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Study Safety and Preliminary Efficacy of DCC-2036 in Patients With Leukemias (Ph+ CML With T315I Mutation)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00827138
Recruitment Status : Completed
First Posted : January 22, 2009
Last Update Posted : July 18, 2014
Information provided by (Responsible Party):
Deciphera Pharmaceuticals LLC

Tracking Information
First Submitted Date  ICMJE January 21, 2009
First Posted Date  ICMJE January 22, 2009
Last Update Posted Date July 18, 2014
Study Start Date  ICMJE March 2009
Actual Primary Completion Date January 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 21, 2009)
Assess the safety and tolerability of the drug [ Time Frame: Completion of the study ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 21, 2009)
Determine the Pharmacokinetic profile and preliminary evidence of clinical response [ Time Frame: Completion of the study ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Study Safety and Preliminary Efficacy of DCC-2036 in Patients With Leukemias (Ph+ CML With T315I Mutation)
Official Title  ICMJE A Multicenter Phase 1 Clinical and Pharmacokinetic Study of DCC-2036 in Subjects With Leukemias (Ph+CML With T315I Mutation Only)
Brief Summary Rationale: DCC-2036 is a potent broad spectrum inhibitor of BCR-ABL kinase. Inhibition of BCR-ABL has been validated for effective treatment of chronic myeloid leukemia (CML). The emergence of mutant forms of BCR-ABL which resist inhibition by imatinib, dasatinib, and nilotinib is associated with loss of efficacy in treatment of the disease. DCC-2036 is a potent inhibitor of resistant mutants of BCR-ABL including the T315I mutation, and would therefore be expected to effectively treat patients who fail to respond to other BCR-ABL inhibitors. DCC-2036 also inhibits FLT3-ITD, TIE2, KDR, LYN and TRKA kinases. Purpose: to assess the safety and tolerability in patients after continuous administration of DCC-2036 and to determine recommended doses for the conduct of a Phase 2 efficacy trial.
Detailed Description

This study will include patients with one of the following: (1) Philadelphia chromosome-positive (Ph+) Chronic myeloid leukemia (CML); (2) FLT3 (gene) internal tandem duplication positive acute myeloid leukemia [FLT3 (gene) ITD-AML]. The investigational drug DCC-2036 has shown in the laboratory to affect different kinds of proteins in CML or AML cancer cells, which may help to stop these cancer cells from growing. This is a Phase 1 study. This Phase 1 study will test the highest safe dose of the investigational drug, DCC-2036, how often the drug should be given, and how well Ph+ CML and AML patients will tolerate DCC-2036. Patients' study doctor will review their past medical history, surgery(s), known allergies, and past/current medications. In addition, blood tests and bone marrow biopsies will be taken to determine if persons are eligible to participate in this study.

During the first part of this study, patients will receive different amounts of DCC-2036 to determine the highest safe dose. Multiple dose levels of DCC-2036 will be tested and as long as no medically unacceptable side effects are noted, the dose will be increased for the next group of study patients. When the highest dose is reached, a larger number of patients will be enrolled to receive DCC-2036 at the highest (safe) dose level. Additional study patients will be enrolled in a group called an "Expansion Group" and receive the study drug at the highest well tolerated dose. Evaluation of the safety and efficacy (how well the study medication treats leukemia) will be studied in this trial. Disease assessment will be monitored as follows: (1) Blood samples will be collected for disease response and for mutational analysis if disease has gotten worse (progressed); (2) Bone marrow samples may be collected by having an area of the hip or chest bone numbed with an anesthetic and a small amount of bone marrow drawn through a needle; (3) For CML patients only, blood samples will be collected for BCR-ABL transcript levels. Patient safety is of primary importance in this Phase 1 study. Safety assessment will be monitored as follows: (1) Physical examinations will be performed regularly during your doctor's visits; (2) Routine blood tests will be performed on a regular basis to assess potential side effects that may be caused by study medication on different organs like (and not limited to) liver, kidney and bone marrow; (3) Based on reports of potential side effects to the heart that may be caused by study medication, patients will be required to have echocardiograms and blood draws to measure the level of serum N-terminal fragment pro B-type natriuretic peptide (NT-proBNP). An echocardiogram is a noninvasive test that uses sound waves to produce images of your heart. These images will tell the doctor how a patient's heart is beating and pumping. The NT-proBNP is a blood test that will help the patient's doctor evaluate how well the heart works. After initial testing is completed, patients will then be required to have these safety evaluations performed at intervals of 3-cycles (approximately every 3 months) for as long as they are taking the study medication. Patients who experience muscle weakness or peripheral neuropathy will be assessed by blood draws to measure creatine phosphokinase (CPK) levels. Measuring CPK levels may help the patient's doctor determine whether or not the symptoms they are experiencing are the result of muscle damage or due to other causes. The most common eye disorders include blurred vision, dry eyes, and visual impairment. Patients will be required to have complete eye (ophthalmologic) evaluations. After initial ophthalmologic exams, patients will be required to have an exam after the completion of every 3 cycles of study medication (approximately every 3 months) and at the time they stop taking study medication. Blood samples will be collected for pharmacokinetic analysis. Pharmacokinetics is the study of the bodily absorption, distribution, metabolism, and excretion of drugs. Blood samples will also be collected for pharmacodynamic analysis. Pharmacodynamic analysis measures biomarkers that are either proteins or genes (also called DNA) that are associated with a disease that may also be related to how you respond to a treatment or what type of side effects may happen. The investigational drug DCC-2036 has not been approved by the United States Food and Drug Administration (FDA). The FDA allows DCC-2036 to be used in research studies only. DCC-2036 will be given to patients only during this study and not after the study is over.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Chronic Myeloid Leukemia
Intervention  ICMJE Drug: DCC-2036
150 mg BID tablets, continuous dosing of 28 day cycles
Other Name: rebastinib
Study Arms  ICMJE Experimental: DCC-2036
This is a single arm study
Intervention: Drug: DCC-2036
Publications *

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 30, 2013)
Original Estimated Enrollment  ICMJE
 (submitted: January 21, 2009)
Actual Study Completion Date  ICMJE January 2013
Actual Primary Completion Date January 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria: Subjects must meet all of the following inclusion criteria to be eligible:

  • Ph+ CML in Chronic Phase with T315I mutation
  • 18 years or older
  • The subject has an ECOG performance status of ≤ 2.
  • Adequate organ function as indicated by the following laboratory assessments performed within 14 days prior to the first dose of study drug Hepatic: Serum bilirubin ≤1.5 times upper limit (X ULN) of normal unless due to leukemic involvement or Gilbert's syndrome; aspartate aminotransferase or alanine aminotransferase ≤ 2.5 X ULN; alkaline phosphatase ≤ 2.5 X ULN Renal: Serum creatinine ≤ 1.5 X ULN or 24 hour creatinine clearance ≥ 50 mL/min
  • Female subjects of childbearing potential must have a negative serum or urine beta-human chorionic gonadotropin pregnancy test within 14 days prior to the start of study drug
  • Sexually active subjects who are fertile must agree to use an effective barrier method of contraception while on therapy and for 30 days following discontinuation of study drug. Non-fertile subjects or those not sexually active are also eligible.
  • The subject is capable of understanding and complying with the protocol and has signed the informed consent document.

Exclusion Criteria: Subjects presenting with any of the following will not qualify for entry into the study:

  • Subject has received chemotherapy or a TKI ≤ 7 days, investigational agent ≤ 14 days, or radiotherapy ≤ 28 days prior to the start of study drug or has not recovered from the acute toxicities associated with any prior treatments including approved therapies, investigational agents, and prior stem cell or bone marrow transplant. The following exceptions apply: i) Hydroxyurea is permitted at any time prior to study enrollment; ii) Glucocorticoids (natural or synthetic) are allowed up to 48 hours prior to the start of the study drug (with the exception of steroids for pre-medication and topical/nasal steroid use which are allowed at any time)
  • The subject has AP or BP-CML
  • Received immunosuppressive therapy ≤ 28 days prior to the first dose of study drug
  • NY Heart Association class III or IV heart disease, active ischemia or any other uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac arrhythmia requiring therapy, uncontrolled hypertension or congestive heart failure
  • Myocardial infarction within 3 months of the start of study drug
  • Active, uncontrolled systemic infection considered opportunistic, life threatening, or clinically significant
  • Any other severe concurrent disease and/or uncontrolled medical conditions, which in the judgment of the investigator, could predispose subjects to unacceptable safety risks or compromise compliance with the protocol
  • Human immunodeficiency virus positive
  • If female, the subject is pregnant or lactating
  • Allergic or hypersensitive to any component of the investigational drug product
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries Australia
Administrative Information
NCT Number  ICMJE NCT00827138
Other Study ID Numbers  ICMJE Protocol 2036-01
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Deciphera Pharmaceuticals LLC
Study Sponsor  ICMJE Deciphera Pharmaceuticals LLC
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Jorge Cortes, MD M.D. Anderson Cancer Center
Principal Investigator: Hedy P Smith, MD Tufts Medical Center
Principal Investigator: Moshe Talpaz, MD Univ. of Michigan Comprehensive Cancer Center
Principal Investigator: Kapil Bhalla, MD University of Kansas
Principal Investigator: Richard A Larson, MD University of Chicago
Principal Investigator: H.Jean Khoury, MD Emory University
Principal Investigator: B. Douglas Smith, MD Sidney Kimmel Cancer Center at Johns Hopkins
Principal Investigator: Ehab Atallah, MD Medical College of Wisconsin
Principal Investigator: David Snyder, M.D. City of Hope Medical Center
Principal Investigator: Javier Pinilla-Ibarz, MD,PhD H. Lee Moffitt Cancer Center and Research Institute
PRS Account Deciphera Pharmaceuticals LLC
Verification Date July 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP