MDACC Study Summary 2007-0169

Study Summary
No. 2007-0169:.......Leukemia......Srdan Verstovsek......Leukemia

Study Summary Title



Study Summary Number:	2007-0169

Study Title:	A Phase 1/2, Open-Label Study of the JAK2 Inhibitor INCB018424 Administered Orally to Patients with Primary Myelofibrosis (PMF) and Post Polycythemia Vera/Essential Thrombocythemia Myelofibrosis (Post-PV/ET MF).

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:	713-792-7305 Contact us about clinical trials

General Information



Disease Group:	Leukemia	Supported By:	Incyte Incyte

Phase of Study:	Phase I/Phase II	Return Visit:	Cycle 1 - Day 1, 15 (Optional Day 8 and 22) Cycle 2, 3, 4 - Day 1 Every 3 months after Cycle 4 Participants will go to local laboratory for CBC and serum chemistry testing on Day 8 and Day 22 of cycle 1 and results will be monitored by the Investigtor

Treatment Agents:	JAK2 Inhibitor INCB018424	Home Care:	Study medications to be taken orally once or twice per day.

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

Estimated Length of Stay in Houston:	0

Description/
Intervention:

The goal of this clinical research study is to find the highest tolerable dose
of INCB018424 that can be given to patients with myelofibrosis as well as to
see if the study drug can help to control the disease. To further study safety
and effectiveness of the selected starting doses, the researchers will study
the treatment's effect on each participant's quality of life, their ability to
perform routine daily activities, their body composition, and the size of their
spleen, in Part 3. Part 3 will also allow for individual dose adjustments
based on effectiveness and safety information

Information from this study will be used to develop a better understanding of
how the study medication works in people with and without a specific genetic
mutation (a JAK2 mutation).

Study Objectives / Outcomes

To determine the safety and tolerability of oral INCB018424 in patients with Primary Myelofibrosis (PMF) and Post Polycythemia Vera/Essential Thrombocythemia Myelofibrosis (Post-PV/ET MF).

To determine the Dose Limiting Toxicity (DLT) and the Maximum Tolerated Dose (MTD) of oral INCB018424 in patients with PMF and Post-PV/ET MF.

To determine a therapeutic dose for the expanded cohort.

To study preliminary effectiveness of oral INCB018424 in a patient population diagnosed with PMF and Post-PV/ET MF.

To determine the pharmacokinetics (PK) of oral INCB018424.

To assess pharmacodynamic activity including phosphorylation status of signal transducer and activator of transcription (STAT) protein in blood cells and determination of plasma protein marker and cytokine levels.

To evaluate alternative dosing schedules to potentially improve safety, tolerability and efficacy.

To obtain preliminary data on changes in symptoms of myelofibrosis (MF) and changes in quality of life.

To obtain preliminary data on changes in daily voluntary physical activity and exercise capacity as assessed by Stepwatch™ Activity Monitor (SAM) and the six minute walk test (6MWT), respectively.

To obtain preliminary data on changes in body composition, grip strength and quadriceps size.

To obtain preliminary data on correlation between MRI-based assessment of spleen and liver volume and organ size assessed by palpation

To determine the duration of maintenance of spleen volume reduction as measured by MRI.

To obtain preliminary data on the effect of dose on an individual patient basis as appropriate.

Study Status Information



Study Activation / Registration Date:	06/21/2007

IRB Review and Approval Date:	05/18/2007

Study Type:	Phase Ii Or Phase I/Ii

Recruitment Status:	Open

Projected Accrual:	206

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) Must be at least 18 years of age with life expectancy of at least 12 weeks

2) Must be diagnosed with PMF or Post-PV/ET MF, irrespective of JAK2 mutation status.

3) Patients with myelofibrosis requiring therapy, including those previously treated by myelofibrosis directed therapy who have subsequently relapsed or are refractory; or, if newly diagnosed, should be intermediate or high risk according to Lille (Dupriez) Scoring System (Dupriez et al, 1996), (adverse prognostic risk factors are: Hgb < 10g/dL, WBC < 4 or > 30x10^9/L; risk group: 0 factor=low, 1 factor = intermediate, 2 factors = high); or with symptomatic splenomegaly that is > 10 cm below costal margin.

4) Must have palpable spleen measuring 10 cm or greater below the costal margin (Patients in Part 3, Group III only). However, with permission of the sponsor, patients with spleen size of ≤ 10 cm, or in rare cases, with prior splenectomy, but ongoing hepatomegaly may be enrolled in Part 3, Group III.

5) Have adequate bone marrow reserve as demonstrated by: a) absolute neutrophil count (ANC) that is > 1500/�L b)platelet count that is > 100,000/�L without the assistance of growth factors.

6) Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2, in Part 1, Part 2, Part 3 Group l and ll and status of 1 or 2 in Part 3 Group lll.

7) Have adequate liver and renal function. a)Total bilirubin ≤ 2.0 mg/dL. b)Alanine aminotransferase (ALT) ≤ 2.5x institutional upper limit of normal (ULN) or ≤ 5x institutional upper limit of normal if the liver is involved by malignancy as judged by the treating physician and the Investigator with documented justification. c)Creatinine ≤ 2.5 mg/dL.

8) A female of childbearing potential must have a negative serum pregnancy test at screening.

9) Females will be either postmenopausal for at least 1 year with documented FSH > 30 IU/L or surgically sterile for at least 3 months OR females of child-bearing potential who must agree to take appropriate precautions to avoid pregnancy from screening through follow-up. For all females, the pregnancy test result must be negative at Screening. Males must agree to take appropriate precautions to avoid fathering a child from screening through follow-up.

10) Is able to comprehend and is willing to sign an informed consent form.

Exclusion Criteria:

1) Females who are pregnant or are currently breastfeeding

2) Patients who received any anticancer medications or investigational therapy in the 14 days (28 days for Busulfan and pegylated interferon) prior to receiving their first dose of study medication.

3) Patients receiving therapy with intermediate or high dose steroids greater than the equivalent of 10 mg prednisone per day are not allowed.

4) Patients diagnosed with another malignancy, unless disease free. Patients with early stage squamous cell carcinoma of the skin, basal cell carcinoma of the skin or cervical intraepithelial neoplasia may be eligible for participation at the Investigator's discretion

5) Patients with known active hepatitis A, B, C or who are HIV-positive. Evidence for active hepatitis includes elevation of ALT and AST, and other clinical evidence of active helpatitis infection.

6) Patients with any unresolved toxicity greater or equal to Grade 2 from previous anticancer therapy, except for stable chronic toxicities not expected to resolve, such as peripheral neurotoxicity.

7) Patients with New York Heart Association Criteria Class IV impairments (Patients in Part 3, Group III only). Patients with Class III impairments may only be enrolled if in the judgment of the investigator, the potential benefits outweigh the potential risks (See Appendix XIV). This exclusion does not apply to subjects enrolling in the study under Amendment 7.

8) Patients with Incomplete recovery from any prior surgical procedures or who have had surgery within 4 weeks prior to study entry, excluding the placement of vascular access.

9) Presence of acute active infection requiring antibiotics.

10) Patients with uncontrolled intercurrent illness or any concurrent condition that, in the Investigator's opinion, would jeopardize the safety of the patient or compliance with the protocol.

11) Any current or planned therapy with CYP3A4 and CYP1A2 inhibitors or inducers (including smoking) unless approved by the Sponsor. (see Appendix VII)

12) Prior treatment with another oral JAK inhibitor is not permitted unless agree to by both the Investigator and the Sponsor. Any prior oral JAK inhibitor therapy must have been completed at least 14 days or 6 half-lives, whichever is longer, prior to the first dose of study medication.

13) In addition, the following will preclude participation by the patient in the 6MWT, and if occurring at the Screening Visit from participation in the study exept with Sponsor's approval. 1. History of or current unstable angina. 2. History recent (within 2 years) myocardial infarction. 3. Patients unable to walk. 4. Patients with unstable gait that persists with the use of assistive device (cane or walker) 5. Resting heart rate > 120 beats per minute. 6. Resting systolic blood pressure > 180 mm Hg. 7. Resting diastolic blood pressure > 100 mm Hg.

Links

Registration Number: NCT00509899
Study Information on Clinical Trials Registry (clinicaltrials.gov)