blood- and bone marrow cancer
Conditions
Interventions
Subjects will receive at least one cycle of 45mg/m2 of guadecitabine as once
daily doses on Days 1 to 5 of a 28-day cycle, of which the 5th (last) dose in
the first cycle will be spiked with approxi
Sponsors
Astex Pharmaceuticals, Inc
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: Subjects must fulfill all of the following inclusion criteria:;1. Male or female subjects, >=18 years of age at Screening;2. Body Mass Index (BMI) of 19.0 to 32.0 kg/m2, inclusive. Weight of at least 50 kg;3. For subjects with AML, MDS only:;a. Cytologically or histologically confirmed diagnosis of AML (except M3 acute promyelocytic leukemia) or MDS according to the 2008 World Health Organization (WHO) classification with the disease being refractory, relapsed, or unresponsive to standard treatment;b. Platelets >= 75,000/mm3;c. Absolute neutrophil count (ANC) >= 1000 cells/mm3;4. For subjects with solid tumors only:;a. Cytologically or histologically confirmed advanced solid tumor that is metastatic or unresectable, and for whom standard life-prolonging measures are not available.;b. Platelets >= 100,000/mm3;c. Absolute neutrophil >= 100 cells/mm3;5. Subjects with life expectancy of at least 16 weeks;6. Subjects with Eastern Cooperative Oncology Group (ECOG) performance status of 0-2;7. Subjects with acceptable organ function, as evidenced by laboratory data:;a. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =50 mL/min;d. International normalized ratio (INR) =40 mU/mL);or;b. practicing true abstinence for at least 28 days prior to dosing and agreeing to continue until 3 months after last study drug administration and having a negative urine pregnancy test at Screening and Day -1. Abstinence is acceptable only if it is consistent with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of birth control.;or;c. using 2 forms of highly effective contraception, out of which one should be a physical barrier (condom or diaphragm or cervical cap with spermicidals), and another method such as adequate hormonal method (e.g. contraceptive implants, injectables, oral contraceptives) or non-hormonal methods (e.g. intrauterine device [IUD]) from Screening or at least 28 days prior to study drug administration (whichever is earlier) until 3 months after the last study drug administration and having a negative urine pregnancy test at Screening and Day -1. Contraceptive measures which may be considered highly effective comprise combined hormonal contraception (oral, vaginal, or transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation, IUD, or intrauterine hormone-releasing system.;11. Males with partners of childbearing potential may be enrolled if they:;a. are documented to be surgically sterile (vasectomy) for at least 6 months before study drug administration;or;b. agree to practice true abstinence for at least 3 months after the last study drug administration (see also Inclusion Criterion 10b);or;c. agree to use 2 adequate forms of highl
Exclusion criteria
Exclusion criteria: Subjects meeting any of the following exclusion criteria will be excluded from the study:;1. Subjects who have known hypersensitivity to guadecitabine or decitabine;2. Subjects who have received radiation therapy, other locoregional therapy, or chemotherapy within 4 weeks prior to the first dose of study drug. Subjects must have recovered from any significant toxicities associated with previous therapies.;3. Subjects who have previously participated in human ADME studies and treated with radiolabeled drug.;4. Subjects who are at poor medical risk because of other systemic diseases or active uncontrolled infections;5. Subjects with a life-threatening illness, medical condition or organ system dysfunction, or other reasons which, in the Investigator*s opinion, could compromise the subject*s safety, interfere with the metabolism of guadecitabine, or compromise the integrity of the study outcomes;6. Subjects with abnormal left ventricular ejection fraction (=Grade 3 severity according to New York Heart Association (NYHA);8. Subjects with active hepatitis B infection should be on adequate antiviral therapy;9. Subjects with prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, non-metastatic prostate cancer with normal prostate specific antigen (PSA) or other cancer from which the subject has been disease free for at least three years;10. Subjects with known history or active disease of human immunodeficiency virus (HIV) or hepatitis B or hepatitis C (HCV), unless there is evidence for cured hepatitis C;11. History of alcohol abuse or drug addiction (including soft drugs like cannabis products);12. Average intake of more than 24 units of alcohol per week for male subjects and 17 units per week for female subjects (1 unit of alcohol equals 10 mL of pure alcohol, i.e. approximately 250 mL of beer, 75 mL of wine or 25 mL of spirits);13. Participation in a drug study within 60 days prior to first study drug administration in the current study;14. Donation or loss of more than 500 mL of blood within 60 days prior to the first study drug administration.;15. Women of child-bearing potential must not be pregnant or breastfeeding and must have a negative pregnancy test at screening.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary objectives: To evaluate the cumulative amounts and mass balance, and the time course of excretion of, 14C-radiolabeled drug material in urine and feces after subcutaneous administration of 14C-radiolabeled guadecitabine in subjects with AML, MDS, or solid tumors. To identify the major route(s) of elimination and excretion after subcutaneous administration of 14C-radiolabeled guadecitabine in subjects with AML, MDS, or solid tumors. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary objectives: To determine total 14C-radioactivity in whole blood and plasma, blood/plasma ratio and protein binding after subcutaneous administration of 14C-radiolabeled guadecitabine in subjects with AML, MDS, or solid tumors. To determine the pharmacokinetic profile of guadecitabine and active metabolite decitabine in plasma after subcutaneous administration of 14C-radiolabeled guadecitabine in subjects with AML, MDS, or solid tumors. To measure and identify, if applicable, the metabolites of guadecitabine (and secondary metabolites of decitabine) in plasma, urine and feces in subjects with AML, MDS, or solid tumors. To assess the safety and tolerability after subcutaneous administration of guadecitabine administered once daily for 5 consecutive days in 28-day cycles to subjects with AML, MDS, or solid tumors. | — |
Countries
Netherlands
Outcome results
None listed