A Phase 1 Study Evaluating the Safety and Pharmacokinetics of ABT-348 as Monotherapy and in Combination With Azacitidine in Subjects With Advanced Hematologic Malignancies
1. Histological or cytological confirmation of one of the following (Arms A, B and D):
- Relapsed or refractory acute myelogenous leukemia (AML), untreated AML in
subjects who are > 60 years of age and do not have favorable cytogenetics (i.e.,
lack t(8,21) or inv(16)/t(16,16) or acute lymphoblastic leukemia (ALL) in
subjects who have failed or are unsuitable for standard therapy.
- Chronic myelogenous leukemia (CML) subjects that have not responded or relapsed
on imatinib and failed second line Tyrosine Kinase Inhibitor (TKI) therapy and
are not a candidate for allogeneic bone marrow transplant.
- B-cell chronic lymphocytic leukemia (CLL) subjects that have not responded or
relapsed on fludarabine or in the opinion of the Principal Investigator are
unsuitable for fludarabine therapy and have not responded to or relapsed on
- Myelodysplasia (MDS) including chronic myelomonocytic leukemia (CMML) subjects
with International Prognostic Scoring System (IPSS) risk categories of
Intermediate-2 (INT-2) or High risk, or any myelodysplasia with symptomatic
anemia resistant to erythropoietin, immunosuppressant, or DNA methyltransferase
inhibitor therapy (e.g., azacitidine/decitabine).
1a. Histological or cytological confirmation of one of the following (Arm C):
- Relapsed or refractory AML, untreated AML in subjects who are > 60 years of age
and do not have favorable cytogenetics (i.e., lack t(8,21).
- Untreated MDS including CMML with IPSS risk categories of INT-2 or High risk or
with more than 10% blasts in the bone marrow, or any myelodysplasia with
symptomatic anemia resistant to erythropoietin, or immunosuppressant, or subject
has no response after four cycles of DNA methyltransferase inhibitor therapy or
subject has progressed on DNA methyltransferase inhibitor therapy.
2. Eastern Cooperative Oncology Group Status of 0-2
3. Hematologic function for subjects with CLL and CML demonstrated by hemoglobin > 9
g/dL, platelets > 100,000/µL, ANC > 1500/mm3
4. Serum creatinine value of ≤ 1.8 times the upper limit of normal (ULN) and either an
estimated creatinine clearance value as determined by the Cockcroft-Gault formula or
based on a 24 hour urine collection creatinine clearance value of ≥ 50 mL/min
5. Adequate liver function as demonstrated by serum bilirubin < 2 x ULN and AST and ALT
< 2.5 x ULN
6. QTc interval < 500 msec
7. Left Ventricular Ejection Fraction > 50%
8. Women of child-bearing potential and men must agree to use adequate contraception
prior to the study entry, for the duration of study participation and up to 3 months
following completion of therapy.
9. Capable of understanding and complying with parameters as outlined in the protocol
and able to sign informed consent, approved by an Institutional Review Board (IRB)
prior to the initiation of any screening or study-specific procedures.
1. Subject has known active CNS involvement. The subject has untreated brain or
2. ALL or AML subject has received acute anti-cancer therapy within 14 days prior to
Study Day 1
3. CML, CLL or myelodysplasia (MDS) subjects has received acute anti-cancer therapy
within 28 days or biologic therapy within 6 weeks prior to Study Day 1. Per
Investigator discretion, hydroxyurea may be used anytime during the study. Tyrosine
kinase inhibitors may not be administered 7 days prior to Study Day 1.
4. Subjects with poorly controlled diabetes mellitus
5. Subject has unresolved toxicities from prior anti-cancer therapy, grade 2 or higher
clinically significant toxicity (excluding alopecia)
6. Subject has had major surgery within 28 days prior to Study Day 1
7. Subject currently exhibits symptomatic or persistent, uncontrolled hypertension
defined as diastolic blood pressure > 90 mmHg or systolic blood pressure > 140 mmHg
8. Subject has proteinuria grade > 1
9. Subject is unable to swallow or absorb oral tablets normally
10. Subject is receiving therapeutic anticoagulation therapy. Low-dose anticoagulation
(e.g., low-dose heparin or warfarin) for catheter prophylaxis will be allowed
11. Subject has infection with HIV, Hepatitis B, or Hepatitis C
12. Female subjects who are pregnant or breast feeding
13. Any medical condition which in the opinion of the study investigator places the
subject at an unacceptably high risk for toxicities
14. Clinically significant uncontrolled condition(s)
15. Subjects in Arm C who have advanced malignant hepatic tumors
16. Subjects in Arm C who have hypersensitivity to azacitidine or mannitol
17. Subjects have received CYP3A inhibitors or inducers within 7 days prior to the first
dose of study drug.
18. Subjects enrolled in Arm D who have hypersensitivity to drugs formulated with
polyethoxylated castor oil (Cremophor).