Dociparstat Sodium (CX-01) Combined With Standard Induction Therapy for Newly Diagnosed Acute Myeloid Leukemia

Study Overview
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Brief Summary
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This was an exploratory Phase 2, open label, randomized, multicenter, parallel group study to determine whether there was evidence that the addition of dociparstat (CX-01) at 2 different does levels to standard induction therapy (cytarabine+idarubicin, 7+3) and consolidation therapy had an additive therapeutic effect for subjects newly diagnosed with acute myeloid leukemia (AML) when compared with subjects receiving standard induction chemotherapy alone.

Detailed Description
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The primary efficacy endpoint was to assess whether dociparstat in conjunction with standard induction therapy for AML increased the complete remission rate based on the International Working Group AML response criteria. A total of 75 subjects were to be randomized in a 1:1:1 ratio to 1 of the following treatment groups: Group 1: cytarabine + idarubicin Group 2: cytarabine + idarubicin + dociparstat 0.125 mg/kg/hr Group 3: cytarabine + idarubicin + dociparstat 0.25 mg/kg/hr Subjects received up to 2 induction cycles and up to 2 consolidation cycles and participated in the study for up to 18 months. Clinical laboratory tests were conducted routinely, and bone marrow aspirates and biopsies were performed during the induction cycles. Safety was monitored through adverse events and clinical laboratory results.

Official Title
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A Randomized, Phase II Study of CX-01 Combined With Standard Induction Therapy for Newly Diagnosed Acute Myeloid Leukemia

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Dociparstat sodium
* Drug: Idarubicin
* Drug: Cytarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects had to meet all the following criteria to be eligible for enrollment in this study: Had newly diagnosed, de novo or secondary, previously untreated acute myeloid leukemia (AML). Had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Exclusion Criteria: Subjects who met any of the following criteria were not eligible for enrollment in this study: Had acute promyelocytic leukemia Had prior chemotherapy for AML. Had prior intensive chemotherapy or stem cell transplantation for the treatment of myelodysplastic syndrome. Had central nervous system (CNS) leukemia.

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control (idarubicin+cytarabine)<br>Induction: Idarubicin 12 mg/m2/day by slow (10 to 30 minutes) intravenous (IV) injection/infusion daily (Days 1, 2, and 3) Cytarabine 100 mg/m2/day continuous 24-hour IV infusion (Days 1 to 7) Re-induction: Idarubicin 12 mg/m2/day slow (10 to 30 minutes) IV injection/infusion daily (Days 1 and 2) Cytarabine 100 mg/m2/day continuous 24-hour IV infusion (Days 1 to 5) Consolidation: • Cytarabine 1.0 g/m2 over 3 hours, every 12 hours (Days 1, 3, and 5) | Drug: Idarubicin<br>* Subjects received 12 mg/m2/day idarubicin by slow (10 to 15 minutes) intravenous (IV) injection daily on Days 1, 2 and 3 of induction therapy, and on Days 1 and 2 of re-induction therapy.<br>* Other names: Idamycin;Drug: Cytarabine<br>* Subjects received 100 mg/m2/day cytarabine by continuous intravenous (IV) infusion on Days 1 through 7 of induction therapy and on Days 1 through 5 of re-induction therapy. During consolidation therapy, subjected received 1.0 g/m2 cytarabine IV infusion given over 3 hours every 12 hours on Days 1, 3, and 5.<br>|
| Experimental: Dociparstat 0.125 mg/kg<br>Induction: Dociparstat 4 mg/kg initial bolus 30 minutes post-idarubicin dose (Day 1), followed by dociparstat 0.125 mg/kg/hr continuous 24-hour intravenous (IV) infusion (Days 1 to 7) Idarubicin 12 mg/m2/day slow IV injection/infusion daily (Days 1, 2, and 3) Cytarabine 100 mg/m2/day continuous 24-hour IV infusion (Days 1 to 7) Re-induction: Dociparstat 4 mg/kg initial bolus 30 minutes post-idarubicin dose (Day 1), followed by dociparstat 0.125 mg/kg/hr continuous 24-hour IV infusion (Days 1 to 5) Idarubicin 12 mg/m2/day slow IV injection/infusion daily (Days 1 and 2) Cytarabine 100 mg/m2/day continuous 24-hour IV infusion (Days 1 to 5) Consolidation: Dociparstat 4 mg/kg initial bolus 30 minutes post-3-hour cytarabine infusion (Day 1), followed by dociparstat 0.125 mg/kg/hr continuous 24-hour IV infusion on (Days 1 to 5; total 120 hours) Cytarabine 1.0 g/m2 over 3 hours, every 12 hours (Days 1, 3, and 5) | Drug: Dociparstat sodium<br>* Subjects received 4 mg/kg dociparstat intravenous (IV) bolus followed by doses of 0.125 or 0.25 mg/kg/hr dociparstat given on Days 1 through 7 with standard induction therapy, on Days 1 through 5 or 7 with standard re-induction therapy, and on Days 1, 3, and 5 with standard consolidation therapy.<br>* Other names: Dociparstat;Drug: Idarubicin<br>* Subjects received 12 mg/m2/day idarubicin by slow (10 to 15 minutes) intravenous (IV) injection daily on Days 1, 2 and 3 of induction therapy, and on Days 1 and 2 of re-induction therapy.<br>* Other names: Idamycin;Drug: Cytarabine<br>* Subjects received 100 mg/m2/day cytarabine by continuous intravenous (IV) infusion on Days 1 through 7 of induction therapy and on Days 1 through 5 of re-induction therapy. During consolidation therapy, subjected received 1.0 g/m2 cytarabine IV infusion given over 3 hours every 12 hours on Days 1, 3, and 5.<br>|
| Experimental: Dociparstat 0.25 mg/kg<br>Induction: Dociparstat 4 mg/kg initial bolus 30 minutes post-idarubicin dose (Day 1), followed by dociparstat 0.25 mg/kg/hr continuous 24-hour intravenous (IV) infusion (Days 1 to 7) Idarubicin 12 mg/m2/day slow IV injection/infusion daily (Days 1, 2, and 3) Cytarabine 100 mg/m2/day continuous 24-hour IV infusion (Days 1 to 7) Re-induction: Dociparstat 4 mg/kg initial bolus 20 minutes post-idarubicin dose (Day 1), followed by dociparstat 0.25 mg/kg/hr continuous 24-hour IV infusion (Days 1 to 5) Idarubicin 12 mg/m2/day slow IV injection/infusion daily (Days 1 and 2) Cytarabine 100 mg/m2/day continuous 24-hour IV infusion (Days 1 to 5) Consolidation: Dociparstat 4 mg/kg initial bolus 30 minutes post-3-hour cytarabine infusion (Day 1), followed by dociparstat 0.25 mg/kg/hr continuous 24-hour IV infusion (Days 1 to 5; total 120 hours) Cytarabine 1.0 g/m2 over 3 hours, every 12 hours (Days 1, 3, and 5) | Drug: Dociparstat sodium<br>* Subjects received 4 mg/kg dociparstat intravenous (IV) bolus followed by doses of 0.125 or 0.25 mg/kg/hr dociparstat given on Days 1 through 7 with standard induction therapy, on Days 1 through 5 or 7 with standard re-induction therapy, and on Days 1, 3, and 5 with standard consolidation therapy.<br>* Other names: Dociparstat;Drug: Idarubicin<br>* Subjects received 12 mg/m2/day idarubicin by slow (10 to 15 minutes) intravenous (IV) injection daily on Days 1, 2 and 3 of induction therapy, and on Days 1 and 2 of re-induction therapy.<br>* Other names: Idamycin;Drug: Cytarabine<br>* Subjects received 100 mg/m2/day cytarabine by continuous intravenous (IV) infusion on Days 1 through 7 of induction therapy and on Days 1 through 5 of re-induction therapy. During consolidation therapy, subjected received 1.0 g/m2 cytarabine IV infusion given over 3 hours every 12 hours on Days 1, 3, and 5.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Who Achieved Morphologic Complete Remission | Morphologic complete remission (CR) was evaluated by International Working Group (IWG) criteria and defined as absolute neutrophil count (ANC) >1000/microliter; platelet count >100,000, <5% blasts in bone marrow aspirate, no blasts with Auer rods, and no evidence of extramedullary disease. | During induction and re-induction phases of treatment (up to 60 days after the start of each treatment cycle) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Event-free Survival | Event-free survival was measured as date of randomization until treatment failure. Treatment failure was defined as failure to achieve composite completed morphological remission during the induction and re-induction phase of the study lasting up to 60 days, relapse from complete response, or death from any cause, whichever occurred first. | Randomization up to 30 months | 
| Time to Leukemia-free Survival | Leukemia-free survival was assessed as a secondary endpoint only in subjects who achieved composite complete remission and was measured from randomization until disease relapse or death from any cause, whichever occurred first. Assessments were performed every 3 months until death or 18 months after the last subject was randomized, whichever occurred first. | Randomization until disease relapse or patient death from any cause, whichever occurs first, assessed up to 30 months | 
| Number of Subjects Who Achieved Overall Survival | Overall survival was measured from the date of randomization until death from any cause. Assessments were performed every 3 months and continued until death or 18 months after the last patient was randomized, whichever came first. | Randomization to end of study (18 months) | 
| Number of Subjects Who Achieved Composite Complete Remission | The composite complete remission (CR) rate included CR, CR without recovery of platelets (CRp), and CR without recovery of neutrophils and/or platelets (CRi), as defined by the International Working Group criteria during the induction and re-induction phases of treatment. CR was defined as an Absolute Neutrophil Count (ANC) >1000/μL, platelet count >100,000/μL, <5% blasts in bone marrow aspirate, no blasts with Auer rods, and no evidence of extramedullary disease. CRi was defined as an ANC <1000/μL and/or platelet count <100,000/, <5% blasts in bone marrow aspirate, no blasts with Auer rods, and no evidence of extramedullary disease. | Up to 60 days after the start of each treatment cycle | 
| Duration of Morphologic Complete Remission | The duration of morphologic complete remission was assessed only in subjects who had achieved morphologic complete remission and was defined as the time from achievement of complete response to the detection or relapse. Relapse was defined as the reappearance of leukemia blasts in the peripheral blood, >5% blasts in the bone marrow not attributable to another cause, or appearance/reappearance of extramedullary disease and with a bone marrow blast percentage of >5% but ≤20%. If the latter, a repeat bone marrow examination was performed at least 7 days after the first marrow examination; documentation of the bone marrow blast percentage of >5% was necessary to establish relapse. Assessments were performed every 3 months and continued until death or 18 months after the last subject was randomized, whichever occurred first. Duration of morphologic complete remission (time from the achievement of complete response to the detection of relapse) | Randomization to end of study (18 months) | 
| Time to Recovery of Neutrophils | Neutrophil recovery was assessed from randomization to Absolute Neutrophil Count (ANC) recovery (ANC >500/µL and >1000/µL) for up to 60 days after the start of each treatment cycle. | Randomization to ANC recovery, for up to 60 days after the start of each treatment cycle | 
| Time to Platelet Recovery | Platelet recovery was measured from randomization to platelet recovery (platelet count >20,000/µL and >100,000/µL) | Randomization to platelet recovery, for up to 60 days after the start of each treatment cycle | 
| Number of Subjects Who Died by Day 30 | Mortality (rate of death) of subjects by Day 30, measured from the first day of induction treatment to 30 days post-induction. | 30 days (from first day of induction treatment to 30 days after) | 
| Number of Subjects Who Died by Day 60. | Mortality (rate of death) of subjects by Day 60, measured from the first day of induction treatment to 60 days post-induction. | 60 days (from the first day of induction treatment to 60 days after) | 
| Number of Subjects Who Died by Day 90 | Mortality (rate of death) of subjects at Day 90, measured from the first day of induction treatment to 90 days post-induction. | 90 days (from the first day of induction treatment to 90 days after) |