Clinical trial NCT01110473 (phase 1, status: completed)
Conditions: acute lymphoblastic leukemia, acute myelogenous leukemia, b-cell chronic lymphocytic leukemia, chronic myelogenous leukemia, myelodysplasia
ICD codes: C91.01, C91.02, C91.00, C95.91, C95.92, Z80.6, Z85.6, C90.11, C90.12, C91.01, C91.11, C91.12, C91.10, C95.91, C95.92, Z80.6, Z85.6, C90.11, C90.12, C91.01
Drugs: abt-348, abt-348, abt-348 and azacitidine, abt-348
SMILES: NC1=C2C(SC=C2C2=CC=C(NC(=O)NC3=CC(F)=CC=C3)C=C2)=C(C=N1)C1=CN(CCO)N=C1, NC1=C2C(SC=C2C2=CC=C(NC(=O)NC3=CC(F)=CC=C3)C=C2)=C(C=N1)C1=CN(CCO)N=C1, NC1=C2C(SC=C2C2=CC=C(NC(=O)NC3=CC(F)=CC=C3)C=C2)=C(C=N1)C1=CN(CCO)N=C1, NC1=C2C(SC=C2C2=CC=C(NC(=O)NC3=CC(F)=CC=C3)C=C2)=C(C=N1)C1=CN(CCO)N=C1
Eligibility criteria:

        Inclusion Criteria:

          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
                  alkylating therapy.

               -  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.

        Exclusion Criteria:

          1. Subject has known active CNS involvement. The subject has untreated brain or meningeal
             metastases.

          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).