MDACC Study Summary 2010-0785

Study Summary
No. 2010-0785:.......Leukemia......Jorge Cortes......Leukemia

Study Summary Title



Study Summary Number:	2010-0785

Study Title:	Dasatinib (BMS-354825) combined with SMO inhibitor (BMS-833923; XL139) in CML with resistance or suboptimal response to a prior TKI

Physician

New Patient Referral



Name:	Jorge Cortes	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:	713-794-5783 Contact us about clinical trials

General Information



Disease Group:	Leukemia	Supported By:	Bristol-Myers Squibb, Inc.

Phase of Study:	Phase I	Return Visit:

Treatment Agents:	BMS-833923 Dasatinib	Home Care:

Treatment Loc:	Both at MDACC & and Other Sites

Estimated Length of Stay in Houston:


Description/ Intervention:	The goal of this clinical research study is to learn the highest tolerable dose of the combination of dasatinib and BMS-833923 that can be given to patients with CML. Researchers also want to learn about any effects the study drug combination may have on the disease.

Study Objectives / Outcomes

Primary Objective:
To determine safety, tolerability and a recommended Phase 2 dose (RP2D) for the combination of BMS-833923 plus dasatinib in subjects with chronic phase CML

Secondary Objectives:
1) Assess the efficacy of BMS-833923 plus dasatinib in previously-treated CML, using hematologic, cytogenetic and molecular definitions

a) Chronic-phase, with suboptimal response or resistance to imatinib or nilotinib

b) Chronic-phase, with suboptimal response or resistance to dasatinib

c) Advanced-phase, with resistance to imatinib or nilotinib

2) Assess the effect of BMS-833923 at steady state on the pharmacokinetics (PK) of dasatinib and characterize steady state PK of BMS-833923 in presence of dasatinib

3) Define the safety and maximum-tolerated dose (MTD) of the combination of BMS-833923 plus dasatinib in subjects with advanced-phase CML

Exploratory Objectives
1) Describe the effects of BMS-833923 plus dasatinib on CML progenitor cell population

2) Describe the effects of BMS-833923 plus dasatinib on biomarkers of the HH pathway

3) Assess the potential to hold therapy in subjects with prolonged complete molecular response (CMR)

Study Status Information



Study Activation / Registration Date:	08/31/2011

IRB Review and Approval Date:	08/31/2011

Study Type:	Phase I

Recruitment Status:	Closed

Projected Accrual:	36 - 40

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) Target Population: a) Confirmed prior diagnosis of chronic myeloid leukemia (CML) or Ph+ALL. i) Any number of prior therapies for CML or Ph+ ALL is allowed;

2) **continued from above: b) Evidence of disease, classified as i) Chronic-phase CML (CML-CP), with cytogenetically-documented Ph+ cells on BMA </= 6 weeks prior to treatment start (1) must have all of the following (a) < 15% blasts in peripheral blood and BMA (b) < 30% blasts + promyelocytes in blood and BMA (c) < 20% basophils in blood and BM (d) >/= 100 x 10(9)/L platelets (unless related to treatment), and (e) no extramedullary disease other than hepatosplenomegaly (2) Second chronic phase included, for purposes of this study (3) Cytogenetic Bcr-Abl variants and additional chromosomal abnormalities ('clonal evolution') included

3) **continued from above: ii) Advanced-phase, with hematologic relapse documented </= 2 weeks prior to treatment start (1) For CML-Adv, must have at least one of the following: (a) >/= 15% blasts in blood or BMA, (b) >/= 20% basophils in PB or BMA, (c) Platelets < 100 x 10(9)/L, unrelated to prior drug therapy (d) Extra-medullary infiltrates, other than in spleen or liver, with myeloid or lymphoid blast morphology (2) Ph+ ALL, with cytogenetically-documented progression and/or with >/= 5% blasts in blood or BMA (3) Cytogenetics to be performed, but results are not required to start therapy in patients with hematologic progression

4) **continued from above: c) Resistance or suboptimal response to prior Abl-kinase inhibitor, specifically: i) Chronic-phase with resistance to imatinib, dasatinib or nilotinib, defined as (1) Loss of CCyR at any time or failure to achieve CCyR after >/= 18 months (2) Loss of MCyR at any time or failure to achieve PCyR after >/= 12 months (3) Failure to achieve any CyR (ie, 65% Ph+) after >/= 6 months (4) Hematologic relapse or failure to achieve CHR after >/= 3 months; ii) Chronic-phase with suboptimal response to imatinib, defined as (1) Failure to achieve PCyR after >/= 6 months (2) Failure to achieve CCyR after >/= 12 months iii) Chronic-phase with suboptimal response to nilotinib or dasatinib, defined as (1) Failure to achieve PCyR after >/= 3 months (2) Failure to achieve CCyR after >/= 6 months of therapy

5) **continued from above: iv) Advanced-phase with resistance to imatinib or nilotinib (not eligible with hematologic resistance to dasatinib), defined as (1) Hematologic relapse or failure to achieve CHR after >/= 3 months (2) Ph+ ALL with cytogenetic or hematologic progression

6) Medical Conditions: a) Toxicity of any prior therapy must have resolved, returned to Grade 0 - 1 (Grade 2 for hematologic) or be considered irreversible b) Performance Status 0 - 1 at study entry

7) Signed Written Informed Consent: a) Subject must be able to provide written informed consent indicating that he/she is aware of the experimental nature of the therapy, alternatives, potential benefits, side effects, risks, and discomforts, and has been informed of the procedures to be followed b) Subject must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, and requirements of the study

8) Age and Reproductive Status: a) Subjects >/= 18 years of age. b) Women of childbearing potential (WOCBP) must use an acceptable method of contraception to avoid pregnancy throughout the study, for at least 1 month after the last dose of dasatinib and at least 3 months after the last dose of BMS-833923 in order that the risk of pregnancy is minimized. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of beta HCG) within 72 hours prior to the start of investigational product

Exclusion Criteria:

1) Target Disease Exceptions: a) Known Abl-kinase T315I or T315A mutation (test not required) b) Having Complete Cytogenetic Response (CCyR) at baseline evaluation

2) Medical History and Concurrent Diseases: a) Any serious or uncontrolled medical disorder or active infection that would impair the ability of the subject to receive protocol therapy, including i) Pleural or pericardial effusion of Grade >/= 2 in previous 12 months ii) Clinically-significant gastrointestinal disease (eg, uncontrolled nausea or malabsorption syndrome) that would compromise absorption of study drug, including inability to swallow tablets intact (dasatinib tablets may not be broken) iii) Thromboembolic disease requiring ongoing anticoagulation iv) Clinically-significant coagulation or platelet function disorder (other than related to thrombocytopenia), eg, von Willebrand's disease v) Other active malignancy requiring concurrent intervention vi) Symptomatic pancreatitis </= 6 months prior to study treatment; b) Uncontrolled or significant cardiovascular disease, including any of the following:

3) **continued from above: i) Myocardial infarction, uncontrolled angina or congestive heart failure within 6 months prior to study entry ii) Left ventricular ejection fraction (LVEF) <45% iii) Significant cardiac conduction abnormality, including (1) History of clinically-significant ventricular arrhythmia (2) History of second or third degree heart block or diagnosed congenital long QT syndrome (unless a pacemaker has been implanted) (3) Prolonged QTcF interval >/= 450 msec on baseline ECG

4) Physical and Laboratory Test Findings: a) Grade >/= 3 peripheral blood counts (only applies to CML-CP), ie,: i) ANC < 1,000 cells/mm(3) ii) Platelet count < 50,000 cells/mm(3) iii) Hemoglobin < 8 g/dL (transfusion-support permitted) b) Laboratory abnormalities (per CTCAE v 3.0): i) Serum calcium (corrected for albumin) or phosphate below ILLN (Institutional lower limit of normal; eligible if repleted by supplementation) ii) Baseline Mg (hypomagnesemia) and amylase or lipase Grade >/= 1 iii) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 X IULN. Total bilirubin > 1.5 X institutional upper limit of normal (IULN; unless Gilbert syndrome has been diagnosed) iv) Reduced renal function, defined as serum creatinine > 3 X IULN v) Other chemistry abnormalities Grade >/= 2

5) Allergies and Adverse Drug Reaction: a) History of allergy to dasatinib or compounds chemically related to BMS-833923; b) Unacceptable adverse event ("intolerance") attributed to prior dasatinib treatment

6) Sex and Reproductive Status: a) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least one month (4 weeks) before and for at least 3 months after the last dose of study medication. b) Women who are pregnant or breastfeeding. c) Women with a positive pregnancy test at enrollment or prior to administration of study medication. d) Sexually active fertile men not using effective birth control (double barrier method, or condom plus IUD or hormonal method) if their partners are WOCBP while on study treatment and for at least 3 months following treatment with BMS-833923

7) Prohibited Treatments and/or Therapies: a) Prior therapies for CML or Ph+ ALL are permitted, with the following restriction i) Therapy permitted with corticosteroids, hydroxyurea or anagrelide (where available) prior to treatment start and during the first 4 weeks on study ii) Must be >/= 6 months after stem cell transplantation iii) Must be >/= 28 days after any investigational agent iv) Must be >/= 7 days after any standard chemotherapy agent; b) Concomitant use of medications known to have a risk of causing "Torsades de Pointes"; c) Concomitant use of strong inhibitors of the CYP3A4 isoenzyme

8) Other Exclusion Criteria: a) Dementia or serious psychiatric condition that may compromise the informed consent process and increase the risks associated with study participation b) Prisoners or subjects who are involuntarily incarcerated c) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness

Links

Registration Number: NCT01218477
Study Information on Clinical Trials Registry (clinicaltrials.gov)