A Phase 3, Multicenter, Randomized, Open-Label Study of Guadecitabine (SGI-110) Versus Treatment Choice in Adults With Myelodysplastic Syndromes (MDS) or Chronic Myelomonocytic Leukemia (CMML) Previously Treated With Hypomethylating Agents
Overview
- Phase
- Phase 3
- Intervention
- Guadecitabine
- Conditions
- Myelodysplastic Syndromes
- Sponsor
- Astex Pharmaceuticals, Inc.
- Enrollment
- 417
- Locations
- 112
- Primary Endpoint
- Overall Survival (OS)
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
A Phase 3, randomized, open-label, parallel-group, multicenter study designed to evaluate the efficacy and safety of guadecitabine in participants with MDS or CMML who failed or relapsed after adequate prior treatment with azacitidine, decitabine, or both. This global study will be conducted in approximately 15 countries. Approximately 408 participants from approximately 100 study centers will be randomly assigned in a 2:1 ratio to either guadecitabine (approximately 272 participants) or Treatment Choice (approximately 136 participants). The study consists of a 21-day screening period, a treatment period, a safety follow-up visit, and a long-term follow-up period. The study is expected to last more than 2 years, and the duration of individual participant participation will vary. Participants may continue to receive treatment for as long as they continue to benefit.
Detailed Description
Multicenter, randomized, open-label, parallel-group study of guadecitabine vs Treatment Choice (TC). Approximately 408 participants will be randomly assigned 2:1 to either guadecitabine or TC. * Guadecitabine: approximately 272 participants. * TC: approximately 136 participants. Before randomization, the investigator will assign each participant to one of the following TC options: * Low dose cytarabine (LDAC). * Standard Intensive Chemotherapy (IC) of a 7+3 regimen. * Best Supportive Care (BSC) only. BSC will be provided to all participants as per standard and institutional practice. Participants randomized to TC will not be allowed to cross over to guadecitabine. Data will be reviewed by an independent Data Monitoring Committee at regular intervals, primarily to evaluate safety during study conduct. Randomization will be stratified by disease category (MDS vs CMML), bone marrow (BM) blasts (BM blasts \>10% vs BM blasts ≤10%), TC option (LDAC vs IC vs BSC), and study center region. Guadecitabine: 60 milligrams per square meter (mg/m\^2) given subcutaneously (SC) daily on Days 1-5 in 28-day cycles (delayed as needed to allow blood count recovery). Treatment should be given for at least 6 total cycles in the absence of unacceptable toxicity or disease progression requiring alternative therapy. Beyond 6 cycles, treatment should continue as long as the participant continues to benefit. BSC should be given according to standard and institutional practice. Treatment Choice (TC): Before randomization, the investigator will assign each participant to one of the following TC options: * Low dose cytarabine (LDAC) given as 20 mg/m\^2 SC or intravenously (IV) once daily for 14 days in 28-day cycles (delayed as needed to allow blood count recovery). Treatment should be given for at least 4 cycles in the absence of disease progression or unacceptable toxicity. * Standard Intensive Chemotherapy (IC) of a 7+3 regimen: given as cytarabine 100-200 mg/m\^2/day given as continuous infusion for 7 days and an anthracycline given as per institutional standard practice such as daunorubicin (45-60 mg/m\^2/day), or idarubicin (9-12 mg/m\^2/day), or mitoxantrone (8-12 mg/m\^2/day) by intravenous infusion for 3 days. * Best Supportive Care (BSC) only: given according to standard and institutional practice. BSC includes, but is not limited to blood transfusions (Red blood cells \[RBCs\] or platelets), growth factors including erythropoiesis stimulating agents (ESA), granulocyte stimulating factors (GSFs), iron chelating therapy, and broad-spectrum antibiotics and/or antifungals.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Adult participants ≥18 years of age who are able to understand and comply with study procedures and provide written informed consent before any study-specific procedure.
- •Cytologically or histologically confirmed diagnosis of MDS or CMML according to the 2008 World Health Organization (WHO) classification.
- •Performance status (ECOG) of 0-
- •Previously treated MDS or CMML, defined as prior treatment with at least one hypomethylating agent (HMA; azacitidine and/or decitabine) for intermediate or high risk MDS or CMML whose disease progressed or relapsed as follows:
- •Participant received HMA for at least 6 cycles and was still transfusion dependent.
- •Participant received HMA for at least 2 complete cycles and had disease progression prior to Cycle 6 defined as
- •i. ≥50% increase in bone marrow blasts from pre-HMA-treatment levels or from nadir post-HMA-treatment levels to \>5% (for participants with pretreatment or nadir blasts ≤5%) or to \>10% (for participants with pretreatment or nadir blasts \>5%), and/or ii. Transfusion dependent and ≥2 gram/deciliter (g/dL) reduction of Hgb from pre-HMA-treatment levels.
- •Other prior treatments for MDS such as lenalidomide, cytarabine, intensive chemotherapy, hydroxyurea, erythropoietin and other growth factors, or hematopoietic cell transplant (HCT) are allowed.
- •Participants must have either:
- •Bone marrow blasts \>5% at randomization, OR
Exclusion Criteria
- •Participants who have been diagnosed as having AML with peripheral blood or bone marrow blasts of ≥20%.
- •Participants who may still be sensitive to repeated treatment with decitabine or azacitidine such as participants who had response to prior decitabine or azacitidine treatment, but relapsed \>6 months after stopping treatment with these agents.
- •Prior treatment with guadecitabine.
- •Hypersensitivity to decitabine, guadecitabine, or any of their excipients.
- •Second malignancy currently requiring active therapy, except breast or prostate cancer stable on or responding to endocrine therapy.
- •Treated with any investigational drug within 2 weeks of the first dose of study treatment.
- •Total serum bilirubin \>2.5 × upper limit of normal (ULN) (except for participants with Gilbert's Syndrome for whom direct bilirubin is \<2.5×ULN), or liver cirrhosis or chronic liver disease Child-Pugh Class B or C.
- •Known active HIV, HBV, or HCV infection. Inactive hepatitis carrier status or low viral hepatitis titer on antivirals is allowed.
- •Known significant mental illness or other condition such as active alcohol or other substance abuse or addiction that, in the opinion of the investigator, predisposes the participant to high risk of noncompliance with the protocol.
- •Refractory congestive heart failure unresponsive to medical treatment, active infection resistant to all antibiotics, or advanced non-MDS associated pulmonary disease requiring \>2 liters per minute oxygen.
Arms & Interventions
Guadecitabine
Participants received Guadecitabine 60 mg/m\^2, SC, on Days 1-5 of each 28-day cycle for at least 6 cycles in the absence of unacceptable toxicity or disease progression requiring alternative therapy. Participants received Guadecitabine treatment beyond 6 cycles as long as the participant continued to benefit based on investigator judgment and participant response and tolerability (or up to a maximum of 36 cycles).
Intervention: Guadecitabine
Treatment Choice
Participants received one of the three treatment choice options: 1. LDAC 20 mg/m\^2 SC/IV once daily for 14 days of each 28-day cycles for at least 4 cycles in absence of disease progression or unacceptable toxicity.Participants who were responding or had stable disease were to continue treatment as per standard institutional practice. 2. Standard IC of a 7+3 regimen:Cytarabine 100-200 mg/m\^2/day given as continuous infusion for 7 days and anthracycline(daunorubicin(45-60 mg)/idarubicin(9-12 mg)/mitoxantrone(8-12 mg)/m\^2) by IV infusion for 3 days of each 28-day cycles. 3. BSC as needed during the treatment included,but was not limited to,blood transfusions(RBCs or platelets),growth factors including erythropoiesis stimulating agents,granulocyte stimulating factors,iron chelating therapy,and broad-spectrum antibiotics and/or antifungals. Duration for treatment choice was as per locally approved prescribing information and institutional standard practice or up to a maximum 30 cycles.
Intervention: Treatment Choice
Outcomes
Primary Outcomes
Overall Survival (OS)
Time Frame: From randomization up to death (up to approximately 38.6 months)
OS was defined as the number of days from the day the participant was randomized to the date of death due to any cause. Survival time was censored on the last date the participant is known alive with no event of death. OS time will be estimated using the Kaplan-Meier method.
Secondary Outcomes
- Percentage of Participants With Transfusion Independence for Any 8 Consecutive Weeks(Up to approximately 46.6 months)
- Leukemia-free Survival(From randomization up to 46.6 months)
- Disease Response (DR) Rate(Up to approximately 46.6 months)
- Survival Rate at 1 Year After Randomization(From randomization up to 12 months)
- Number of Red Blood Cell (RBC) and Platelet Transfusions(Up to 6 months)
- Percentage of Participants With Marrow Complete Response (mCR) Along With Transfusion Independence Rate(Up to approximately 46.6 months)
- Number of Days Alive and Out of the Hospital (NDAOH)(Up to 6 months)
- Duration of Complete Response (CR)(Up to approximately 46.6 months)
- Time to First Response, Complete Response (CR) and Best Response(From study Day 1 to the earliest date that a response was first documented (up to approximately 46.6 months))
- Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)(From first dose through end of study (up to approximately 46.6 months))
- Change From Baseline in Health-related Quality of Life (QOL) By EuroQol 5-level 5-dimension (EQ-5D-5L) Summary Index(Baseline to Month 6)
- Change From Baseline in Health-related QOL: EuroQOL Visual Analogue Scale (EQ-VAS) Score(Baseline to Month 6)
- 30-day and 60-day All-cause Mortality(From first dose until 60 days after study treatment initiation)