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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


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Acute Lymphoblastic Leukemia, Acute Myelogenous Leukemia, B-cell Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Myelodysplasia

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Trial Information

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


The primary objectives of this study are to determine safety and pharmacokinetics of ABT-348
as monotherapy and when given in combination with azacitidine. The secondary objectives
are to determine the maximum tolerated dose and recommended Phase 2 dose of ABT-348 when
administered as monotherapy and when given in combination with azacitidine in subjects with
advanced hematologic malignancies.


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).

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Determine the safety profile (adverse events by toxicity grade and relationship to study drug, serious adverse events, adverse events leading to discontinuation and relevant clinical laboratory abnormalities) of ABT-348 as monotherapy or in combination

Outcome Time Frame:

At each treatment visit

Safety Issue:

Yes

Principal Investigator

Gary Gordon, MD

Investigator Role:

Study Director

Investigator Affiliation:

AbbVie

Authority:

United States: Food and Drug Administration

Study ID:

M10-943

NCT ID:

NCT01110473

Start Date:

April 2010

Completion Date:

September 2013

Related Keywords:

  • Acute Lymphoblastic Leukemia
  • Acute Myelogenous Leukemia
  • B-cell Chronic Lymphocytic Leukemia
  • Chronic Myelogenous Leukemia
  • Myelodysplasia
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Myelodysplastic Syndromes
  • Preleukemia
  • Hematologic Neoplasms

Name

Location

Site Reference ID/Investigator# 59324Scottsdale, Arizona  85259
Site Reference ID/Investigator# 26523Atlanta, Georgia  30322
Site Reference ID/Investigator# 26522Houston, Texas  77030-4009