This study compares the efficacy of Tamibarotene in combination with azacitidine to azacitidine in combination with placebo in participants who are Retinoic Acid Receptor Alpha (RARA) positive, and newly diagnosed with higher-risk myelodysplastic syndrome (HR-MDS), and who have not received treatment for this diagnosis. The primary goal of the study is to compare the complete remission rate between the two treatment arms.
A subset of participants have MDS characterized by an overexpression of the RARA gene. A blood test will be used to identify participants with RARA-positive MDS. Assessment of the RARA biomarker for study eligibility will be done by collection of blood samples from potential study participants at the pre-screening visit and testing at a central laboratory. Participants who meet eligibility requirements will be randomized 2:1 to receive either Tamibarotene plus azacitidine or placebo plus azacitidine.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
246
Administered as specified in the treatment arm
Administered as specified in the treatment arm
Administered as specified in the treatment arm
Percentage of Participants With Complete Remission (CR)
CR was determined by the investigator per the modified International Working Group Myelodysplastic Syndrome (IWG MDS). CR was defined as participants with hemoglobin ≥11 grams/deciliter (g/dL), neutrophils ≥1.0\*10\^9/L, platelets ≥100\*10\^9/L, blasts 0%, bone marrow blasts (BMBs) ≤5% and normal maturation of all cell lines, persistent dysplasia were noted.
Time frame: Up to 45 months
Duration of Overall Response (DOR)
DOR: duration from date of first documented evidence of CR, partial remission (PR), marrow CR (mCR), or hematologic improvement (HI) to date of documented disease progression or relapse of disease as determined by investigator per modified IWG MDS criteria or death due to any cause, whichever occurred first. CR: hemoglobin (Hb)≥11 g/dL, neutrophils ≥1.0\*10\^9/L, platelets ≥100\*10\^9/L, blasts 0%, BMBs≤5% \& normal maturation of all cell lines, persistent dysplasia. PR: Hb ≥11 g/dL, neutrophils ≥1.0\*10\^9/L, platelets ≥100\*10\^9/L, blasts 0%, BMBs decreased by ≥50% from baseline, but \>5%. mCR: Hb ≥11 g/dL, neutrophils ≥1.0\*10\^9/L, platelets ≥100\*10\^9/L, blasts 0%, BMBs decreased by≥50% from baseline, \& ≤5%. Subcategories of HI included erythroid response (Hgb increase by ≥1.5 g/dL), platelet response (absolute increase of≥30\*10\^9/L if starting with \>20\*10\^9/L platelets; increase from \<20 to \>20\*10\^9/L and by ≥100%),neutrophil response (≥100% increase \& absolute increase \>0.5\*10\^9/L).
Time frame: Up to 45 months
Number of Participants Who Achieved Transfusion Independence (TI)
TI was defined as a period of at least 56 days with no red blood cell (RBC) or platelet transfusion since the date of randomization to the last dose of study drug + 30 days, the initiation of post-treatment therapy, or death, whichever occurred first.
Time frame: Up to 45 months
Percentage of Participants Who Achieved Overall Response (OR)
OR: Participants who achieved CR, PR, mCR, or subcategories of HI, as determined by investigator per modified IWG MDS criteria. CR was defined as hemoglobin ≥11 g/dL, neutrophils ≥1.0\*10\^9/L, platelets ≥100\*10\^9/L, blasts 0%, bone marrow blasts (BMBs) ≤5% and normal maturation of all cell lines, persistent dysplasia were noted. PR was defined as hemoglobin ≥11 g/dL, neutrophils ≥1.0\*10\^9/L, platelets ≥100\*10\^9/L, blasts 0%, BMBs decreased by ≥50% from baseline, but \>5%. mCR was defined as hemoglobin ≥11 g/dL, neutrophils ≥1.0\*10\^9/L, platelets ≥100\*10\^9/L, blasts 0%, BMBs decreased by ≥50% from baseline, and ≤5%. Subcategories of HI included erythroid response (Hgb increase by ≥1.5 g/dL), platelet response (absolute increase of ≥30\*10\^9 /L if starting with \>20\*10\^9/L platelets increase from \<20\*10\^9/L to \>20\*10\^9/L and by at least 100%), neutrophil response (at least a 100% increase and an absolute increase \>0.5\*10\^9 /L).
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University of Arizona
Tucson, Arizona, United States
University of Southern California
Los Angeles, California, United States
University of California, Los Angelas
Los Angeles, California, United States
Yale Cancer Center
New Haven, Connecticut, United States
Comprehensive Hematology and Oncology
St. Petersburg, Florida, United States
Moffitt Cancer Center
Tampa, Florida, United States
University of Illinois Cancer Center
Chicago, Illinois, United States
Orchard Healthcare Research Inc.
Skokie, Illinois, United States
University of Iowa
Iowa City, Iowa, United States
Tulane Cancer Center
New Orleans, Louisiana, United States
...and 118 more locations
Time frame: Up to 45 months
Duration of Complete Response (DOCR)
DOCR was defined as the duration from the date of first documented evidence of CR to the date of documented relapse of disease or disease progression, as determined by the investigator per the modified IWG MDS criteria, or death due to any cause, whichever occurred first. CR was defined as participants with hemoglobin ≥11 g/dL, neutrophils ≥1.0\*10\^9/L, platelets ≥100\*10\^9/L, blasts 0%, BMBs ≤5% and normal maturation of all cell lines, persistent dysplasia were noted. Among CR responders, DOCR was calculated as: DOCR (months) = (first date of documented relapse of disease, disease progression, or death due to any cause - date of first documented evidence of CR + 1) / 30.4375.
Time frame: Up to 45 months
Time to Complete Remission (TCR)
TCR was defined as the duration from the date of randomization to the date of the first documented evidence of CR as determined by the investigator per the modified IWG MDS criteria. Among CR responders, this outcome measure was calculated as: Time to CR= (date of the first documented evidence of CR - date of randomization + 1) / 30.4375. CR was defined as hemoglobin ≥11 g/dL, neutrophils ≥1.0\*10\^9/L, platelets ≥100\*10\^9/L, blasts 0%, bone marrow blasts ≤5% and normal maturation of all cell lines, persistent dysplasia were noted.
Time frame: Up to 45 months
Time to Initial Response (TIR)
TIR: duration from date of randomization to the date of first documented evidence of CR, PR, mCR, or HI as determined by investigator per modified IWG MDS criteria. CR: hemoglobin (Hb) ≥11 g/dL, neutrophils ≥1.0\*10\^9/L, platelets ≥100\*10\^9/L, blasts 0%, bone marrow blasts (BMBs) ≤5% and normal maturation of all cell lines, persistent dysplasia. PR: Hb ≥11 g/dL, neutrophils ≥1.0\*10\^9/L, platelets ≥100\*10\^9/L, blasts 0%, BMBs decreased by ≥50% from baseline, but \>5%. mCR: Hb ≥11 g/dL, neutrophils ≥1.0\*10\^9/L, platelets ≥100\*10\^9/L, blasts 0%, BMBs decreased by ≥50% from baseline, and ≤5%. Subcategories of HI included erythroid response (Hgb increase by ≥1.5 g/dL), platelet response (absolute increase of ≥30\*10\^9/L if starting with \>20\*10\^9/L platelets increase from \<20 to \>20\*10\^9/L and by at least 100%), neutrophil response (at least a 100% increase and absolute increase\>0.5\*10\^9 /L).
Time frame: Up to 45 months
Change in Health-Related Quality of Life (HRQoL) as Assessed by the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire 30 Scale (EORTC QLQ-30)
HRQoL was evaluated by EORTC QLQ-C30 global health status/quality of life composite scale in all randomized participants. The QLQ-30 is a cancer-specific, self-administered questionnaire that contains 30 questions, covering global, functional, and symptom scales. Scores range from 0 to 100. Higher scores on global and functional scales indicated better quality of life (QoL), while higher scores on the symptom scales indicated declining QoL.
Time frame: Up to 45 months
Change in HRQOL as Assessed by the European Quality of Life 5 Dimensions Scale (EuroQoL-5D)
The EQ-5D-3L essentially consisted of- the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The EQ-5D-3L descriptive system comprised of the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension had 3 levels: no problems, some problems, extreme problems. Total scale range for each dimension reported was 1 to 3. The EQ VAS recorded the respondent's self-rated health on a vertical, visual analogue scale where the endpoints are labelled 'Best imaginable health state' and 'Worst imaginable health state'. This information can be used as a quantitative measure of health outcome as judged by the individual respondents. Total scale range for VAS dimension reported was 0 to 100.
Time frame: Up to 45 months
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
An AE was defined as any untoward medical occurrence that developed or worsened in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. TEAEs are defined as those AEs with onset after the first dose of study drug or existing events that worsened after the first dose during the study up until the last dose of study drug + 30 days. SAEs included death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section.
Time frame: Up to 45 months