MDACC Study Summary 2007-0373

Study Summary
No. 2007-0373:.......Leukemia......Srdan Verstovsek......Leukemia

Study Summary Title



Study Summary Number:	2007-0373

Study Title:	A Phase 1 Dose-Escalation Study of the Safety, Pharmacokinetics, and Pharmacodynamics of XL019 Administered to Subjects with Myeloproliferative Disorders

Physician

New Patient Referral



Name:	Srdan Verstovsek	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:	713-745-3429 Contact us about clinical trials

General Information



Disease Group:	Leukemia	Supported By:	Exelixis Exelixis

Phase of Study:	Phase I	Return Visit:	Weekly during the first month, then every 2 weeks for 4 months, then monthly

Treatment Agents:	XL019	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:	N/A


Description/ Intervention:	The goal of this clinical research study is to find a safe and tolerable dose of XL019 that can be given to patients with myelofibrosis. The safety of this drug, including how often it should be taken, will also be studied.

Study Objectives / Outcomes

Primary Objective

To evaluate the safety and tolerability of XL019 as a single agent when orally administered once daily (qd) or once every Monday, Wednesday, and Friday (qMWF) in subjects with PMF, post-PV MF, or post-ET MF.
To determine the maximum tolerated dose (MTD) and or a CAD at a sub-MTD level that has demonstrated clinical response for XL019, as well as the DLTs for XL019 when orally administered qd or qMWF in subjects with PMF, post-PV MF, or post-ET MF

Secondary objectives:

To determine the plasma pharmacokinetics (PK) and estimate renal elimination of XL019 and its putative metabolite EXEL-5887 when XL019 is orally administered once daily (QD) or once every Monday, Wednesday, and Friday or qMWF in subjects with PMF, post-PV MF, or post-ET MF.
To evaluate the pharmacodynamic correlates of XL019 activity in peripheral blood and bone marrow in subjects with PMF, post-PV MF, or post-ET MF.
To evaluate the long-term safety and tolerability of XL019 as a single agent when orally administered qd or qMWF in 28-day cycles in subjects with PMF, post-PV MF, or post-ET MF.
To evaluate preliminary efficacy of XL019 as a single agent when orally administered qd or qMWF in 28-day cycles in subjects with PMF, post-PV MF, or post-ET MF based on the following endpoints: (i) response rate (hematologic, cytogenetic, bone marrow fibrosis); (ii) reduction in splenomegaly and/or hepatomegaly; (iii) time to response; (iv) duration of response; (v) reduction in JAK2-V617F allele burden; (vi) transfusion dependence; and (vii) impact on quality of life (QOL); and (viii) impact on functional exercise capacity.
To evaluate the correlation between changes in portal hypertension and XL019 treatment in subjects with PMF, post-PV MF, or post-ET MF.

Study Status Information



Study Activation / Registration Date:	07/30/2007

IRB Review and Approval Date:	07/30/2007

Study Type:	Phase I

Recruitment Status:	Closed

Projected Accrual:	100

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 PMF, post-PV MF, or post-ET MF and requires therapy, including subjects who have received prior MF-directed therapy and relapsed or subjects with refractory disease; or if newly diagnosed, then with intermediate or high risk according to the Lille scoring system (adverse prognostic factors are: Hgb <10 g/dL, WBC <4000/mm^3 or >30,000/mm^3; risk group: 0 = low, 1 = intermediate, 2 = high), or with symptomatic spleen that is >/=10 cm below costal margin.

2) The subject is unwilling to undergo or is not a candidate for peripheral stem cell/bone marrow transplant.

3) The subject is >/=18 years old.

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

5) The subject has adequate organ function as follows: a) Serum creatinine </=1.5 times the upper limit of normal (ULN) or calculated creatinine clearance >/=60 mL/min; b) Bilirubin </=2.0 mg/dL; c) ALT and AST </=2.5 times the upper limit of normal if no liver involvement or </=5 times the upper limit of normal with liver involvement

6) For subjects who have received transfusions due to MF, the subject has a documented blood transfusion history for 8 weeks prior to study enrollment.

7) The subject has a corrected QT interval (QTc) </=0.46 seconds using the Bazette Formula.

8) The subject has the capability of understanding the informed consent document 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 following their last dose of XL019.

10) Female subjects of childbearing potential must have a negative pregnancy test at screening. 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 prior chemotherapy, antiestrogens, or ovarian suppression

11) The subject has no other diagnosis of malignancy or evidence of other malignancy for 2 years prior to screening for this study (except non-melanoma skin cancer or in situ carcinoma of the cervix)

Exclusion Criteria:

1) The subject has received anticancer treatment (eg, chemotherapy, radiotherapy, immunotherapy, biologic therapy, or investigational agent) within 14 days, other than hydroxyurea or anagrelide, prior to the first dose of study drug.

2) The subject has received hydroxyurea or anagrelide within 7 days prior to the first dose of study drug

3) The subject has not recovered to Grade </=1 from clinically significant AEs due to investigational agents, peripheral stem cell/bone marrow transplant, or other medications administered more than 14 days prior to the first dose of study drug

4) The subject has received treatment for diabetes mellitus with oral hypoglycemic agents or insulin for >5 years duration prior to screening

5) The subject has a history of dementia or peripheral neuropathy, or any other clinically significant neurologic diseases, or the subject has evidence of peripheral neuropathy.

6) The subject has uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, hypertension, symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within 3 months, or cardiac arrhythmias.

7) The subject is pregnant or breastfeeding.

8) The subject is known to be positive for the human immunodeficiency virus (HIV).

9) The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee

10) The subject has a known allergy or hypersensitivity to any of the components of the XL019 formulation.

11) The subject has a Total Neuropathy Score-Clinical (TNSc: the modified TNS version based exclusively on the clinical evaluation of the subjects) >/=2 based on neurologic examination at screening

12) The subject has abnormal nerve conduction study (NCS) results at screening

Links

Registration Number: NCT00522574
Study Information on Clinical Trials Registry (clinicaltrials.gov)