A Pilot Study of Dociparstat Sodium (ODSH) in Acute Myeloid Leukemia

Phase 1

Completed

• Conditions: Acute Myeloid Leukemia
• Interventions: Drug: Dociparstat sodium

• Registration Number: NCT02056782
• Lead Sponsor: Chimerix

Brief Summary

This was an open-label pilot study that evaluated the safety and preliminary evidence of a therapeutic effect of dociparstat in conjunction with standard induction and consolidation therapy for acute myeloid leukemia (AML).

Detailed Description

The primary objectives of this study were the following:

1. To evaluate the safety and tolerability of dociparstat in patients with acute myeloid leukemia (AML) receiving cytarabine and idarubicin induction or cytarabine consolidation chemotherapy.

2. To determine whether there is preliminary evidence of an effect of dociparstat on time to transfusion-independent platelet recovery in AML patients receiving cytarabine and idarubicin induction or cytarabine consolidation chemotherapy.

The secondary objectives of this study were the following:

1. To determine whether there is preliminary evidence of an effect of dociparstat on remission rate following cytarabine and idarubicin induction in AML patients.

2. To determine whether there is preliminary evidence of an effect of dociparstat on improving platelet nadir counts in AML patients receiving cytarabine and idarubicin induction or cytarabine consolidation chemotherapy.

3. To determine whether there is preliminary evidence of an effect of dociparstat on decreasing the number of platelet transfusions in AML patients receiving cytarabine and idarubicin induction or cytarabine consolidation chemotherapy.

4. To determine whether there is preliminary evidence of an effect of dociparstat on reducing overall side effects of chemotherapy in AML patients receiving cytarabine and idarubicin induction or cytarabine consolidation chemotherapy.

This study enrolled patients with newly diagnosed, previously untreated AML; subjects with acute promyelocytic leukemia and acute megakaryoblastic leukemia subtypes were excluded.

All patients were to receive standard induction chemotherapy with cytarabine 100 mg/m2/day by continuous intravenous (IV) infusion over 24 hours daily for 7 days (Days 1-7) plus idarubicin 12 mg/m2/day by IV injection daily for 3 days (Days 1-3). For consolidation, patients younger than 60 were to receive cytarabine at a dose of 3 grams/m2 over 3 hours, every 12 hours on days 1, 3, and 5.

Induction cycle: dociparstat 4 mg/kg IV bolus Day 1, 30 minutes after completion of administration of the first dose of idarubicin, then dociparstat 0.25 mg/kg/hour for 24 hours daily by continuous IV infusion Days 1-7.

Consolidation cycle: dociparstat mg/kg IV bolus Day 1 administered 30 minutes after completion of infusion of the first dose of cytarabine then dociparstat 0.25 mg/kg/hour for 24 hours daily by continuous IV infusion Days 1-5

In total, there were 7 days in the induction cycle and 5 days in the consolidation cycles.

Study Timeline

• Study Start: 2013-12
• Study First Submitted: 2014-01-22
• Study First Submitted QC: 2014-02-04
• Study First Posted: 2014-02-06
• Primary Completion: 2015-02
• Study Completion: 2015-06
• Results First Submitted: 2015-08-06
• Status Verified: 2022-05
• Results First Submitted QC: 2022-05-20
• Last Update Submitted: 2022-05-20
• Results First Posted: 2023-02-21
• Last Update Posted: 2023-02-21

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 12

Inclusion Criteria

All patients had to meet the following criteria to be eligible for this study:

1. Had newly diagnosed, previously untreated acute myeloid leukemia (AML). Acute promyelocytic leukemia and acute megakaryoblastic leukemia subtypes were excluded
2. Had no prior chemotherapy for AML; however, prior hydroxyurea to control white blood cell count was allowed
3. Was aged 18 years or older.
4. Had an Eastern Cooperative Oncology Group (ECOG) Performance status of 0-2.
5. Had a cardiac ejection fraction ≥ 50% (echocardiography or Multi-Gated Acquisition Scan [MUGA]).
6. Had adequate hepatic and renal function (aspartate aminotransferase [AST], alanine aminotransferase [ALT], bilirubin and creatinine < 2.5 x upper normal limit).
7. Was able to provide informed consent and signed an approved consent form that conformed to federal and institutional guidelines.

Exclusion Criteria

Patients who met any of the following criteria were not eligible to be enrolled in this study:

1. Had acute promyelocytic leukemia.
2. Had acute megakaryoblastic leukemia.
3. Had central nervous system (CNS) leukemia
4. Had the presence of uncontrolled bleeding.
5. Had the presence of significant active infection that was uncontrolled, as judged by the Investigator.
6. Had a history of severe congestive heart failure or other cardiac disease that contraindicated the use of anthracyclines, including idarubicin.
7. Had pre-existing liver disease.
8. Had renal insufficiency, which, in the opinion of the Investigator, might have adversely affected the schedule and dose of therapy with cytarabine, as well as the management of tumor lysis syndrome. Patients with creatinine levels ≥2 mg/dL were not eligible.
9. Had use of recreational drugs or history of drug addiction, within the prior 6 months.
10. Had known history of positive hepatitis B surface antigens or hepatitis C virus (HCV) antibodies.
11. Had known history of positive test for human immunodeficiency virus (HIV) antibodies
12. Had psychiatric or neurologic conditions that could have compromised patient safety or compliance, or interfered with the ability to give proper informed consent.
13. Had history of other active malignant disease within 5 years, other than cured basal cell carcinoma of the skin, cured in situ carcinoma of the cervix, or localized prostate cancer that had received definitive therapy. Such prostate cancer patients who were receiving hormonal therapy were eligible.
14. Had the presence of disseminated intravascular coagulation, as confirmed by laboratory studies demonstrating evidence of both increased thrombin generation (decreased fibrinogen, prolonged prothrombin time [PT] and partial thromboplastin time [aPTT]), as well as increased fibrinolysis (elevated D-dimer level).
15. Had received any form of anticoagulant therapy.
16. Had the presence of a known bleeding disorder or coagulation abnormality.
17. Had received treatment with any other investigational agent within 7 days prior to study entry. All prior toxicities should have been resolved to no greater than Grade 1 (with the exception of alopecia).
18. Were pregnant or breast-feeding patients.
19. Were of childbearing potential and were not using adequate contraception.
20. Had any condition that required maintenance of platelet counts at 50,000/μL or higher.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Dociparstat	Dociparstat sodium	The following induction regimen was administered: * Cytarabine (100 mg/m2/day) via continuous intravenous (IV) infusion 24 hours daily for 7 days. * Idarubicin (12 mg/m2/day) IV on Days 1, 2, and 3. * Dociparstat (4 mg/kg) given over 5 minutes IV, immediately after the idarubicin dose on Day 1, followed by a continuous IV infusion (0.25 mg/kg/hr for 24 hours daily) for a total of 7 days.

Primary Outcome Measures

Name	Time	Method
Time (Days) to Transfusion-independent Platelet Recovery (Platelet Counts Values ≥ 20,000/μL and ≥ 50,000/μL Without a Platelet Transfusion)	Day 1 to Day 35 (35 days)	A primary endpoint of this study was evidence of an effect of dociparstat on transfusion independent platelet recovery time. The time (days) to transfusion-independent platelet recovery will be defined as the number of days from the first day of chemotherapy until the first of 5 consecutive days with platelet counts values ≥ 20,000/μL and ≥ 50,000/μL without a platelet transfusion.

Secondary Outcome Measures

Name	Time	Method
Number of Subjects Who Achieved a Morphologic Complete Remission	Day 1 to Day 35 (35 days)	A secondary endpoint of this study was to determine whether there was preliminary evidence of an effect of dociparstat on remission rate following cytarabine and idarubicin induction in acute myeloid leukemia (AML) patients, which included complete remission (CR) rate (with neutrophil and platelet count recovery) after the first induction cycle.; Morphologic CR was defined as absolute neutrophil count (ANC) \>1000/μL, platelet count \>100,000/μL, \<5% bone marrow blasts, no Auer rods, and no evidence of extramedullary disease.