MDACC Study Summary 2007-0502

Study Summary
No. 2007-0502:.......Leukemia......Jorge Cortes......Leukemia

Study Summary Title



Study Summary Number:	2007-0502

Study Title:	A Phase I Dose-Escalation Study of the Safety, Pharmacokinetics, and Pharmacodynamics of XL228 Administered Intravenously to Subjects with Chronic Myeloid Leukemia (CML) or Philadelphia-Chromosome-Positive Acute Lymphocytic Leukemia (Ph+ ALL) (XL228-001)

Physician

New Patient Referral



Name:	Jorge Cortes	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:	713-794-5783 Contact us about clinical trials

General Information



Disease Group:	Leukemia	Supported By:	Exelixis, Inc.

Phase of Study:	Phase I	Return Visit:	2-3 times per week

Treatment Agents:	XL228	Home Care:	n/a

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

Estimated Length of Stay in Houston:	None anticipated. However, will admit to hematology service beds if inpatient hospitalization is required.


Description/ Intervention:	The goal of this clinical research study is to determine the highest safe dose of XL228 that can safely be given to patients with CML or Ph+ ALL. How often XL228 should be given and how well people with CML or Ph+ ALL tolerate XL228 will also be studied.

Study Objectives / Outcomes

Primary objectives:

To assess the safety and tolerability of XL228 administered as once-weekly and twice-weekly 1-hour intravenous (IV) infusion in subjects with CML or Ph+ ALL.
To determine the maximum tolerated dose (MTD) dose limiting toxicity (DLT) of XL228 administered as once-weekly and/or twice-weekly 1-hour IV infusions in subjects with CML or Ph+ ALL.

Secondary objectives:

To evaluate plasma pharmacokinetics (PK) and estimate renal elimination of XL228 administered as a once-weekly and twice-weekly 1-hour IV infusion in subjects with CML or Ph+ ALL.

Exploratory objectives:

To evaluate hematologic, cytogenetic, and molecular response after repeated weekly administration of XL228 in subjects with CML or Ph+ ALL.
To evaluate the pharmacodynamic correlates of XL228 activity in plasma, circulating peripheral blood cells, and bone marrow leukemia cells in subjects with CML or Ph+ ALL.
To determine a clinically active dose (CAD) at a sub-MTD level that has demonstrated clinical response for XL228 administered as once-weekly and/or twice-weekly IV infusions in subjects with CML or Ph+ ALL.
To evaluate biomarkers that may predict response to XL228 and/or XL228-related toxicity.

Study Status Information



Study Activation / Registration Date:

IRB Review and Approval Date:	10/11/2007

Study Type:	Phase I

Recruitment Status:	Closed

Projected Accrual:	63

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) The subject has a confirmed diagnosis as evidenced by the presence of the BCR-ABL translocation [t(9;22)] by fluorescence in situ hybridization (FISH), cytogenetics, or quantitative polymerase chain reaction (QPCR) of one of the following: a) CML, as defined by the MD Anderson Criteria, modified: chronic phase (CP), accelerated phase (AP), blast phase (BP); or b) Ph+ ALL, as defined by the MD Anderson Criteria, modified.

2) The subject has one of the following: a) known T315I Abl mutation; b) known resistance to or intolerance of imatinib and either dasatinib or nilotinib as defined below: 1) in CML-CP, primary resistance is defined as failure to achieve a CHR following 3 months on therapy; failure to achieve any cytogenetic response (CyR) following 6 months on therapy, failure to achieve a major cytogenetic response (MCyR) following 12 months on therapy, or failure to achieve a complete cytogenetic response(CCyR) following 18 months on therapy.

3) **continued from above: Secondary resistance is defined as a loss of CHR (defined by leukocytosis confirmed with at least one WBC>15x10(3)/uL not felt to be due to a secondary cause); loss of a MCyR (defined by >/= 30% increase in the number of metaphases); or disease progression to AP or BP. In CML-AP or CML-BP, resistance is defined as the failure to achieve a hematologic response, an increasing WBC, or an overt disease progression;

4) **continued from above: 2) Intolerance is defined as discontinuation of prior therapy due to AEs at the lowest approved dose or if a subject can only tolerate prior therapy at less tan the lowest approved dose.

5) The subject is at least 18 years old.

6) The subject has an Eastern Cooperative Oncology Group (ECOG) performance status </= 2.

7) The subject has organ function as follows: serum creatinine </= 1.5 times the upper limit of normal (ULN) or calculated creatinine clearance >/= 60 mL/minute, total bilirubin </= 1.5 mg/dL, and alanine aminotransferase and aspartate transaminase </= 2.5 times the ULN if no liver involvement, or </= 5 times the ULN with liver involvement.

8) The subject is capable of understanding and complying with the protocol and has signed the informed consent document.

9) Sexually active subjects (male and female) must use medically acceptable methods of contraception during the course of the study and for at least 3 months after their last dose of XL228.

10) Female patients of childbearing potential must have a negative pregnancy test at baseline (within 4 days of first dose of XL228). Females of childbearing potential are defined as sexually mature women without prior hysterectomy or who have had any evidence of menses in the past 12 months. However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to chemotherapy, antiestrogens, or ovarian suppression.

Exclusion Criteria:

1) The subject has received anticancer treatment (eg, chemotherapy, radiotherapy, cytokines, investigational agent, or hormones), except interferon, imatinib, dasatinib, or nilotinib within 14 days before the first dose of Xl228.

2) The subject has received interferon, imatinib, dasatinib or nilotinib within 7 days of the first dose of XL228.

3) The subject has received immunosuppressive therapy (eg, cyclosporine, steroids, tacrolimus for graft-versus-host disease [GVHD]) within 28 days before the first dose of XL228.

4) The subject is currently taking medication known to be a potent CYP3A4 inhibitor or inducer.

5) The subject meets any of the following cardiac criteria: a) Inability to measure QT interval (eg, subject has a pacemaker or left bundle branch block); b) Corrected QT interval (QTc) of > 460 msec.; c) Known family history of congenital long QT syndrome or unexplained sudden death (NOTE: Subjects with a family history of these events may be potentially eligible if agreed to by the sponsor); d) History of sustained ventricular arrhythia;

6) **continued from above: e) History of significant heart disease (eg, congestive heart failure, myocardial infarction, angina) (NOTE: Subjects who have had chronic heart failure may still be enrolled if echocardiogram or MUGA (multi gated acquisition scan) are normal AND with sponsor approval); f) Current atrial tachyarrhythmia; g) Heart rate of < 50 beats per minute (bpm); h) Uncontrolled hypertension (>150 mm Hg systolic or > 100 mm Hg diastolic).

7) The subject is currently taking drugs known to be associated with Torsades de Pointes or significant QT interval prolongation.

8) The subject has not recovered to CTCAE v3.0 Grade </= 1 from toxicities related to peripheral stem cell or bone marrow transplant.

9) The subject has not recovered to CTCAE v3.0 Grade </= 1 from clinically significant AEs due to anticancer therapy.

10) The subject has known allergy or hypersensitivity to any component of the investigational drug product.

11) The subject has uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, diabetes, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

12) The subject has a fasting blood glucose > 160 mg/dL at baseline. (NOTE: If random plasma glucose results are < 160 mg/dL at baseline, then the subject meets this eligibility criteria)

13) The subject is pregnant or breastfeeding.

14) The subject is known to be positive for the human immunodeficency virus (HIV).

15) The subject has an inability or unwillingness to abide by the study protocol or cooperate fully with the investigator or designee.

Links

Registration Number: NCT00464113
Study Information on Clinical Trials Registry (clinicaltrials.gov)