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CX-01 Combined With Azacitidine in the Treatment of Relapsed or Refractory Myelodysplastic Syndrome and Acute Myeloid Leukemia

Primary Purpose

Myelodysplastic Syndromes, Acute Myeloid Leukemia, AML

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
CX-01
Azacitidine
Bone marrow biopsy
Peripheral blood draw
Sponsored by
Washington University School of Medicine
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Myelodysplastic Syndromes

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • One of the following diagnoses:

    • MDS with International Prostate Symptom Score (IPSS) score of INT-1 or higher and one of the following:

      • Symptomatic anemia with either hemoglobin < 10.0 g/dL or requiring red blood cell (RBC) transfusion
      • Thrombocytopenia with a history of two or more platelet counts < 50,000/µL or a significant hemorrhage requiring platelet transfusions
      • Neutropenia with two or more absolute neutrophil count (ANC) < 1,000/µL
    • Non-M3 AML
  • Prior treatment with ≥ 4 cycles of a hypomethylating agent (decitabine or azacitidine) without response OR documented disease progression on or after hypomethylating agent therapy
  • Age ≥ 18 years old

  • Adequate renal and hepatic function defined as all of the following:

    • total bilirubin ≤ 1.5 x upper limit of normal (ULN), except in cases of Gilbert's disease
    • aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN
    • serum creatinine < 2.0 x ULN
  • Peripheral blood blast count < 10,000/ µL.
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
  • Females must be surgically or biologically sterile or postmenopausal or, if of childbearing potential, must agree to use an adequate method of contraception during the study until 30 days after the last treatment. Males must be surgically or biologically sterile or agree to use an adequate method of contraception during the study until 30 days after the last treatment.
  • Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

  • Prior allogeneic stem cell transplant
  • Central nervous system (CNS) leukemia
  • Diagnosed with AML and eligible for standard induction chemotherapy or stem cell transplantation.
  • At an increased risk of hemorrhage.
  • Known allergies, hypersensitivity, or intolerance to any form of heparin or azacitidine
  • Presence of significant active bleeding or condition requiring maintenance of a platelet count > 50,000/µL
  • Presence of any condition requiring any form of anticoagulant therapy (heparin flushes for IV catheter are permitted)
  • Receiving concomitant chemotherapy, radiation therapy, or immunotherapy during the duration of treatment on protocol, or within 21 days prior to enrollment
  • Known seropositivity for or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). Patients who are seropositive because of hepatitis B virus vaccine are eligible.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia
  • Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 28 days of study entry.

Sites / Locations

  • Washington University School of Medicine

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

CX-01 + Azacitidine

Arm Description

CX-01 will be administered as a 5-minute bolus infusion at a dose of 4mg/kg on Day 1 of each 28-day cycle, followed by a continuous intravenous infusion at a dose of 0.25 mg/kg/hour for Days 1 through 7 of each cycle. The dose of CX-01 should be calculated based on actual body weight (kg) as measured on Day 1 of each cycle. Azacitidine will be administered as a 15-minute intravenous infusion at a dose of 75mg/m^2 on Days 1-7 of each 28-day cycle. Azacitidine dose should be calculated based on actual body weight and height to determine BSA. CX-01 may be administered before or after azacitidine, at the discretion of the treating physician. Up to 6 cycles of treatment allowed

Outcomes

Primary Outcome Measures

Overall response rate (partial response or higher)
Overall response rate = the percentage of patients obtaining partial response or higher Patients will be assessed for response according to modified International Working Group (IWG) criteria

Secondary Outcome Measures

Progression-free survival (PFS)
The interval from the date of first dose of study drug to disease progression or death. Described by median time-to-event and a 95% confidence interval, if estimable, using Kaplan-Meier models
Disease-free survival (DFS)
The interval from the date of first documentation of a CR to date of recurrence or death. This is determined only for patients achieving a CR Described by median time-to-event and a 95% confidence interval, if estimable, using Kaplan-Meier models
Overall survival (OS)
The date of first dose of study drug to the date of death from any cause. Described by median time-to-event and a 95% confidence interval, if estimable, using Kaplan-Meier models
Safety and tolerability of regimen as measured by adverse events tabulated by patient
-The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be utilized for all toxicity reporting.

Full Information

First Posted
December 13, 2016
Last Updated
December 4, 2019
Sponsor
Washington University School of Medicine
Collaborators
Cantex Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT02995655
Brief Title
CX-01 Combined With Azacitidine in the Treatment of Relapsed or Refractory Myelodysplastic Syndrome and Acute Myeloid Leukemia
Official Title
A Pilot Study of CX-01 Combined With Azacitidine in the Treatment of Relapsed or Refractory Myelodysplastic Syndrome and Acute Myeloid Leukemia
Study Type
Interventional

2. Study Status

Record Verification Date
December 2019
Overall Recruitment Status
Completed
Study Start Date
April 7, 2017 (Actual)
Primary Completion Date
September 13, 2018 (Actual)
Study Completion Date
April 29, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Washington University School of Medicine
Collaborators
Cantex Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The investigators hypothesize that CX-01 will disrupt the bone marrow microenvironment and increase the cytotoxic effects of azacitidine on myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) hematopoietic stem cells by disrupting the High-mobility group box protein 1 (HMGB1) interaction with toll-like receptor 4 (TLR4) and receptors for advanced glycation end products (RAGE), the CXC chemokine CXCL12/chemokine receptor 4 (CXCR4) axis, and by disrupting other leukocyte and vascular adhesion molecules. In addition, CX-01 may also help promote count recovery after treatment given its affinity for platelet factor-4 (PF4). The selection of CX-01 dose for study in relapsed or refractory MDS and AML has been based upon the dual requirements to have sufficient drug administered to have potential activity but without clinically significant anticoagulation. The study dose chosen (4 mg/kg bolus followed by 0.25 mg/kg/hour) fulfills both of these criteria. In addition, this dose is expected to result in serum levels of CX-01 which are significantly higher than the IC90 identified in preclinical studies for inhibition of HMGB1-RAGE, toll-like receptor 2 (TLR2) and TLR4 interaction. Therefore, the chosen dose represents a rational balance between effective dosing and safety in thrombocytopenic patients with MDS and AML. This dose was previously established to be safe and tolerable when combined with cytarabine and idarubicin in patients with AML.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myelodysplastic Syndromes, Acute Myeloid Leukemia, AML, MDS

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
20 (Actual)

8. Arms, Groups, and Interventions

Arm Title
CX-01 + Azacitidine
Arm Type
Experimental
Arm Description
CX-01 will be administered as a 5-minute bolus infusion at a dose of 4mg/kg on Day 1 of each 28-day cycle, followed by a continuous intravenous infusion at a dose of 0.25 mg/kg/hour for Days 1 through 7 of each cycle. The dose of CX-01 should be calculated based on actual body weight (kg) as measured on Day 1 of each cycle. Azacitidine will be administered as a 15-minute intravenous infusion at a dose of 75mg/m^2 on Days 1-7 of each 28-day cycle. Azacitidine dose should be calculated based on actual body weight and height to determine BSA. CX-01 may be administered before or after azacitidine, at the discretion of the treating physician. Up to 6 cycles of treatment allowed
Intervention Type
Drug
Intervention Name(s)
CX-01
Other Intervention Name(s)
2-O, 3-O desulfated heparin, ODSH
Intervention Description
CX-01 at a dose of 4mg/kg on Day 1 of each 28-day cycle, followed by a continuous intravenous infusion at a dose of 0.25 mg/kg/hour for Days 1 through 7 of each cycle.
Intervention Type
Drug
Intervention Name(s)
Azacitidine
Other Intervention Name(s)
Vidaza®, Ladakamycin
Intervention Description
Azacitidine at a dose of 75mg/m^2 on Days 1-7 of each 28-day cycle.
Intervention Type
Procedure
Intervention Name(s)
Bone marrow biopsy
Intervention Description
-Baseline, day 28 of even-numbered cycle through Cycle 6, and end of study
Intervention Type
Procedure
Intervention Name(s)
Peripheral blood draw
Intervention Description
-Day 1 of each cycle, day 3 of each cycle, day 7 of each cycle, day 28 of every even-numbered cycle through Cycle 6, and end of study
Primary Outcome Measure Information:
Title
Overall response rate (partial response or higher)
Description
Overall response rate = the percentage of patients obtaining partial response or higher Patients will be assessed for response according to modified International Working Group (IWG) criteria
Time Frame
30 days following completion of treatment (estimated to be 28 weeks)
Secondary Outcome Measure Information:
Title
Progression-free survival (PFS)
Description
The interval from the date of first dose of study drug to disease progression or death. Described by median time-to-event and a 95% confidence interval, if estimable, using Kaplan-Meier models
Time Frame
Up to 5 years
Title
Disease-free survival (DFS)
Description
The interval from the date of first documentation of a CR to date of recurrence or death. This is determined only for patients achieving a CR Described by median time-to-event and a 95% confidence interval, if estimable, using Kaplan-Meier models
Time Frame
Up to 5 years
Title
Overall survival (OS)
Description
The date of first dose of study drug to the date of death from any cause. Described by median time-to-event and a 95% confidence interval, if estimable, using Kaplan-Meier models
Time Frame
Up to 5 years
Title
Safety and tolerability of regimen as measured by adverse events tabulated by patient
Description
-The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be utilized for all toxicity reporting.
Time Frame
30 days following completion of therapy (estimated to be 28 weeks)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: One of the following diagnoses: MDS with International Prostate Symptom Score (IPSS) score of INT-1 or higher and one of the following: Symptomatic anemia with either hemoglobin < 10.0 g/dL or requiring red blood cell (RBC) transfusion Thrombocytopenia with a history of two or more platelet counts < 50,000/µL or a significant hemorrhage requiring platelet transfusions Neutropenia with two or more absolute neutrophil count (ANC) < 1,000/µL Non-M3 AML Prior treatment with ≥ 4 cycles of a hypomethylating agent (decitabine or azacitidine) without response OR documented disease progression on or after hypomethylating agent therapy Age ≥ 18 years old Adequate renal and hepatic function defined as all of the following: total bilirubin ≤ 1.5 x upper limit of normal (ULN), except in cases of Gilbert's disease aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN serum creatinine < 2.0 x ULN Peripheral blood blast count < 10,000/ µL. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 Females must be surgically or biologically sterile or postmenopausal or, if of childbearing potential, must agree to use an adequate method of contraception during the study until 30 days after the last treatment. Males must be surgically or biologically sterile or agree to use an adequate method of contraception during the study until 30 days after the last treatment. Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable). Exclusion Criteria: Prior allogeneic stem cell transplant Central nervous system (CNS) leukemia Diagnosed with AML and eligible for standard induction chemotherapy or stem cell transplantation. At an increased risk of hemorrhage. Known allergies, hypersensitivity, or intolerance to any form of heparin or azacitidine Presence of significant active bleeding or condition requiring maintenance of a platelet count > 50,000/µL Presence of any condition requiring any form of anticoagulant therapy (heparin flushes for IV catheter are permitted) Receiving concomitant chemotherapy, radiation therapy, or immunotherapy during the duration of treatment on protocol, or within 21 days prior to enrollment Known seropositivity for or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). Patients who are seropositive because of hepatitis B virus vaccine are eligible. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 28 days of study entry.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Peter Westervelt, M.D., Ph.D.
Organizational Affiliation
Washington University School of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Links:
URL
http://www.siteman.wustl.edu
Description
Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Learn more about this trial

CX-01 Combined With Azacitidine in the Treatment of Relapsed or Refractory Myelodysplastic Syndrome and Acute Myeloid Leukemia

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