Phase I/II, Multi-center, Dose-escalating Study of the Tolerability, Pharmacokinetics, and Clinical Activity of the Combined Administration of Oral Rigosertib with Azacitidine in Patients with Myelodysplastic Syndrome or Acute Myeloid Leukemia
Azacitidine,RIGOSERTIB SODIUM (ON 01910.Na)
The goal of the Phase I part of this clinical research study is to find the highest tolerable dose of rigosertib combined with Vidaza® (azacitidine) that can be given to patients with MDS, AML, or CMML. The goal of Phase II is to learn if rigosertib combined with azacitidine can help control MDS, AML, or CMML. The safety of this drug combination will also be studied.
Disease Group: Leukemia
Treatment Agent: Azacitidine,RIGOSERTIB SODIUM (ON 01910.Na)
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Onconova Therapeutics Inc.
Primary objectives: To assess the safety and tolerability of the combination of azacitidine (AZA) and oral rigosertib at increasing doses in a population of patients with myelodysplastic syndrome (MDS), non-proliferative acute myeloid leukemia (AML), or chronic myelomonocytic leukemia (CMML) and, To assess the pharmacokinetics of rigosertib at the recommended Phase II dose level. Secondary objectives: To evaluate the activity of the combination of azacitidine and oral rigosertib with respect to: Proportion of patients developing complete or partial response or bone marrow response according to International Working Group (IWG) criteria Hematological improvements in absolute neutrophil count, platelet count, and erythroid response/transfusion independence according to IWG criteria.
IRB Review and Approval Date: 05/09/2017
Recruitment Status: Open
Projected Accrual: Up to 80
1) >/=18 years of age;
2) Diagnosis of MDS, CMML, or RAEB-t/non-proliferative AML (as defined by 20-30% BMBL, WBC </=25,000 x 10^9/L and stable for at least 4 weeks without intervention) according to WHO criteria or FAB classification, either previously treated or previously untreated. The diagnosis must be confirmed via BM aspirate and/or biopsy within 6 weeks prior to Screening. Note: patients with RAEB-t/non proliferative AML (as defined by 20-30% BMBL,WBC </=25,000x10^9/L and stable for at least 4 weeks without intervention) are not eligible for the Phase II Part 1 RPTD component of the study and patients with CMML will not be eligible for Phase II Part 2 of the study;
3) If the patient has been diagnosed with MDS, it must be classified as Int-1, Intermediate-2 (Int-2) or High-risk, according to IPSS classification; Note: Only Int-2 or High-risk patients will be enrolled at the French site;
4) Off all other treatments for MDS, CMML, or AML, including ESA, for at least 4 weeks prior to Screening. Filgrastim (G-CSF) is allowed before and during the study, as clinically indicated;
5) For AML patients, no more than 1 prior salvage therapy;
6) ECOG performance status of 0, 1 or 2;
7) Willing to adhere to the prohibitions and restrictions specified in this protocol;
8) The patient must sign an informed consent form (ICF) indicating that s/he understands the purpose of and procedures required for the study and is willing to participate in the study.
1) Prior treatment with rigosertib;
2) Anemia due to factors other than MDS, CMML, or AML (including hemolysis or gastrointestinal [GI] bleeding);
3) Any active malignancy within the past year, except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix or breast;
4) Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia;
5) Active infection not adequately responding to appropriate therapy;
6) Total bilirubin >/=2.0 mg/dL not related to Gilbert’s disease or hemolysis;
7) Alanine transaminase (ALT)/aspartate transaminase (AST) >/=2.5 x upper limit of normal (ULN);
8) Serum creatinine >/=2.0 mg/dL;
9) Ascites requiring active medical management including paracentesis;
10) Hyponatremia (defined as serum sodium value of <130 mEq/L);
11) Female patients who are pregnant or lactating;
12) Female patients of childbearing potential and male patientswith partners of childbearing potential who are unwilling to follow strict contraception requirements (including 2 reliable methods in combination: one non-hormonal, highly-reliable method [diaphragm, condoms with spermicidal foam or jelly, or sterilization] plus one additional reliable method [birth control pills, intrauterine device, contraceptive injections, or contraceptive patches]) before entry and throughout the study, up to and including the 30-day nontreatment follow-up period;
13) Female patients with reproductive potential who do not have a negative blood or urine pregnancy test at Screening;
14) Major surgery without full recovery or major surgery within 3 weeks of Screening;
15) Uncontrolled hypertension (defined as a systolic pressure >/=160 mmHg and/or a diastolic pressure >/=110 mmHg);
16) New onset seizures (within 3 months prior to Screening) or poorly controlled seizures;
17) Any other investigational agent or chemotherapy, radiotherapy, or immunotherapy administered within 4 weeks prior to Screening;
18) Chronic use (>2 weeks) of corticosteroids (>10 mg/24 hr equivalent prednisone) within 4 weeks of Baseline/First Dose;
19) Investigational therapy within 4 weeks of Screening;
20) Psychiatric illness or social situation that would limit the patient’s ability to tolerate and/or comply with study requirements.
21) Patients with RAEB-t/non-proliferative AML (as defined by 20-30% BMBL, WBC </= 25,000 x 10^9/L and stable for at least 4 weeks without intervention) are not eligible to participate in the Phase II Part 1 RPTD portion of the study. Patients with CMML will not be eligible to participate in the Phase II Part 2 Expansion portion of the study.
Information and next steps
Phase I/Phase II
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