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Study Summary
No. 2009-0129:.......Leukemia......Guillermo Garcia-Manero......Leukemia
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Study Summary Title
Study Summary
Number:		2009-0129
Study Title:A PHASE 1 STUDY OF ORAL ARRY-614 IN PATIENTS WITH LOW OR
INTERMEDIATE-1 RISK MYELODYSPLASTIC SYNDROME
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Physician New Patient Referral
Name:Guillermo Garcia-ManeroPatients Call:800-392-1611 (in U.S.A.) 713-792-6161 (outside U.S.A.)
Dept:LeukemiaReferring MD
Call:		800-392-1611 (in U.S.A.) 713-792-6161 (outside U.S.A.)
Phone:713-792-7026
Contact us about clinical trials
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General Information
Disease Group:LeukemiaSupported By:Array BioPharma
Phase of Study:Phase IReturn
Visit:		Days 1, 8, 15 and 22 of each cycle, 30 days after discontinuation and 4 month
followup
Treatment
Agents:		ARRY-614Home Care:Self-medicated
Treatment Loc:Both at MDACC & outside MDACC at one or more Collaborating Sites or Institutions
Estimated
Length of Stay
in Houston:		NA
Description/
Intervention:		The goal of this clinical research study is find the highest tolerable dose of
2 different schedules of ARRY-614 that can be given to patients with MDS. The
safety of this drug will also be studied.
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Study Objectives / Outcomes
Primary Objectives and Endpoints
1. To determine the safety profile and the maximum tolerated dose (MTD) of ARRY-614 as determined by dose-limiting toxicities (DLTs), the following endpoints will be evaluated:
    • Incidence and severity of adverse events (AEs), graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 3.0;
    • Findings of clinical laboratory abnormalities;
    • Changes in triplicate 12-lead electrocardiogram (ECG) parameters.

2. To characterize the plasma pharmacokinetic (PK) of ARRY-614 and a metabolite, AR00451575, the following endpoint will be evaluated:
    • Exposure-related PK parameters generated from ARRY-614 and AR00451575 plasma concentration-time data using standard PK analysis.

Secondary Objective and Endpoints
1. To obtain preliminary estimates of efficacy of ARRY-614, the following endpoints will be evaluated:
    • Erythroid hematological improvement (HI-E);
    • Cytogenetic response;
    • Response (complete response [CR], partial response [PR] and marrow CR);
    • Platelet hematological improvement (HI-P);
    • Neutrophil hematological improvement (HI-N);
    • Duration of response.

Exploratory Objectives and Endpoints
1. To obtain a preliminary assessment of the target inhibition in bone marrow and the biological activity of p38 MAPK inhibition in bone marrow and peripheral blood, the following endpoints will be evaluated:
    • Peripheral blood:
      • Assessment of effects on basal cytokine and growth factor levels (e.g., TNF-á, IL-6, erythropoietin [EPO]).
    • Bone marrow, as material is available:
      • Assessment of target inhibition (e.g., levels of phospho-p38, phospho-HSP27);
      • Assessment of effects on basal cytokine and growth factor levels (e.g., TNF-á, IL-6, EPO);
      • Assessment of effects on apoptosis (e.g., caspase 3);
      • Potential assessment of activation of other biological pathways (e.g., MEK).

2. Description of any possible PK/pharmacodynamic (PD) or PD/efficacy correlations.
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Study Status Information
Study Activation / Registration Date:
IRB Review and Approval Date:08/11/2009
Study Type:Phase I
Recruitment Status:Open
Projected Accrual:70
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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) Patients must meet all of the following criteria to be eligible for enrollment in the study.

2) Diagnosis of MDS by bone marrow biopsy.

3) Classification by the IPSS as low or intermediate-1 risk MDS according to cytogenetics, blood cytopenias and % bone marrow blasts.

4) Male or female, >/= 18 years of age at time of signing consent.

5) Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1 or 2.

6) Adequate liver and renal function: a. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and ALT/serum glutamic pyruvic transaminase (SGPT) </= 2.5 × ULN; b. Bilirubin < 1.5 mg/dL; c. Serum creatinine </= 2 mg/dL and a calculated creatinine clearance of >/= 50 mL/min (using the Cockcroft and Gault method).

7) Female patients of childbearing potential must have a negative serum or urine beta-human chorionic gonadotropin (beta-HCG) test.

8) Male patients and female patients of childbearing potential must agree to use an effective method of contraception per institutional standard.

9) Signed informed consent prior to initiation of any study-related procedures that are not considered standard of care.

10) Patients who require oral anticoagulants with coumarin derivates (e.g., warfarin, phenprocoumon) are eligible provided there is an increased vigilance with respect to international normalized ratio (INR) testing, per the oral anticoagulant package insert instructions.

11) Patients must meet all of the following criteria to be eligible for enrollment in the dose escalation phase of the study.

12) Patients may have received prior therapies for MDS. Newly diagnosed and previously untreated cases are also eligible if they require treatment and are not eligible for or refuse other treatment options.

13) All prior treatment, except hematopoietic growth factors, must have been discontinued prior to Day 1 of treatment in this study. The washout periods prior to first dose of ARRY-614 for prior treatments are: a. Azacitidine and decitabine: 2 weeks; b. Steroids: 4 weeks.

14) Patients must meet all of the following criteria to be eligible for enrollment in the expansion phase of the study.

15) Patients must be RBC transfusion dependent, defined as requiring >/= 4 units of RBCs administered with a pretreatment hemoglobin value of </= 9 g/dL in the 8 weeks prior to Day 1 of treatment in this study.

16) No more than 3 prior treatments for MDS are allowed. "Treatment" excludes the use of hematopoietic growth factors and immunotherapy. Newly diagnosed and previously untreated cases are also eligible if they require treatment and are not eligible for or refuse other treatment options.

17) All prior treatment must have been discontinued prior to Day 1 of treatment in this study. The washout periods prior to first dose of ARRY-614 for prior treatments are: a. Azacitidine and decitabine: 2 weeks; b. Growth factors such as EPO (Procrit®), granulocyte colony-stimulating factor (G-CSF, Neupogen®), granulocyte-macrophage colony-stimulating factor (GM-CSF, Leukine®): 1 week; c. Growth factors such as Aranesp® and Neulasta®: 3 weeks; d. Steroids: 4 weeks.
Exclusion Criteria:1) Patients meeting any of the following criteria are ineligible for enrollment in the study.

2) History of a bone marrow transplant.

3) Concomitant malignancies or previous malignancies with less than a 2-year disease-free interval at the time of enrollment. Patients with adequately resected basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, or Stage A low-grade prostate cancer may enroll irrespective of the time of diagnosis.

4) Medical, psychiatric, cognitive, or other conditions that compromise the patient's ability to understand the patient information, to give informed consent, to comply with the study protocol, or to complete the study.

5) Any severe concurrent disease or condition (including active systemic infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia) which, in the judgment of the Investigator, would make the patient inappropriate for study participation.

6) Significant gastrointestinal abnormalities, including an inability to take oral medication, requirement for intravenous (IV) alimentation, active peptic ulcer, or prior surgical procedures affecting absorption.

7) Use of an investigational agent that is not expected to be cleared by the first dosing of study drug or that has demonstrated to have late side effects. Patients should have recovered from the side effects to a Grade 0 or 1 (except alopecia).

8) Known positive serology for the human immunodeficiency virus (HIV), hepatitis C and/or active hepatitis B.

9) Patients meeting any of the following criteria are ineligible for enrollment in the dose escalation phase of the study.

10) On Day 1 receiving any treatment for MDS other than transfusions or hematopoietic growth factors.

11) Patients meeting any of the following criteria are ineligible for enrollment in the expansion phase of the study.

12) Secondary MDS requiring concurrent therapy for the primary cancer.

13) On Day 1 receiving any treatment for MDS other than transfusions.
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Links
Registration Number: NCT00916227
Study Information on Clinical Trials Registry (clinicaltrials.gov)
Other Links:
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Results

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