Efficacy and Safety of ON 01910.Na in Myelodysplastic Syndrome (MDS) Patients With Trisomy 8 or Classified as Intermediate-1, -2 or High Risk

Phase 2

Completed

Conditions: Myelodysplastic Syndrome

Interventions: Drug: ON 01910.Na

Registration Number: NCT00906334

Lead Sponsor: Traws Pharma, Inc.

Brief Summary: This study will explore the efficacy and safety of a regimen of ON 01910.Na as a 48-hour continuous intravenous infusion once a week for 3 weeks of a 4-week cycle in MDS patients with Trisomy 8 or classified as Intermediate-1, -2 or High Risk who are not responding to current therapeutic options. The rationale for this trial is based upon data from laboratory studies with ON 01910.Na and upon activity that has been observed in other clinical trials with ON 01910.Na in patients with MDS.

Detailed Description: This is a phase 2, study in which 14 MDS patients with Trisomy 8 or classified as Intermediate-1, -2 and High risk who meet all other inclusion/exclusion criteria will receive ON 01910.Na 800 mg/m\^2/24h as an continuous intravenous infusion (CIV) over 48 hours once a week for 3 weeks of a 4-week cycle. As of Amendment 3 to the Protocol, the regimen is changed to 1800 mg/24h for 72 hours every other week for the first four 2-week cycles and every 4 weeks afterwards. The total study duration is 31 weeks, which includes a 2-week screening phase, a 27-week dosing phase, and a 4-week follow-up phase that begins after the last dose of ON 01910.Na. Beginning at week 4, and every 2 weeks thereafter, patients will be assessed for response. Patients who drop out for any reason will not be replaced. Patients who achieve by week 29 a complete or partial response or stabilization of their disease are eligible to receive an additional 24 weeks of ON 01910.Na 1800 mg/24 h over 72 hours per week of a 4-week cycle.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 14

Inclusion Criteria

Diagnosis of MDS confirmed within 2 weeks prior to study entry according to the World Health Organization (WHO) Criteria or the French-American-British (FAB) Classification.
Trisomy 8 cytogenetics (simple or combined to other karyotypes) or patient classified as Intermediate-1 with bone marrow blasts equal to or greater than 5%, Intermediate-2 or High Risk MDS according to the IPSS score, or Patients with peripheral blood blasts equal to or greater than 5%.
At least one cytopenia (Absolute Neutrophil Count < 1800/µl or Platelet Count <100,000/µl or Hemoglobin < 10 g/dL).
Failure of, or insufficient response to Azacytidine or Decitabine administered for 4 to 6 cycles in patients classified as Intermediate-2 or High risk or to Erythrocyte stimulating agents (failure or insufficient response defined as transfusion dependence or Hemoglobin remaining below 10 g/dl) in Low or Intermediate-1 Risk Trisomy 8 patients.
Failed to respond to, relapsed following, or opted not to participate in bone marrow transplantation.
Off all other treatments for MDS (including filgrastim (G-CSF) and erythropoietin) for at least four weeks. As an exception, filgrastim (G-CSF) can be used before, during and after the protocol treatment for patients with documented febrile neutropenia (< 500/µl).
ECOG Performance Status 0, 1 or 2.
Willing to adhere to the prohibitions and restrictions specified in this protocol.
Patient (or his/her legally authorized representative) must have signed an informed consent document indicating that he/she understands the purpose of and procedures required for the study and is willing to participate in the study.

Exclusion Criteria

Anemia due to factors other than MDS (including hemolysis or gastrointestinal bleeding).
Hypoplastic MDS (cellularity <10%).
Any active malignancy within the past year except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix or breast.
History of HIV-1 seropositivity.
Uncontrolled intercurrent illness including, but not limited to symptomatic congestive heart failure, unstable angina pectoris or cardiac arrhythmia.
Active infection not adequately responding to appropriate therapy.
Total bilirubin > 1.5 mg/dL not related to hemolysis or Gilbert's disease, ALT or AST > 2 X ULN.
Serum creatinine > 2.0 mg/dL or calculated creatinine clearance < 60 ml/min/1.73 m^2.
Ascites requiring active medical management including paracentesis, or hyponatremia (defined as serum sodium value of <134 Meq/L).
Women patients who are pregnant or lactating; Male patients with female sexual partners who are unwilling to follow the strict contraception requirements described in this protocol; Patients who do not agree to use adequate contraceptive [including prescription oral contraceptives (birth control pills), contraceptive injections, intrauterine device (IUD), double-barrier method (spermicidal jelly or foam with condoms or diaphragm), contraceptive patch, or surgical sterilization] before entry and throughout the study; Female patients with reproductive potential who do not have a negative serum beta-HCG pregnancy test at screening.
Major surgery without full recovery or major surgery within 3 weeks of ON 01910.Na treatment start.
Uncontrolled hypertension (defined as a systolic pressure equal to or greater than 160 mmHg and/or a diastolic pressure equal to or greater than 110 mmHg).
New onset seizures (within 3 months prior to the first dose of ON 01910.Na) or poorly controlled seizures
Any concurrent investigational agent or chemotherapy, radiotherapy or immunotherapy.
Treatment with standard MDS therapies or investigational therapy within 4 weeks of starting ON 01910.Na.
Psychiatric illness/social situations that would limit the patient's ability to tolerate and/or comply with study requirements.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
800 mg/m^2 ON 01910.Na	ON 01910.Na	800 mg/m\^2 ON 01910.Na administered as a continuous intravenous infusion (CIV) over 24 hours for 48 hours (i.e. 2 consecutive 24-hour infusions) every week for the first 3 weeks of 4-week cycle.
1800 mg ON 01910.Na	ON 01910.Na	1800 mg ON 01910.Na administered as a continuous intravenous infusion (CIV) over 24 hours for 72 hours (i.e., 3 consecutive 24-hour infusions) every 2 weeks for the first four 2-week cycles and every 4 weeks afterwards.

Primary Outcome Measures

Name	Time	Method
Overall Response Rate (ORR)	29 weeks	The Overall Response Rate is defined as the proportion of patients who achieve a Complete Response, a Partial Response, A Complete Bone Marrow Response or a Hematologic Improvement (HI) according to the 2006 International Working Group (IWG) criteria.
Number of patients with adverse events	From date of signing informed consent until 30 days after last dose of study drug up to 29 weeks	The NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 will be used to determine the grade of adverse events.

Secondary Outcome Measures

Name	Time	Method
Cytogenetic Response	29 weeks	Cytogenetic Response is defined as the number of patients who achieve a cytogenic response according to 2006 International Working Group criteria. Complete response is defined as the disappearance of the chromosomal abnormality without appearance of new ones. Partial response is defined as at least 50% reduction of the chromosomal abnormality.
Erythroid Response	29 weeks	The number of patients who achieve an Erythroid Response according to 2006 International Working Group (IWG). Erythroid Response is defined as a Hgb increase equal to or greater than 1.5 g/dL and a relevant reduction of units of red blood cells (RBC) transfusions by an absolute number of at least 4 RBC transfusions/8 weeks compared with the pretreatment transfusion number in the previous 8 wells. Only RBC transfusions given for a Hgb of 9.0 g/dL or lower pretreatment will count in the RBC transfusion response evaluation. Pretreatment values of Hgb must be lower than 11 g/dL.
Time to Acute Myeloid Leukemia (AML) Progression	29 and 53 weeks	Time to Acute Myeloid Leukemia (AML) Progression is calculated from date of first study drug administration to date of AML progression recorded on the Off Study Summary clinical report form. Patients who do not have AML disease progression are censored at the last bone marrow or bone marrow morphology assessment date.
Neutrophil Response	29 weeks	The number of patients who achieve a Neutrophil Response according to 2006 International Working Group (IWG). Neutrophil Response is defined as at least a 100% increase and an absolute increase greater than 0.5 x 10\^9/L. Pretreatment values must be less than 1.0 x 10\^9/L.
Time to Disease Progression	29 weeks	Time to Disease Progression is calculated from date of first dose of study drug administration to date of disease progression recorded on the hematology response assessment clinical report form.
Duration of Response	29 weeks	Duration of response is calculated from date of first occurrence of any of the following responses: Complete Response (CR), Partial Response (PR), Marrow Complete Response (BMCR) or Hematologic Improvement (HI) as defined by the 2006 International Working Group (IWG) criteria) until the date of disease progression. Patients who did not have disease progression are censored at the last bone marrow or bone marrow morphology assessment date.
Proportion of patients who achieve a Complete Hematologic Response	Up to 29 weeks	The proportion of patients who achieve a Complete Remission (CR) Hematologic Response according to 2006 International Working Group (IWG) criteria. Bone marrow blasts are determined in bone marrow differential count.
Time to Overall Response	29 weeks	Time to Overall Response is calculated from date of first study drug administration to date of first occurrence of any of the following responses: Complete Response (CR), Partial Response (PR), Marrow Complete Response (BMCR) or Hematologic Improvement (HI) as defined by the 2006 International Working Group (IWG) criteria.
Bone Marrow Complete Response	Weeks 5, 13, 21 and 29	The proportion of patients who achieve a Bone Marrow Complete Response (BMCR) according to 2006 International Working Group (IWG) criteria. Bone marrow blasts are determined in bone marrow differential count.
Platelet Response	29 weeks	The number of patients who achieve a Platelet Response according to 2006 International Working Group (IWG). Platelet Response is defined as an absolute of greater than or equal to 30 x 10\^9 for patients starting with less than 20 x 10\^9/L. increase and an absolute increase greater than 0.5 x 10\^9/L. Pretreatment values must be less than 1.0 x 10\^9/L.
Overall Survival	29 and 53 weeks	Overall Survival is calculated from date of first study drug administration to date of death. In event of no death prior to study termination or data analysis cutoff, overall survival is censored at the last known date patient was alive
The proportion of patients who achieve a Partial Remission (CR)	Up to 29 weeks	The proportion of patients who achieve a Partial Remission (PR) Hematologic Response according to 2006 International Working Group (IWG) criteria. Bone marrow blasts are determined in bone marrow differential count.