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Arsenic Trioxide With or Without Ascorbic Acid in Treating Patients With Myelofibrosis

Primary Purpose

Essential Thrombocythemia, Polycythemia Vera, Primary Myelofibrosis

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Arsenic Trioxide
Ascorbic Acid
Laboratory Biomarker Analysis
Pharmacological Study
Sponsored by
Roswell Park Cancer Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Essential Thrombocythemia

Eligibility Criteria

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

Inclusion Criteria:

  • Diagnosis of primary myelofibrosis, essential thrombocythemia related myelofibrosis, or polycythemia vera related myelofibrosis requiring therapy, including:

    • Those previously treated and relapsed or refractory
    • Or, if newly diagnosed, with intermediate or high risk according to Lille scoring system (adverse prognostic factors are: hemoglobin [Hb] < 10 g/dl, white blood cell count [WBC] < 4 or > 30 x 10^9/L; risk group: 0 = low, 1 = intermediate, 2 = high)
    • Or with symptomatic splenomegaly (must be >= 23 cm by ultrasound in the longitudinal axis)
  • Signed informed consent: patients must have signed consents for both the arsenic trioxide with ascorbic acid protocol and for the hematologic malignancy procurement protocol to be eligible to participate
  • Patients must have been off any primary myelofibrosis (PMF)-directed experimental therapy for 4 weeks prior to entering this study and have recovered from the toxic effects (grade 0-1) of that therapy; treatment with hydroxyurea and erythropoietin are permitted until study initiation
  • Serum bilirubin levels =< 2 times the upper limit of the normal range for the laboratory (ULN); higher levels are acceptable if these can be attributed by treating physician to active hemolysis or ineffective erythropoiesis due to myelofibrosis
  • Serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) levels =< 2 x ULN
  • Serum creatinine levels =< 1.5 x ULN
  • Women of childbearing potential must have a negative serum or urine pregnancy test prior to arsenic trioxide treatment and should be advised to avoid becoming pregnant
  • Men must be advised to not father a child while receiving treatment with arsenic trioxide
  • Both women of childbearing potential and men must practice effective methods of contraception (those generally accepted as standard of care measures)
  • Women of childbearing potential are women who are not menopausal for 12 months or who have not undergone previous surgical sterilization
  • If the subject is a woman of childbearing potential, she must use a medically acceptable form of contraception during the study period and for 30 days thereafter
  • If the subject is a man he must be surgically sterile or must use a medically approved method of contraception for the duration of the study and for 60 days following the last dose of arsenic trioxide

Exclusion Criteria:

  • Nursing and pregnant females; should a woman become pregnant or suspects she is pregnant while participating in this study, she should inform her treating physician immediately
  • New York Heart Association (NYHA) grade II or greater congestive heart failure
  • Unstable angina
  • Corrected QT interval (QTc) > 450 in the presence of potassium >= 4 mEq/L and magnesium >= 1.7 mEq/L
  • Eastern Cooperative Oncology Group (ECOG) > 2
  • Major surgical procedure, open biopsy, or significant traumatic injury within 28 days, or anticipation of the need for major surgical procedure during the course of the study
  • Biopsy or other minor surgical procedure, excluding placement of a vascular access device or bone marrow biopsy, within 7 days prior to study enrollment
  • Ongoing serious, non-healing wound, ulcer, or bone fracture
  • Known hypersensitivity to any component of arsenic trioxide

Sites / Locations

  • Roswell Park Cancer Institute

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (arsenic trioxide with or without ascorbic acid)

Arm Description

Patients receive arsenic trioxide PO QD in orange juice on days 1-21. Patients may also receive ascorbic acid PO QD on days 1-21. Treatment repeats every 28 days for up to 168 days in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Adverse events, and their attribution throughout the study
The frequency of toxicities will be tabulated by grade across all dose levels and courses. The frequency of toxicities will also be tabulated for the dose chosen as the MTD.
Dose-limiting toxicity (DLT) as assessed by the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) version 3.0 (Stage 1)
DLT is defined as any non-hematologic treatment-emergent grade 3 or greater adverse event deemed possibly, probably, or definitely related to the study drug. Exceptions are grade 3 nausea or vomiting, unless in the setting of maximal antiemetic treatment. Hematologic toxicities are not included in the definition of a DLT. The frequency of toxicities will be tabulated by grade across all dose levels and cycles.
Maximum tolerated dose (MTD), defined as the dose level at which 0 or 1 of 6 subjects experience DLT, and 2 of 3 or 2 of 6 experience DLT at the next higher dose level, assessed by the NCI CTC version 3.0 (Stage 1)
The frequency of toxicities will be tabulated by grade across all dose levels and cycles. The frequency of toxicities will also be tabulated for the dose chosen as the MTD.

Secondary Outcome Measures

Change in absolute number of circulating CD34+ cells in the peripheral blood (Stage 2 only)
Change in JAK2/MPL (Stage 2 only)
Change in plasma levels of chemokines as measured by ELISA (Stage 2)
Including: sVCAM-1, NE, MMP-2, MMP-9, SDF-1, TGF-B, and VEGF.
Change in plasma levels of cytokines as measured by ELISA (Stage 2)
Including: sVCAM-1, NE, MMP-2, MMP-9, SDF-1, TGF-B, and VEGF.
Change in plasma levels of proteases as measured by enzyme-linked immunosorbent assay (ELISA) (Stage 2)
Including: soluble vascular cell adhesion molecule 1 (sVCAM-1), neutrophil elastase (NE), matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9), stromal cell derived growth factor-1 (SDF-1), TGF-B, and VEGF.
Disease response assessed using the IWG-MRT response criteria

Full Information

First Posted
November 16, 2009
Last Updated
July 20, 2022
Sponsor
Roswell Park Cancer Institute
Collaborators
Cephalon, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT01014546
Brief Title
Arsenic Trioxide With or Without Ascorbic Acid in Treating Patients With Myelofibrosis
Official Title
A Phase I Study of Oral Arsenic Trioxide With or Without Ascorbic Acid in Adults With Myelofibrosis
Study Type
Interventional

2. Study Status

Record Verification Date
July 2022
Overall Recruitment Status
Terminated
Why Stopped
low accrual
Study Start Date
April 2010 (undefined)
Primary Completion Date
February 2015 (Actual)
Study Completion Date
February 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Roswell Park Cancer Institute
Collaborators
Cephalon, Inc.

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This phase I trial studies the side effects and best dose of arsenic trioxide with or without ascorbic acid in treating patients with myelofibrosis. Drugs used in chemotherapy, such as arsenic trioxide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving arsenic acid together with ascorbic acid may kill more cancer cells.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the safety and maximum tolerated dose of oral arsenic trioxide with or without ascorbic acid in subjects with myelofibrosis. SECONDARY OBJECTIVES: I. To estimate the incidence, severity, and attribution of treatment-emergent adverse events. II. To estimate the rate of complete or major clinical-hematological response from treatment with arsenic trioxide and ascorbic acid in this subject population as measured by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) response criteria. III. To measure arsenic trioxide levels in the plasma of patients treated with and without ascorbic acid on this protocol. IV. To estimate the efficacy of arsenic trioxide with ascorbic acid in subjects with myelofibrosis, as determined by a reduction in Janus kinase 2 (JAK2) V617F, JAK22T875N, and mutations of the thrombopoietin receptor (MPL515L/K) allele frequency in peripheral blood neutrophils. V. To examine the effect of treatment on biological markers of myeloproliferation, cytokine production and hematopoietic stem cell mobilization. In particular, the following markers of disease will be measured: cluster of differentiation (CD)34+ cell count in peripheral blood measured by cytofluorimetry, plasma vascular endothelial growth factor (VEGF), transforming growth factor-beta (TGF-B), stromal cell-derived factor-1 (SDF-1), neutrophil elastase levels by commercial assays. VI. To examine single nucleotide polymorphism (SNP) in the arsenic trioxide pathway in subjects with myelofibrosis treated with arsenic trioxide and ascorbic acid. OUTLINE: This is a dose-escalation study of arsenic trioxide. Patients receive arsenic trioxide orally (PO) once daily (QD) in orange juice on days 1-21. Patients may also receive ascorbic acid PO QD on days 1-21. Treatment repeats every 28 days for up to 168 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then every 4 months for 1 year.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Essential Thrombocythemia, Polycythemia Vera, Primary Myelofibrosis

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
Treatment (arsenic trioxide with or without ascorbic acid)
Arm Type
Experimental
Arm Description
Patients receive arsenic trioxide PO QD in orange juice on days 1-21. Patients may also receive ascorbic acid PO QD on days 1-21. Treatment repeats every 28 days for up to 168 days in the absence of disease progression or unacceptable toxicity.
Intervention Type
Drug
Intervention Name(s)
Arsenic Trioxide
Other Intervention Name(s)
Arsenic (III) Oxide, Arsenic Sesquioxide, Arsenous Acid, Arsenous Acid Anhydride, Arsenous Oxide, Trisenox, White Arsenic
Intervention Description
Given PO
Intervention Type
Dietary Supplement
Intervention Name(s)
Ascorbic Acid
Other Intervention Name(s)
2-(1,2-dihydroxyethyl)-4,5-dihydroxy-furan-3-one, Asorbicap, C Vitamin, C-Long, Ce-Vi-Sol, Cecon, Cenolate, Cetane, Cevalin, L-Ascorbic Acid, VIT C, Vitamin C, Vitamin-C
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
Pharmacological Study
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Adverse events, and their attribution throughout the study
Description
The frequency of toxicities will be tabulated by grade across all dose levels and courses. The frequency of toxicities will also be tabulated for the dose chosen as the MTD.
Time Frame
Up to 30 days post-treatment
Title
Dose-limiting toxicity (DLT) as assessed by the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) version 3.0 (Stage 1)
Description
DLT is defined as any non-hematologic treatment-emergent grade 3 or greater adverse event deemed possibly, probably, or definitely related to the study drug. Exceptions are grade 3 nausea or vomiting, unless in the setting of maximal antiemetic treatment. Hematologic toxicities are not included in the definition of a DLT. The frequency of toxicities will be tabulated by grade across all dose levels and cycles.
Time Frame
At 28 days
Title
Maximum tolerated dose (MTD), defined as the dose level at which 0 or 1 of 6 subjects experience DLT, and 2 of 3 or 2 of 6 experience DLT at the next higher dose level, assessed by the NCI CTC version 3.0 (Stage 1)
Description
The frequency of toxicities will be tabulated by grade across all dose levels and cycles. The frequency of toxicities will also be tabulated for the dose chosen as the MTD.
Time Frame
At 28 days
Secondary Outcome Measure Information:
Title
Change in absolute number of circulating CD34+ cells in the peripheral blood (Stage 2 only)
Time Frame
Baseline to 24 weeks
Title
Change in JAK2/MPL (Stage 2 only)
Time Frame
Baseline to 24 weeks
Title
Change in plasma levels of chemokines as measured by ELISA (Stage 2)
Description
Including: sVCAM-1, NE, MMP-2, MMP-9, SDF-1, TGF-B, and VEGF.
Time Frame
Baseline to 24 weeks
Title
Change in plasma levels of cytokines as measured by ELISA (Stage 2)
Description
Including: sVCAM-1, NE, MMP-2, MMP-9, SDF-1, TGF-B, and VEGF.
Time Frame
Baseline to 24 weeks
Title
Change in plasma levels of proteases as measured by enzyme-linked immunosorbent assay (ELISA) (Stage 2)
Description
Including: soluble vascular cell adhesion molecule 1 (sVCAM-1), neutrophil elastase (NE), matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9), stromal cell derived growth factor-1 (SDF-1), TGF-B, and VEGF.
Time Frame
Baseline to 24 weeks
Title
Disease response assessed using the IWG-MRT response criteria
Time Frame
Up to 24 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
19 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Diagnosis of primary myelofibrosis, essential thrombocythemia related myelofibrosis, or polycythemia vera related myelofibrosis requiring therapy, including: Those previously treated and relapsed or refractory Or, if newly diagnosed, with intermediate or high risk according to Lille scoring system (adverse prognostic factors are: hemoglobin [Hb] < 10 g/dl, white blood cell count [WBC] < 4 or > 30 x 10^9/L; risk group: 0 = low, 1 = intermediate, 2 = high) Or with symptomatic splenomegaly (must be >= 23 cm by ultrasound in the longitudinal axis) Signed informed consent: patients must have signed consents for both the arsenic trioxide with ascorbic acid protocol and for the hematologic malignancy procurement protocol to be eligible to participate Patients must have been off any primary myelofibrosis (PMF)-directed experimental therapy for 4 weeks prior to entering this study and have recovered from the toxic effects (grade 0-1) of that therapy; treatment with hydroxyurea and erythropoietin are permitted until study initiation Serum bilirubin levels =< 2 times the upper limit of the normal range for the laboratory (ULN); higher levels are acceptable if these can be attributed by treating physician to active hemolysis or ineffective erythropoiesis due to myelofibrosis Serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) levels =< 2 x ULN Serum creatinine levels =< 1.5 x ULN Women of childbearing potential must have a negative serum or urine pregnancy test prior to arsenic trioxide treatment and should be advised to avoid becoming pregnant Men must be advised to not father a child while receiving treatment with arsenic trioxide Both women of childbearing potential and men must practice effective methods of contraception (those generally accepted as standard of care measures) Women of childbearing potential are women who are not menopausal for 12 months or who have not undergone previous surgical sterilization If the subject is a woman of childbearing potential, she must use a medically acceptable form of contraception during the study period and for 30 days thereafter If the subject is a man he must be surgically sterile or must use a medically approved method of contraception for the duration of the study and for 60 days following the last dose of arsenic trioxide Exclusion Criteria: Nursing and pregnant females; should a woman become pregnant or suspects she is pregnant while participating in this study, she should inform her treating physician immediately New York Heart Association (NYHA) grade II or greater congestive heart failure Unstable angina Corrected QT interval (QTc) > 450 in the presence of potassium >= 4 mEq/L and magnesium >= 1.7 mEq/L Eastern Cooperative Oncology Group (ECOG) > 2 Major surgical procedure, open biopsy, or significant traumatic injury within 28 days, or anticipation of the need for major surgical procedure during the course of the study Biopsy or other minor surgical procedure, excluding placement of a vascular access device or bone marrow biopsy, within 7 days prior to study enrollment Ongoing serious, non-healing wound, ulcer, or bone fracture Known hypersensitivity to any component of arsenic trioxide
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Eunice Wang, MD
Organizational Affiliation
Roswell Park Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Roswell Park Cancer Institute
City
Buffalo
State/Province
New York
ZIP/Postal Code
14263
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Arsenic Trioxide With or Without Ascorbic Acid in Treating Patients With Myelofibrosis

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