...The patient achieved and maintained complete remission for more than 20 months by a de novo APL-treatment regimen including all-trans retinoic acid, arsenic trioxide and tamibarotene. Moreover, the thymic carcinoma has remained stable. Although secondary malignancies of thymic carcinoma have been previously reported, therapy-related leukemia, especially tAPL, is very rare.
    Journal
    |
    KIT (KIT proto-oncogene, receptor tyrosine kinase) • CD33 (CD33 Molecule) • PML (Promyelocytic Leukemia) • CD34 (CD34 molecule)
    |
    carboplatin • paclitaxel • Teysuno (gimeracil/oteracil/tegafur) • arsenic trioxide • Amnolake (tamibarotene) • Calsed (amrubicin)
    over4years
    Impact of CD56 Continuously Recognizable as Prognostic Value of Acute Promyelocytic Leukemia: Results of Multivariate Analyses in the Japan Adult Leukemia Study Group (JALSG)-APL204 Study and a Review of the Literature. (PubMed, Cancers (Basel))
    The CR rate, mortality rate during induction and overall survival of CD56 APL were not significantly different compared with CD56 APL. CD56 is continuously an independent unfavorable prognostic factor for RFS in APL patients treated with ATRA and chemotherapy followed by ATRA or tamibarotene maintenance therapy.
    Clinical • Journal
    |
    NCAM1 (Neural cell adhesion molecule 1)
    |
    Amnolake (tamibarotene)
    almost6years
    Early Results from a Biomarker-Directed Phase 2 Trial of Sy-1425 in Combination with Azacitidine or Daratumumab in Non-APL Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) (ASH 2018)
    In summary, early data suggest SY-1425 in combination has clinical potential in pts with non-APL AML and MDS. Updated results will be presented.
    P2 data • Combination therapy • IO biomarker
    |
    CD38 (CD38 Molecule)
    |
    azacitidine • Darzalex (daratumumab) • Amnolake (tamibarotene)