MDACC Study Summary 2009-0788

Study Summary
No. 2009-0788:.......Leukemia......Guillermo Garcia-Manero......Leukemia

Study Summary Title



Study Summary Number:	2009-0788

Study Title:	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

Physician

New Patient Referral



Name:	Guillermo Garcia-Manero	Patients Call:	800-392-1611 (in U.S.A.) 713-792-6161 (outside U.S.A.)

Dept:	Leukemia	Referring MD Call:	800-392-1611 (in U.S.A.) 713-792-6161 (outside U.S.A.)

Phone:	713-745-3428 Contact us about clinical trials

General Information



Disease Group:	Leukemia	Supported By:	AbbVie

Phase of Study:	Phase I	Return Visit:	weekly

Treatment Agents:	ABT-348 Azacitidine	Home Care:	NA

Treatment Loc:	Both at MDACC & outside MDACC at one or more Collaborating Sites or Institutions

Estimated Length of Stay in Houston:	none

Description/
Intervention:

The goal of this clinical research study is to find the highest tolerable dose
of ABT-348 that can be given alone or with Vidaza (azacitidine) to patients
with either leukemia or MDS. The safety of this drug or drug combination will
also be studied.

ABT-348 is designed to block proteins that cause cancer cells to grow and
multiply. ABT-348 is also designed to block the formation of new blood vessels
for the tumor. This may cause the cancer cells to die. This is the first study
using ABT-348 in humans.

Azacitidine is designed to block certain proteins in cancer cells whose job is
to stop the function of the tumor-fighting proteins. By blocking these
proteins, the tumor-fighting genes may be able to work better.

Study Objectives / Outcomes

The primary objectives of this study are to:

Determine safety and pharmacokinetics of orally and intravenously (IV) administered ABT-348 as monotherapy or when in combination with azacitidine in subjects with advanced hematologic malignancies.

The secondary objectives are to:

Determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RPTD) of ABT-348 when administered orally and IV as a monotherapy or when in combination with azacitidine in subjects with advanced hematologic malignancies.
Exploratory research to evaluate the effect of food on the oral bioavailability of ABT-348 and to find biomarkers that may serve as surrogates for clinical endpoints in future ABT-348 studies or that may be predictive of ABT-348 activity will be conducted.

Study Status Information



Study Activation / Registration Date:	04/15/2010

IRB Review and Approval Date:	04/16/2010

Study Type:	Phase I

Recruitment Status:	Closed

Projected Accrual:	80

Enrollment Eligibility

If you do not meet the enrollment eligibility, there may be other treatment options for you. Please Contact the Referral Office for more information.

Inclusion Criteria:

1) Subject must be greater or equal to 18 years of age.

2) 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.

3) Continued from #2: 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.

4) Continued from #3: 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., azacytibine/decitabine).

5) Continued from #4 -- Arm C: Relapsed or refractory AML, untreated AML in patients 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.

6) Subject has an Eastern Cooperative Oncology Group (ECOG) Performance status of 0 to 2.

7) Subject has adequate hematologic function for subjects with CLL and CML demonstrated by hemoglobin > 9 g/dL, platelets > 100,000/muL (100 x 10^9/L), ANC > 1,500/mm^3 (1.5 x 10^9/L).

8) Subject has adequate renal function as demonstrated by serum creatinine value of </= 1.8 � upper limit of normal (ULN) and either an estimated creatinine clearance value of >/= 50 mL/min as determined by Cockcroft-Gault formula or a creatinine clearance value of >/= 50 mL/min based on a 24-hour urine collection.

9) Subject has adequate liver function as demonstrated by serum bilirubin < 2 � ULN or AST and/or ALT < 2.5 x ULN unless considered due to leukemic organ involvement, in which case serum bilirubin < 2 � ULN and AST and ALT < 5 � ULN is allowed (Gilbert's or related syndrome allowed).

10) Subject has QTc interval less than 500 msec on baseline electrocardiogram.

11) The subject has a documented Left Ventricular Ejection Fraction greater than 50%.

12) Women of childbearing potential and men must agree to use adequate contraception (one of the following listed below) prior to study entry, for the duration of study participation and for 90 days following completion of therapy. Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment. Females will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) or are post-menopausal women (must be amenorrheic for at least 12 months).

13) # 12 continued: Total abstinence from sexual intercourse (for minimum of one complete menstrual cycle prior to Study Day 1); Surgical sterilization (bilateral oophorectomy or hysterectomy); Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) for at least 3 months prior to Study Day 1; Double-barrier method (contraceptive sponge, diaphragm or cervical cap with spermicidal jellies or cream plus a condom). Vasectomized male subjects or vasectomized partner of female subjects; Intrauterine Device (IUD);

14) Subject is capable of understanding and complying with parameters as outlined in the protocol and able to sign informed consent, approved by an Independent Ethic Committee (IEC)/Institutional Review Board (IRB) prior to the initiation of any screening or study-specific procedures, and in the opinion of the Study Investigator with agreement by the subject, currently no other treatment options exist that will provide benefit to the subject and/or the subject is willing to receive.

Exclusion Criteria:

1) Known active CNS involvement. The subject has untreated brain or meningeal metastases. CT scans are not required to rule out brain or meningeal metastases unless there is a clinical suspicion of central nervous system disease. Subjects with treated brain metastases that are radiographically or clinically stable for at least 4 weeks after therapy and have no evidence of cavitation or hemorrhage in the brain lesion(s) are eligible, providing that they are asymptomatic and do not require corticosteroids (must have discontinued steroids at least one week prior to study drug administration).

2) ALL or AML subjects who received acute anti-cancer therapy including chemotherapy, immunotherapy, radiotherapy, hormonal, biologic or any investigational therapy within 14 days or 5 half lives (whichever is shorter) prior to first dose of ABT-348. With the exception of hydroxyurea which may be used anytime during the study per investigator discretion.

3) CML, CLL or myelodysplasia (MDS) subjects who receive acute anti-cancer therapy including chemotherapy (except hydroxyurea and tyrosine kinase inhibitors), immunotherapy, radiotherapy, hormonal or any investigational therapy within 28 days or 5 half lives (whichever is shorter) or biologic therapy within 6 weeks prior to first dose of ABT-348. Per Investigator discretion, hydroxyurea may be used anytime during the study. Tyrosine kinase inhibitors may not be administered 7 days or 5 half-lives, whichever is shorter, prior to first dose of study drug administration.

4) Subjects with poorly controlled diabetes mellitus.

5) Subject has unresolved toxicities from prior anti-cancer therapy, defined as any Common Terminology Criteria for Adverse Events (CTCAE v 4.0) Grade 2 or higher clinically significant toxicity (excluding alopecia).

6) Subject has had major surgery within 28 days of first dose of ABT-348.

7) Subject currently exhibits symptomatic or persistent, uncontrolled hypertension defined as diastolic blood pressure greater than 90 mmHg or systolic blood pressure greater than 140 mmHg. Subjects may be re-screened if blood pressure is shown to be controlled with or without intervention.

8) The subject has proteinuria defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade > 1 at baseline as measured by a urine dipstick (2+ or greater) and confirmed by a 24 hour urine collection (>/= 1 g/24 hrs). Subjects may be re-screened if proteinuria is shown to be controlled with or without intervention.

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 investigator, places the subject at an unacceptably high risk for toxicities.

14) Clinically significant uncontrolled condition(s) including but not limited to: Active uncontrolled infection; Symptomatic congestive heart failure; Unstable angina pectoris or cardiac arrhythmia; Active adrenal insufficiency; Psychiatric illness/social situation that would limit compliance with study requirements

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).

Links

Registration Number: NCT01110473
Study Information on Clinical Trials Registry (clinicaltrials.gov)