A Phase 1-2, Dose Escalation, Multicenter Study of Two Subcutaneous Regimens of SGI-110, a DNA Hypomethylating Agent, in Subjects with Intermediate or High-Risk Myelodysplastic Syndromes (MDS) or Acute Myelogenous Leukemia (AML)
The goal of this clinical research study is to find the highest tolerable dose of SGI-110 when given on different schedules in patients with MDS or AML. The safety of this drug will also be studied.
Disease Group: Leukemia
Treatment Agent: SGI-110
Treatment Location: Both at MD Anderson & Other Sites
Sponsor: Astex Pharmaceuticals, Inc.
Primary Objective Dose Escalation Segment: Determine the overall safety profile, including dose limiting toxicities (DLTs) and determine the recommended Dose Expansion Segment regimen(s) by identifying the optimal biologically effective dose (BED) for each regimen, based on maximum global DNA hypomethylation and gene expression, OR based on the maximum tolerated dose (MTD) whichever occurs first during dose escalation. Dose Expansion Segment: Evaluate the activity of SGI-110 as measured by overall remission rate. Secondary Objectives Determine the pharmacokinetic (PK) profile of SGI-110 and decitabine. Remission duration, hematological improvement and transfusion independence rates. Determine epigenetic modulation in peripheral blood and bone marrow samples and whether any putative biomarkers (eg, cytogenetic or molecular) for SGI-110 response exists.
IRB Review and Approval Date: 12/01/2010
Recruitment Status: Closed
Projected Accrual: up to 400
1) Subjects who are men or women, 18 years of age or older, with a
confirmed diagnosis of IPSS intermediate-1, intermediate-2 or high-risk
MDS including Chronic Myelomonocytic Leukemia (CMML) or AML. a) In the
Dose Escalation Segment, subjects who are refractory, relapsed, or
unresponsive to standard treatment will be the only ones allowed. b) In
the Dose Expansion Segment, HMA treatment naïve MDS subjects (including
CMML), and intermediate-2 or high-risk MDS subjects (including CMML)
relapsed or refractory to prior HMA treatment are allowed, and treatment
naïve AML subjects who are at least 65 years of age will be allowed if
they also have at least one of the following criteria: 1) AML secondary
to MDS, chemotherapy, or radiation therapy,
2) **Continued from above. 2) poor cytogenetics defined as monosomies or partial deletions of chromosome 5 or 7 (del(5q), del(7q), -5, -7), abnormalities involving the long arm of chromosome 3 (q21;q26), t(6;9) (p23;q34), t(9;22) (q34;q11.2), or abnormalities including the long arm of chromosome 11 (11q23), or subjects with 3 or more unrelated cytogenetic abnormalities of any kind; 3) pre-existing clinically significant dysfunction of the heart (left ventricular ejection fraction [LVEF] < 50%) or lung (diffusing capacity of the lung for carbon monoxide [DLCO] or forced expiratory volume in the first second [FEV(1)] < 50% of expected) which is unrelated to the leukemia; 4) poor performance status, Eastern Cooperative Oncology Group (ECOG), of 2; 5) age >/=75 years.
3) Subjects with ECOG performance status of 0 to 2.
4) Subjects with adequate organ function, defined as: a) Hepatic: Total bilirubin </= 2 X upper limit of normal (ULN); aspartate transaminase (AST/SGOT) and alanine transaminase (ALT/SGPT) </= 2.5 X ULN. b) Renal: serum creatinine </= 1.5 X ULN.
5) Women of child-bearing potential must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Woman of child-bearing potential and all men must be practicing two medically accepted methods of birth control. Women of non-childbearing potential are those having hysterectomy; bilateral oophorectomy; or menopause defined as no menses for at least 1 year AND either age >/= 65 years or follicle-stimulating hormone (FSH) levels in the menopausal range. Men should not father a child while receiving SGI-110 treatment and for 2 months following completion of treatment.
6) For subjects with prior allogeneic stem cell transplant, no evidence of active graft-versus host disease (GVHD) and must be >/= 2 weeks off immunosuppressive therapy.
7) Subjects with no major surgery within 4 weeks of first dose of SGI-110.
8) Subjects with no chemotherapy within 2 weeks of first dose of SGI-110 (minimum of 6 weeks for nitrosoureas and 8 weeks for bone marrow transplantation) with the exception of hydroxyurea which will be allowed during Course 1 of treatment.
9) Subjects who sign an approved informed consent form for the study.
10) Subjects who are willing to comply with the protocol.
1) In the Dose Expansion Segment, which includes the 10-day regimen,
subjects who have received 2 complete full dose cycles or more of a HMA
decitabine or azacitidine (except for intermediate-2 or high-risk MDS
subjects (including CMML) relapsed or refractory to prior HMA treatment).
2) Subjects with acute promyelocytic leukemia (M3 classification).
3) Subjects with prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject has been disease free for at least 3 years.
4) Subjects with a life-threatening illness other than MDS or AML, uncontrolled medical condition or organ system dysfunction which, in the investigator’s opinion, could compromise the subject’s safety, or put the study outcomes at risk.
5) Subjects with uncontrolled or symptomatic arrhythmias, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification.
6) Subjects with symptomatic central nervous system (CNS) metastases or lesions for which treatment is required.
7) Subjects who have received prior radiation therapy for extramedullary disease within 2 weeks of randomization.
8) Subjects with Grade >/= 2 toxicity (other than alopecia) continuing from prior anticancer therapy including radiation.
9) Subjects with known history of human immunodeficiency virus (HIV) or active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV).
10) Subjects who have been treated with any investigational drug within 2 weeks of randomization.
11) Subjects who are being treated with systemic corticosteroids as treatment for their MDS or AML. Corticosteroids treatment for other conditions is allowed.
12) Subjects with uncontrolled active systemic infections.
13) Subjects who have hypersensitivity to decitabine, SGI-110, or SGI-110 excipients.
14) With the exception of treatment-naïve elderly AML subjects, where certain co-morbidities are allowed per Inclusion Criterion #1b, subjects with uncontrolled CHF, CAD, COPD, or LVEF of </= 50% are excluded.