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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Roswell Park Cancer Institute
ClinicalTrials.gov Identifier:
NCT01014546
First received: November 16, 2009
Last updated: July 21, 2015
Last verified: July 2015
  Purpose

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.


Condition Intervention Phase
Essential Thrombocythemia
Polycythemia Vera
Primary Myelofibrosis
Drug: Arsenic Trioxide
Dietary Supplement: Ascorbic Acid
Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study of Oral Arsenic Trioxide With or Without Ascorbic Acid in Adults With Myelofibrosis

Resource links provided by NLM:


Further study details as provided by Roswell Park Cancer Institute:

Primary Outcome Measures:
  • Adverse events, and their attribution throughout the study [ Time Frame: Up to 30 days post-treatment ] [ Designated as safety issue: Yes ]
    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) [ Time Frame: At 28 days ] [ Designated as safety issue: Yes ]
    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) [ Time Frame: At 28 days ] [ Designated as safety issue: Yes ]
    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) [ Time Frame: Baseline to 24 weeks ] [ Designated as safety issue: No ]
  • Change in JAK2/MPL (Stage 2 only) [ Time Frame: Baseline to 24 weeks ] [ Designated as safety issue: No ]
  • Change in plasma levels of chemokines as measured by ELISA (Stage 2) [ Time Frame: Baseline to 24 weeks ] [ Designated as safety issue: No ]
    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) [ Time Frame: Baseline to 24 weeks ] [ Designated as safety issue: No ]
    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) [ Time Frame: Baseline to 24 weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: Up to 24 weeks ] [ Designated as safety issue: No ]

Enrollment: 5
Study Start Date: April 2010
Primary Completion Date: February 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (arsenic trioxide with or without ascorbic acid)
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.
Drug: Arsenic Trioxide
Given PO
Other Names:
  • Arsenic (III) Oxide
  • Arsenic Sesquioxide
  • ARSENIC TRIOXIDE
  • Arsenous Acid
  • Arsenous Acid Anhydride
  • Arsenous Oxide
  • Trisenox
  • White Arsenic
Dietary Supplement: Ascorbic Acid
Given PO
Other Names:
  • 2-(1,2-dihydroxyethyl)-4,5-dihydroxy-furan-3-one
  • ASCORBIC ACID
  • Asorbicap
  • C Vitamin
  • C-Long
  • Ce-Vi-Sol
  • Cecon
  • Cenolate
  • Cetane
  • Cevalin
  • L-Ascorbic Acid
  • VIT C
  • Vitamin C
  • Vitamin-C
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies

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.

  Eligibility

Ages Eligible for Study:   19 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01014546

Locations
United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
Sponsors and Collaborators
Roswell Park Cancer Institute
Investigators
Principal Investigator: Meir Wetzler Roswell Park Cancer Institute
  More Information

No publications provided

Responsible Party: Roswell Park Cancer Institute
ClinicalTrials.gov Identifier: NCT01014546     History of Changes
Other Study ID Numbers: I 154609, NCI-2009-01660, I 154609, P30CA016056
Study First Received: November 16, 2009
Last Updated: July 21, 2015
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Arsenic trioxide
Ascorbic Acid
Polycythemia
Polycythemia Vera
Primary Myelofibrosis
Thrombocythemia, Essential
Thrombocytosis
Blood Coagulation Disorders
Blood Platelet Disorders
Bone Marrow Diseases
Hematologic Diseases
Hemorrhagic Disorders
Myeloproliferative Disorders
Vitamins
Antineoplastic Agents
Antioxidants
Growth Substances
Micronutrients
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Protective Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 28, 2015