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

NCT ID: NCT00827138

Last Updated: 2014-07-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 57 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-03-31
• Study Completion Date: 2013-01-31

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.

Conditions

Chronic Myeloid Leukemia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

DCC-2036

This is a single arm study

Group Type: EXPERIMENTAL

DCC-2036

Intervention Type: DRUG

150 mg BID tablets, continuous dosing of 28 day cycles

Interventions

DCC-2036

150 mg BID tablets, continuous dosing of 28 day cycles

Intervention Type: DRUG

Other Intervention Names

rebastinib

Eligibility Criteria

Inclusion Criteria

• 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

• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Deciphera Pharmaceuticals, LLC

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jorge Cortes, MD

Role: PRINCIPAL_INVESTIGATOR

M.D. Anderson Cancer Center

Hedy P Smith, MD

Role: PRINCIPAL_INVESTIGATOR

Tufts Medical Center

Moshe Talpaz, MD

Role: PRINCIPAL_INVESTIGATOR

Univ. of Michigan Comprehensive Cancer Center

Kapil Bhalla, MD

Role: PRINCIPAL_INVESTIGATOR

University of Kansas

Richard A Larson, MD

Role: PRINCIPAL_INVESTIGATOR

University of Chicago

H.Jean Khoury, MD

Role: PRINCIPAL_INVESTIGATOR

Emory University

B. Douglas Smith, MD

Role: PRINCIPAL_INVESTIGATOR

Sidney Kimmel Cancer Center at Johns Hopkins

Ehab Atallah, MD

Role: PRINCIPAL_INVESTIGATOR

Medical College of Wisconsin

David Snyder, M.D.

Role: PRINCIPAL_INVESTIGATOR

City of Hope Medical Center

Javier Pinilla-Ibarz, MD,PhD

Role: PRINCIPAL_INVESTIGATOR

H. Lee Moffitt Cancer Center and Research Institute

Locations

City of Hope

Duarte, California, United States

H. Lee Moffitt Cancer Center & Research Institute

Tampa, Florida, United States

Emory University

Atlanta, Georgia, United States

University of Chicago

Chicago, Illinois, United States

The University of Kansas Cancer Center

Kansas City, Kansas, United States

Sidney Kimmel Cancer Center at Johns Hopkins

Baltimore, Maryland, United States

Tufts Medical Center

Boston, Massachusetts, United States

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, United States

MD Anderson Cancer Center

Houston, Texas, United States

Medical College of Wisconsin

Milwaukee, Wisconsin, United States

Countries

United States

References

Cortes J, Talpaz M, Smith HP, Snyder DS, Khoury J, Bhalla KN, Pinilla-Ibarz J, Larson R, Mitchell D, Wise SC, Rutkoski TJ, Smith BD, Flynn DL, Kantarjian HM, Rosen O, Van Etten RA. Phase 1 dose-finding study of rebastinib (DCC-2036) in patients with relapsed chronic myeloid leukemia and acute myeloid leukemia. Haematologica. 2017 Mar;102(3):519-528. doi: 10.3324/haematol.2016.152710. Epub 2016 Dec 7.

Reference Type: DERIVED

PMID: 27927766 (View on PubMed)

O'Hare T, Zabriskie MS, Eiring AM, Deininger MW. Pushing the limits of targeted therapy in chronic myeloid leukaemia. Nat Rev Cancer. 2012 Jul 24;12(8):513-26. doi: 10.1038/nrc3317.

Reference Type: DERIVED

PMID: 22825216 (View on PubMed)

Other Identifiers

Protocol 2036-01

Identifier Type: -

Identifier Source: org_study_id