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    BIOMARKER:

    RARA overexpression

    i
    Other names: RARA, Retinoic Acid Receptor Alpha, Nuclear Receptor Subfamily 1 Group B Member 1, RAR-Alpha, NR1B1, Nucleophosmin-Retinoic Acid Receptor Alpha Fusion Protein NPM-RAR Long Form, Retinoic Acid Nuclear Receptor Alpha Variant 1, Retinoic Acid Nuclear Receptor Alpha Variant 2, Retinoic Acid Receptor, Alpha Polypeptide, Retinoic Acid Receptor, Alpha, RAR
    Entrez ID:
    5914
    Related biomarkers:
    Expression
    Fusion
    Others
    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
    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)
    2years
    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
    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)