Phase I Study of ON 01910.Na in Refractory Leukemia or Myelodysplastic Syndrome (MDS)

NCT00854646 | Completed Phase 1

• 1 other identifier: Onconova 04-05
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

Brief Summary

This is an open-label, Phase I study to determine the highest amount of the study drug, ON 01910.Na, that can be safety given to patients with high risk myelodysplastic syndromes (MDS) or refractory leukemias. Patients will receive ON 01910.Na (at a starting dose of 650 mg/m2) intravenously by 3-day continuous infusion once every 2 weeks. Successive courses will use longer infusion times and/or higher doses of the drug until toxicity, effectiveness, or ineffectiveness is recognized. In addition, the amount of drug in the blood will be measured, any antitumor activity will be documented, and the biological effect of ON 01910.Na on cell-cycle pathways will be evaluated in peripheral blood mononuclear cells.

Conditions

Acute Myelocytic Leukemia; Acute Lymphocytic Leukemia; Chronic Myelocytic Leukemia; Chronic Lymphocytic Leukemia; Myelodysplastic Syndromes

Keywords

ON 01910.Na; refractory; leukemia; myelodysplastic; cell cycle

Outcome Measures

Primary Outcomes (1)

• Safety data, including laboratory parameters and adverse events, will be collected for all patients in order to determine the qualitative and quantitative toxicity, and reversibility of toxicity, of ON 01910.Na.

  2 - 4 months

Secondary Outcomes (1)

• To investigate the clinical pharmacology of ON 01910.Na including plasma pharmacokinetics, pharmacodynamics and biological effects on cell-cycle pathways.

  2 - 4 months

Study Arms (1)

ON 01910.Na

EXPERIMENTAL

The starting dose is 650 mg/m2 per day for 3 continuous days every 2 weeks. In successive courses, infusion time may be increased by 1 day up to 7 days every two weeks and/or drug dose may be increased (650, 1050, 1700 mg/m2/day, etc.). After 4 2-week cycles, cycle length may be extended to 3 or 4 weeks. Treatment continues until evidence of disease progression, intolerable adverse events or withdraw of consent.

Drug: ON 01910.Na

Interventions

ON 01910.Na DRUG

The drug is a sterile, concentrated 75mg/mL solution in polyethylene glycol 400, in labeled, sealed glass vials. The Concentrate must be diluted with aqueous infusion solutions (0.9% NaCl, USP and Water for Injection, USP according to instructions) immediately prior to intravenous administration.

Also known as: Sodium(E)2,4,6trimethoxystyryl-4methoxy-3glycylbenzylsulfone, rigosertib sodium

ON 01910.Na

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient must have histologically documented or cytologically confirmed diagnosis of acute myelocytic leukemia refractory to standard induction treatment, or relapsed after standard therapy
• Acute lymphocytic leukemia refractory to induction treatment, or relapsed after effective therapy
• Chronic myelocytic leukemia refractory to imatinib therapy or second line tyrosine kinase inhibition, or relapsed after tyrosine kinase inhibition, in chronic, accelerated, or blastic phase
• Chronic lymphocytic leukemia refractory to standard therapy, or relapsed in second relapse
• A myelodysplastic syndrome (including chronic myelomonocytic leukemia) refractory to a hypomethylating agent
• And a int-2 or high myelodysplastic syndrome relapsed after a hypomethylating agent.
• Patients may not be eligible for, or must have declined, bone marrow transplantation or other chemotherapeutic regimens known to produce consistent remissions.
• Patients with prior radiotherapy are eligible unless leukopenia is ascribed to prior radiation treatment, and then entry to study of ON 01910.Na may be initiated when two successive leukocyte counts are rising.
• ECOG Performance Status of 0, 1, or 2 if patient is in the dose escalation phase or 0 or 1 if patient is in the dose escalation phase.
• Patients may have any hematologic parameters without regard to numbers provided that transfusional support is available and the Investigator stipulates that leukopenia is attributable to disease rather than to prior therapy.
• Total bilirubin ≤ 1.5 mg/dL, unless the patient has active hemolysis, or the elevation is secondary to ineffective erythropoiesis.
• Serum creatinine ≤ 1.5 mg/dL, or a calculated creatinine clearance of ≥ 60 mL/min/1.73 m2.
• Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) while in the study. If a woman becomes pregnant or suspects she is pregnant while on study, her treating physician should be informed immediately.
• Ability to understand and the willingness to sign a written informed consent document.

You may not qualify if:

• Patients who have positive blood cultures until they are afebrile for 3 days on antibiotic therapy which will continue.
• Patients who have leukopenia attributed to prior chemotherapy until two successive leukocyte counts are increasing. Patients with rapidly rising WBC (e.g. \>50% increase over the previous day for 3 consecutive days) or WBC \> 40 x 109/L.
• Patients who have continuing toxicity other than hematologic from prior therapy until it has resolved to grade 1 or less and will not compromise ON 01910.Na administration.
• Patients who are receiving any other investigational agents or concurrent chemotherapy, radiotherapy, or immunotherapy.
• Patients receiving corticosteroids or colony-stimulating factors may continue on these treatments. These agents will not be introduced if previously not employed.
• Patients with known meningeal infiltration may be included in this clinical trial only if intrathecal therapy and/or radiation has been completed, and cerebrospinal fluid cytology is improved.
• Patients with a history of allergic reactions attributable to compounds of similar chemical or biologic composition to ON 01910.Na.
• Patients should have no major third space fluid accumulation, ascites requiring active medical management including paracentesis, peripheral bilateral edema, or hyponatremia (serum sodium value less than 134 Meq/L).
• Patients with uncontrolled intercurrent illness including, but not limited to uncontrolled ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant and nursing women are excluded from this study.
• HIV-positive patients receiving combination anti-retroviral therapy are excluded.

Sponsors & Collaborators

• Traws Pharma, Inc.: lead

Study Sites (1)

Mount Sinai Medical Center

New York, New York, 10029, United States

Location

Related Publications (5)

• Seetharam M, Fan AC, Tran M, Xu L, Renschler JP, Felsher DW, Sridhar K, Wilhelm F, Greenberg PL. Treatment of higher risk myelodysplastic syndrome patients unresponsive to hypomethylating agents with ON 01910.Na. Leuk Res. 2012 Jan;36(1):98-103. doi: 10.1016/j.leukres.2011.08.022. Epub 2011 Sep 14.

  PMID: 21924492 BACKGROUND

• Silverman LR, Greenberg P, Raza A, Olnes MJ, Holland JF, Reddy P, Maniar M, Wilhelm F. Clinical activity and safety of the dual pathway inhibitor rigosertib for higher risk myelodysplastic syndromes following DNA methyltransferase inhibitor therapy. Hematol Oncol. 2015 Jun;33(2):57-66. doi: 10.1002/hon.2137. Epub 2014 Apr 29.

  PMID: 24777753 RESULT

• Navada SC, Silverman LR. The safety and efficacy of rigosertib in the treatment of myelodysplastic syndromes. Expert Rev Anticancer Ther. 2016 Aug;16(8):805-10. doi: 10.1080/14737140.2016.1209413. Epub 2016 Jul 15.

  PMID: 27400247 RESULT

• Garcia-Manero G, Fenaux P. Comprehensive Analysis of Safety: Rigosertib in 557 Patients with Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML). Blood Dec 2016, 128 (22) 2011; ASH 2016.

  RESULT

• Navada SC, Fruchtman SM, Odchimar-Reissig R, Demakos EP, Petrone ME, Zbyszewski PS, Holland JF, Silverman LR. A phase 1/2 study of rigosertib in patients with myelodysplastic syndromes (MDS) and MDS progressed to acute myeloid leukemia. Leuk Res. 2018 Jan;64:10-16. doi: 10.1016/j.leukres.2017.11.006. Epub 2017 Nov 11.

  PMID: 29144985 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Lymphocytic, Chronic, B-Cell; Myelodysplastic Syndromes; Leukemia

Interventions

ON 01910

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Myeloproliferative Disorders; Bone Marrow Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Leukemia, B-Cell

Study Officials

• Lewis R. Silverman, MD

  Icahn School of Medicine at Mount Sinai

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 20, 2009
• First Posted: March 3, 2009
• Study Start: October 1, 2008
• Primary Completion: November 1, 2014
• Study Completion: December 1, 2015
• Last Updated: January 10, 2018

Record last verified: 2018-01

Locations

US (1)