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

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

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.

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndromes; AML; MDS
• Intervention / Treatment: Drug: CX-01; Drug: Azacitidine; Procedure: Bone marrow biopsy; Procedure: Peripheral blood draw

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: CX-01 + Azacitidine; 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

Drug: CX-01; 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.; Other Names: ODSH; 2-O, 3-O desulfated heparin; Drug: Azacitidine; Azacitidine at a dose of 75mg/m^2 on Days 1-7 of each 28-day cycle.; Other Names: Ladakamycin; Vidaza®; Procedure: Bone marrow biopsy; -Baseline, day 28 of even-numbered cycle through Cycle 6, and end of study; Procedure: Peripheral blood draw; -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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	30 days following completion of treatment (estimated to be 28 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Up to 5 years
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	Up to 5 years
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	Up to 5 years
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.	30 days following completion of therapy (estimated to be 28 weeks)

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: Cantex Pharmaceuticals
• Investigators: Principal Investigator: Peter Westervelt, M.D., Ph.D., Washington University School of Medicine

Publications and helpful links

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): April 7, 2017
• Primary Completion (Actual): September 13, 2018
• Study Completion (Actual): April 29, 2019

Study Registration Dates

• First Submitted: December 13, 2016
• First Submitted That Met QC Criteria: December 13, 2016
• First Posted (Estimate): December 16, 2016

Study Record Updates

• Last Update Posted (Actual): December 5, 2019
• Last Update Submitted That Met QC Criteria: December 4, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Fibrinolytic Agents; Fibrin Modulating Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Anticoagulants; Heparin; Azacitidine
• Other Study ID Numbers: 201608032; CNTX-CX-01-2016-MDS-1 (Other Identifier: Cantex Pharmaceuticals)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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