Study of ASTX727 vs IV Decitabine in Participants With MDS, CMML, and AML

Astex Pharmaceuticals, Inc.227 enrolled

Overview

Multicenter PK study of ASTX727 versus IV decitabine. Adult participants who were candidates to receive IV decitabine were randomized 1:1 to receive the ASTX727 tablet Daily×5 in Cycle 1 followed by IV decitabine 20 mg/m\^2 Daily×5 in Cycle 2, or the converse order. After completion of PK studies during the first 2 treatment cycles, participants continued to receive treatment with ASTX727 from Cycle 3 onward (in 28-day cycles) until disease progression, unacceptable toxicity, or the participants discontinued treatment or withdrew from the study.

This Phase 3 study established PK equivalence of ASTX727 to IV decitabine in approximately 227 evaluable participants. Eligible participants were randomized to receive both study treatments: oral investigational drug ASTX727, and IV decitabine, as follows: participants were randomly assigned 1:1 to receive ASTX727 or IV decitabine in Cycle 1 and then cross over to the other therapy in Cycle 2. In the ASTX727 cycle, participants received the ASTX727 tablet Daily×5. Serial PK measurements (blood draws) were done on Days 1, 2, and 5, along with pre-dose PK assessments on Days 1-5 and an assessment at 3 hours post-dose on Day 3. Participants were required to fast from food for 4 hours on days when receiving ASTX727: at least 2 hours before and 2 hours after dosing. In the IV decitabine cycle, participants received a 1-hour infusion of IV decitabine 20 mg/m\^2 Daily×5. Serial PK measurements were done on Days 1 and 5, along with pre-dose and 1-hour post-infusion assessments on Day 3. In Cycles ≥3, participants received the ASTX727 tablet Daily×5 in 28-day cycles. (No PK assessments were done from Cycle 3 onward.)

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

227

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Able to understand and comply with the study procedures, understand the risks involved in the study, and provide written informed consent before the first study-specific procedure; specifically able to comply with the PK assessment schedule during the first 2 treatment cycles. 2. Men or women ≥18 years who are candidates to receive IV decitabine according to FDA or European Medicines Agency (EMA) approved indications: 1. In North America: Participants with MDS previously treated or untreated with de novo or secondary MDS, including all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia \[CMML\]), and subjects with MDS International Prognostic Scoring System (IPSS) int-1, -2, or high-risk MDS. 2. In Europe: Participants with de novo or secondary AML, as defined by the World Health Organization (WHO) criteria, who are not candidates for standard induction chemotherapy. 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. 4. Adequate organ function defined as follows: 1. Hepatic: Total or direct bilirubin ≤2 × upper limit of normal (ULN); aspartate transaminase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine transaminase/serum glutamic pyruvic transaminase (ALT/SGPT) ≤2.5 × ULN. 2. Renal: serum creatinine ≤1.5 × ULN or calculated creatinine clearance or glomerular filtration rate \>50 mL/min/1.73 m2 for subjects with creatinine levels above institutional normal. 5. No major surgery within 30 days of first study treatment. 6. Life expectancy of at least 3 months. 7. Women of child-bearing potential must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women of non-childbearing potential are those who have had a hysterectomy or bilateral oophorectomy, or who have completed menopause, defined as no menses for at least 1 year AND either age ≥65 years or follicle-stimulating hormone levels in the menopausal range. 8. Subjects and their partners with reproductive potential must agree to use effective contraceptive measures during the study and for 3 months after the last dose of study treatment. Effective contraception includes methods such as oral contraceptives or double-barrier method (eg, use of a condom AND diaphragm, with spermicide). Exclusion Criteria: 1. Prior treatment with more than 1 cycle of azacitidine or decitabine. Prior cytotoxic chemotherapy for AML except for hydroxyurea to control high white blood cell (WBC) counts. 2. Hospitalization for more than 2 days for documented febrile neutropenia, pneumonia, sepsis, or systemic infection in the 30 days before screening. 3. Treatment with any investigational drug or therapy within 2 weeks of study treatment, or 5 half-lives, whichever is longer, before the first dose of study treatment, or ongoing clinically significant adverse events (AEs) from previous treatment. 4. Cytotoxic chemotherapy or prior azacitidine or decitabine within 4 weeks of first dose of study treatment. 5. Concurrent MDS therapies, including lenalidomide, erythropoietin, cyclosporine/tacrolimus, granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor, etc. (Prior treatment with these agents is permitted, provided that completion is at least 1 week before the first dose of study treatment.) 6. Poor medical risk because of other conditions such as uncontrolled systemic diseases, active uncontrolled infections, or comorbidities that may put the patient at risk of not being able to complete at least 2 cycles of treatment. 7. 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 subject to high risk of noncompliance with the protocol. 8. Rapidly progressive or highly proliferative disease (total white blood cell count of \>15 × 10\^9/L) or other criteria that render the subject at high risk of requiring intensive cytotoxic chemotherapy within the next 3 months. 9. Life-threatening illness or severe organ system dysfunction, such as uncontrolled congestive heart failure or chronic obstructive pulmonary disease, or other reasons including laboratory abnormalities, which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of ASTX727, or compromise completion of the study or integrity of the study outcomes. 10. Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, prostate cancer or breast cancer under control with hormone therapy, or other cancer from which the subject has been disease free for at least 2 years.

Outcomes

Primary Outcomes

Total 5-day Area Under the Curve From 0 to 24 Hours (AUC0-24) After Treatment With ASTX727 And IV Decitabine

Total 5-day ASTX727 AUC0-24 exposures were calculated using PK data from 3 days of serial PK sampling, Day 1 AUC0-24 (first ASTX727 dose) was added to (Day 2 AUC0-24+ Day 5 AUC0-24) × 2. Decitabine 5-day AUC0-24 exposures after IV decitabine were calculated as follows: (Day 1 AUC0-24+ Day 5 AUC0-24) / 2 was multiplied by 5. If AUC0-24 on Day 2 (for ASTX727) or Day 1 (IV decitabine) was not available, it was replaced by AUC0-24 on Day 5; the converse was also true.

Time frame: ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1 to 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 to 5 of Cycle 1 and 2 (each cycle= 28 days)

Secondary Outcomes

MDS/CMML: Number of Participants With Treatment-emergent Adverse Events (TEAEs)

An AE is defined as any untoward medical occurrence in a clinical investigation participants administered a drug; it does not necessarily have to have a causal relationship with this treatment. TEAEs were defined as events that first occurred or worsened on or after the date of the first dose of study treatment until 30 days after the last dose of study treatment or until the start of a post-treatment alternative anti-cancer treatment, whichever occurred first.

Time frame: From randomization up to 30 days after last dose of study treatment (up to approximately 2.7 years)

AML: Number of Participants With Treatment-emergent Adverse Events (AEs)

Time frame: From randomization up to 30 days after last dose of study treatment (up to approximately 2.4 years)

MDS/CMML: Number of Participants With Grade 3 or Higher TEAEs

TEAEs were defined as events that first occurred or worsened on or after the date of the first dose of study treatment until 30 days after the last dose of study treatment or until the start of a post-treatment alternative anti-cancer treatment, whichever occurred first. Severity of AEs were graded using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Fatal.

Time frame: From randomization up to 30 days after last dose of study treatment (up to approximately 2.7 years)

AML: Number of Participants With Grade 3 or Higher TEAEs

TEAEs were defined as events that first occurred or worsened on or after the date of the first dose of study treatment until 30 days after the last dose of study treatment or until the start of a post-treatment alternative anti-cancer treatment, whichever occurred first. Severity of AEs were graded using CTCAE version 4.03. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Fatal.

Time frame: From randomization up to 30 days after last dose of study treatment (up to approximately 2.4 years)

Maximum Percentage of Long Interspersed Nucleotide Elements (LINE)-1 Demethylation

Summarized data for Cycle 1 and Cycle 2 was reported.

Time frame: Pre-dose on Day 1 of Cycles 1 and 2 (as Baseline), and Days 8, 15 and 22 of Cycles 1 and 2 (each cycle= 28 days)

Total 5-day Area Under the Curve From 0 to Infinity (AUC0-inf) After Treatment With ASTX727 And IV Decitabine

Total 5-day ASTX727 AUC0-inf exposures were calculated using PK data from 3 days of serial PK sampling, Day 1 AUC0-inf (first ASTX727 dose) was added to (Day 2 AUC0-inf+ Day 5 AUC0-inf) × 2. Decitabine 5-day AUC0-inf exposures after IV decitabine were calculated as follows: (Day 1 AUC0-inf+ Day 5 AUC0-inf) / 2 was multiplied by 5. If AUC0-inf on Day 2 (for ASTX727) or Day 1 (IV decitabine) was not available, it was replaced by AUC0-inf on Day 5; the converse was also true.

Total 5-day Area Under the Curve From 0 to Last Quantifiable Concentration (AUC0-last) After Treatment With ASTX727 And IV Decitabine

Total 5-day ASTX727 AUC0-last exposures were calculated using PK data from 3 days of serial PK sampling, Day 1 AUC0-last (first ASTX727 dose) was added to (Day 2 AUC0-last + Day 5 AUC0-last) × 2. Decitabine 5-day AUC0-last exposures after IV decitabine were calculated as follows: (Day 1 AUC0-last + Day 5 AUC0-last) / 2 was multiplied by 5. If AUC0-last on Day 2 (for ASTX727) or Day 1 (IV decitabine) was not available, it was replaced by AUC0-last on Day 5; the converse was also true.

Total 5-day Area Under the Curve From 0 to 8 Hours (AUC0-8) After Treatment With ASTX727 And IV Decitabine

Total 5-day ASTX727 AUC0-8 exposures were calculated using PK data from 3 days of serial PK sampling, Day 1 AUC0-8 (first ASTX727 dose) was added to (Day 2 AUC0-8 + Day 5 AUC0-8) × 2. Decitabine 5-day AUC0-8 exposures after IV decitabine were calculated as follows: (Day 1 AUC0-8 + Day 5 AUC0-8) / 2 was multiplied by 5. If AUC0-8 on Day 2 (for ASTX727) or Day 1 (IV decitabine) was not available, it was replaced by AUC0-8 on Day 5; the converse was also true.

Time frame: ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 to 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 to 5 of Cycle 1 and 2 (each cycle= 28 days)

Area Under the Curve From 0 to Infinity (AUC0-inf) After Treatment With ASTX727 And IV Decitabine

AUC0-inf was calculated using the formula AUClast + (Clast / λZ), where Clast is the last quantifiable concentration and λZ is the elimination rate constant. AUC0-inf will be calculated using the linear up-log down method. Summarized data has been reported for cycle 1 and 2.

Time frame: ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 and 5 of Cycle 1 and 2 (each cycle= 28 days)

Maximum Observed Plasma Concentration (Cmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer

Summarized data of Cmax on Day 1, 2 and 5 respectively for Cycle 1 and 2 has been reported for ASTX727. Similarly, summarized data of Cmax on Day 1 and 5 respectively for Cycle 1 and 2 has been reported for IV Decitabine.

Time to Reach Maximum Plasma Concentration (Tmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer

Summarized data of Tmax on Day 1, 2 and 5 respectively for Cycle 1 and 2 has been reported for ASTX727. Similarly, summarized data of Tmax on Day 1 and 5 respectively for Cycle 1 and 2 has been reported for IV Decitabine.

Apparent Oral Clearance (CL/F) of Oral Decitabine and Cedazuridine

Oral CL/F for oral decitabine was measured only on Day 1 and oral CL/F for oral cedazuridine was measured on Days 1, 2 and 5. Summarized data of Oral CL/F for oral decitabine on Day 1 for Cycle 1 and 2 has been reported for ASTX727. Similarly, summarized data of oral CL/F for oral cedazuridine on Day 1,2 and 5 respectively for Cycle 1 and 2 has been reported for ASTX727.

Time frame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2 (each cycle= 28 days)

Apparent Elimination Half Life (t1/2) of Decitabine, Cedazuridine, and Cedazuridine-epimer

Summarized data of t1/2 on Day 1, 2 and 5 respectively for Cycle 1 and 2 has been reported for ASTX727. Similarly, summarized data of t1/2 on Day 1 and 5 respectively for Cycle 1 and 2 has been reported for IV Decitabine.

Apparent Volume of Distribution (Vz/F) of Oral Decitabine and Cedazuridine

Summarized data of Vz/F on Day 1, 2 and 5 respectively for Cycle 1 and 2 has been reported for ASTX727.

Time frame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2 (each cycle= 28 days)

MDS/CMML: Percentage of Participants With Complete Response (CR), Marrow CR (mCR), Partial Response (PR), Hematologic Improvement (HI) Based on International Working Group (IWG) 2006 Myelodysplastic Syndromes (MDS) Response Criteria

CR: normal peripheral, persistent granulocyte count ≥1.0x10\^9/liter(L), platelet ≥100x10\^9/L, Hemoglobin (Hgb) ≥11g/dL, normal bone marrow with persistent marrow blasts ≤5%. mCR: reduction of bone marrow blasts to≤5%, decrease by 50% or more with/without normalization of peripheral counts.PR: normal peripheral counts, granulocyte count ≥1.0x10\^9/L, platelet count ≥100x10\^9/L, Hgb ≥11 g/dL, normal bone marrow, marrow blasts \>5%, reduced by 50% or more for at least 4 weeks. HI: HI-E: Hb increase ≥1.5 g/dL in absence of RBC transfusions. HI-P: Absolute increase of platelet count from \<20 to \>20X10\^9/L by at least 100%,if more than 20x10\^9/L, by absolute increase of at least 30x10\^9/L in absence of platelet transfusions. HI-N: granulocyte increase ≥100%, by an absolute increase ≥0.5x10\^9/L for at least 8 weeks. Percentage of participants with CR, mCR, PR, and HI based on IWG 2003 MDS response criteria are reported. Response has been reported based on participants with MDS or CMML.

Time frame: Up to approximately 2.7 years

AML: Percentage of Participants With CR, CR With Incomplete Blood Count Recovery (CRi), CR With Incomplete Platelet Recovery (CRp), and CR Plus CRp Based on IWG 2003 AML Response Criteria

CR was defined as absolute neutrophil content (ANC) ≥1000/ microliter (μL), platelets ≥100,000/μL, independence from red blood cell (RBC) and platelet transfusions over the past week, no leukemic blasts and \<5% leukemic blasts. CRp was defined as CR criteria except platelets \<100,000/μL.and platelet transfusion over the past week. CRi was defined as CR criteria except ANC \<1000/μL or platelets \<100,000/μL. Percentage of participants with CR, CRi, CRp, and CR Plus CRp based on IWG 2003 AML response criteria are reported.

Time frame: Up to approximately 2.4 years

AML: Percentage of Participants With CR With Partial Hematologic Recovery (CRh) Based on IWG 2003 AML Response Criteria

CRh was defined as \<5% of blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets \>50,000/μL and ANC \>500/μL), independence from RBC and platelet transfusions within 7 days of bone marrow evaluation, and peripheral blast ≤1%. Percentage of participants with CRh based on IWG 2003 AML response criteria are reported.

Time frame: Day 1 of Cycle 3 up to approximately 2.4 years (each cycle= 28 days)

AML: Time to First Response, Best Response and Complete Response Based on IWG 2003 AML Response Criteria

Time to first response was defined as time in months from the date of first treatment to the first date when any response is achieved. Time to best response was defined in months from the date of first treatment to the first date when a subject's best response, in the order of CR, CRi (or CRp or CRh), or PR, was achieved. Time to CR was defined in months from the date of first treatment to the first date when CR is achieved. CR:ANC ≥1000/ microliter (μL),platelets ≥100,000/μL,independence from RBC and platelet transfusions over the past week, no leukemic blasts, and \<5% leukemic blasts.CRp: CR criteria except ANC ≥1000/μL, platelets \< 100,000/μL.and platelet transfusion over the past week. CRi:CR criteria except ANC \<1000/μL or platelets \<100,000/μL.CRh: \<5% of blasts in the bone marrow,platelets \>50,000/μL and ANC \>500/μL, independence from RBC and platelet transfusions within 7 days and peripheral blast ≤1%. PR: CR criteria except decrease of ≥50% in leukemic blasts.

Time frame: Up to approximately 2.4 years

AML: Duration of Complete Response and Combined CR and CRh Based on IWG 2003 AML Response Criteria

Duration of CR was defined as the time interval from the first CR to time of relapse. Duration of combined CR and CRh was defined as the time interval from the first CR or CRh to time of relapse. Duration of CR and combined CR and CRh was presented using a Kaplan-Meier estimate.

Time frame: Up to approximately 2.4 years

MDS/CMML: Percentage of Participants With Red Blood Cell (RBC) and Platelet Transfusion Independence (TI)

Transfusion independence was defined as no transfusion for 56 consecutive days or more (84 and 112 days) after the first dose of study treatment while maintaining hemoglobin ≥8 grams/deciliter (g/dL) (RBC TI) or maintaining platelets ≥20×109/L (platelet TI).

Time frame: Up to approximately 2.7 years

AML: Percentage of Participants With Red Blood Cell (RBC) and Platelet Transfusion Independence (TI)

Transfusion independence was defined as no transfusion for 56 consecutive days or more (112 days) after the first dose of study treatment while maintaining hemoglobin ≥8 grams/deciliter (g/dL) (RBC TI) or maintaining platelets ≥20×109/L (platelet TI).

Time frame: Up to approximately 2.4 years

MDS/CMML: Leukemia-free Survival (LFS)

LFS was defined as time from the date of randomization to the date when bone marrow or peripheral blood blasts reach ≥20%, or death from any cause. Participants who hadn't reached AML at the time of the analysis were censored at the date of the last follow-up. Leukemia-free survival was presented using a Kaplan-Meier estimate.

Time frame: From randomization up to approximately 2.7 years

MDS/CMML: Overall Survival (OS)

OS was defined as time from the date of randomization to the date of death from any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. Overall survival was presented using a Kaplan-Meier estimate.

Time frame: From randomization up to approximately 2.7 years

AML: Overall Survival (OS)

Time frame: From randomization up to approximately 2.4 years

AML: Survival Rates at 6 Months, 1 Year, and 2 Years

One-year survival rate was defined as the survival rate at the end of the first year from the date of randomization. The survival rates at 6 months and at 2 years were calculated similarly.

Time frame: At Month 6, Year 1 and 2

AML: Event-free Survival (EFS)

EFS was defined as time from the date of randomization to the date of treatment failure \[disease progression/relapse (due to confirmed reappearance of leukemic blasts in peripheral blood or ≥5% leukemic blasts in bone marrow (including relapse), discontinue treatment due to disease progression or treatment-related AE, or alternative anti-leukemia therapy except for HCT\] or death from any cause, whichever occurs first. Participants without documented treatment failure at the time of the analysis were censored at the date of the last follow-up. Event-free survival was presented using a Kaplan-Meier estimate.

Time frame: From randomization up to approximately 2.4 years

AML: Progression-free Survival (PFS)

PFS was defined as time from the date of randomization to the date disease progression due to confirmed reappearance of leukemic blasts in peripheral blood or ≥5% leukemic blasts in bone marrow (including relapse) or death from any cause, whichever occurs first. Participants without documented disease progression/relapse or death at the time of the analysis were censored at the date of the last follow-up. Progression-free survival was presented using a Kaplan-Meier estimate.

Time frame: From randomization up to approximately 2.4 years

Study of ASTX727 vs IV Decitabine in Participants With MDS, CMML, and AML

Overview

Conditions

Interventions

Eligibility

Locations (84)

Outcomes

Primary Outcomes

Secondary Outcomes