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Study Summary
No. 2011-0394:.......Leukemia......Jorge Cortes......Leukemia
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Study Summary Title
Study Summary
Number:
2011-0394
Study Title:A single-arm dose-finding phase Ib multicenter study of the oral smoothened antagonist LDE225 in combination with nilotinib in chronic phase chronic myeloid leukemia patients who have failed prior therapy with other BCR-ABL tyrosine-kinase inhibitors
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Physician New Patient Referral
Name:Jorge CortesPatients 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:713-794-5783
Contact us about clinical trials
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General Information
Disease Group:LeukemiaSupported By:Novartis
Phase of Study:Phase IReturn
Visit:
Treatment
Agents:
LDE225
Nilotinib
Home Care:
Treatment Loc:Both at MDACC & and Other Sites
Estimated
Length of Stay
in Houston:
Description/
Intervention:
Unavailable
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Study Objectives / Outcomes
Primary:
• Determine the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) of LDE225 and nilotinib when administered in combination

Secondary:
• Assess the safety and tolerability profile of the nilotinib + LDE225 combination
• Assess the PK characteristics of nilotinib and LDE225 administered in combination
• Determine kinetics of molecular response
• Determine cytogenetic response rates

Exploratory:
• Assessment of BCR-ABL mutational status at baseline and during treatment
• Feasibility testing of quantitative assay for BCR-ABL positive cells in bone marrow and peripheral blood stem cell compartments
• Feasibility testing of quantitative measure of post-treatment changes in Hh pathway gene expression in bone marrow and peripheral blood stem cell compartments
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Study Status Information
Study Activation / Registration Date:01/24/2012
IRB Review and Approval Date:01/24/2012
Study Type:Phase I
Recruitment Status:Terminated
Projected Accrual:27 - 39
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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) Male or female patients >/= 18 years of age

2) WHO Performance Status of </= 2

3) Philadelphia chromosome positive (9;22 translocation or variant Ph+ translocation confirmed by conventional bone marrow cytogenetics) CML in documented chronic phase with resistance to at least one prior BCR-ABL targeting TKI (imatinib, dasatinib, bosutinib or ponatinib but not nilotinib).

4) Documented chronic phase CML will meet all the criteria defined by: < 15% blasts in peripheral blood and bone marrow; < 30% blasts plus promyelocytes in peripheral blood and bone marrow; < 20% basophils in the peripheral blood; >/= 100 x 10(9)/L [>/= 100,000/mm(3)] platelets; No evidence of extra-medullary leukemic involvement, with the exception of hepatosplenomegaly

5) Patients in CHR (complete hematologic response)

6) Patients must be receiving nilotinib as targeted CML therapy for at least 56 days prior to study start. Patients must have been on nilotinib at a dose of 400 mg b.i.d. for at least 14 days prior to study start without emerging resistance on nilotinib as assessed by the investigator.

7) Adequate end organ function as defined by: Total bilirubin < 1.5 x ULN (upper limit of normal); SGOT(AST) and SGPT(ALT) < 2.5 x ULN; Serum amylase and lipase </= 1.5 x ULN; Alkaline phosphatase </= 2.5 x ULN; Serum creatinine < 1.5 x ULN or 24-hour creatinine clearance >/= 50 mL/min; Total serum creatine phosphokinase < 1.5 x ULN

8) Patients must have the following electrolyte values within normal limits or corrected to within normal limits with supplements prior to the first dose of study medication: Potassium, Magnesium, Phosphate, Total calcium (corrected for serum albumin)

9) Female patients of childbearing potential must have a negative serum pregnancy test within 72 hours before initiation of study drug. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must be using highly effective methods of contraception during dosing and for 6 months after last LDE225 intake. Highly effective contraception methods include: Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception], Female sterilization (have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment

10) *continued from above: Male sterilization (at least 6 months prior to screening) [For female subjects on the study, the vasectomised male partner should be the sole partner for that subject], Combination of any two of the following (1+2 or 1+3, or 2+3): 1. Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception. 2. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 3. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository In case of use of oral contraception women should have been stabile on the same pill for a minimum of 3 months before taking study treatment.

11) *continued from above: Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential. Male patients with female partners of child-bearing potential must use condoms during the treatment period and for 6 months after the treatment cessation. Female partners (WOCBP) of male patients have to use highly effective methods of birth control during the male patient's study participation and for 6 months after study treatment cessation.

12) Written informed consent obtained prior to any screening procedures

13) Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedures

Exclusion Criteria:1) Impaired cardiac function including any one of the following: LVEF < 45% or below the institutional lower limit of the normal range (whichever is higher); Inability to determine the QT interval on ECG; Complete left bundle branch block; Right bundle branch block plus left anterior or posterior hemi-block; Use of a cardiac pacemaker; Congenital long QT syndrome or a known family history of long QT syndrome; History of or presence of clinically significant ventricular or atrial tachyarrhythmias; Clinically significant resting bradycardia (< 50 beats per minute); QTc > 450 msec on the average of three serial baseline ECG (using the QTcF formula) as determined by central reading. If QTcF > 450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient rescreened for QTc; History or clinical signs of myocardial infarction within 1 year of study entry; History of unstable angina within 1 year of study entry;

2) **continued from above: Other clinically significant heart disease (e.g. congestive heart failure or uncontrolled hypertension)

3) Severe and/or uncontrolled concurrent disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol (e.g. uncontrolled diabetes, uncontrolled infection)

4) History of a positive HIV test (HIV testing is not mandatory)

5) History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis

6) Acute or chronic liver, pancreatic, or severe renal disease considered unrelated to study disease

7) History of significant congenital or acquired bleeding disorder

8) Major surgery within 4 weeks prior to Day 1 or those who have not recovered from prior surgery

9) Patients who have received wide field radiotherapy within 4 weeks or limited field radiation for palliation within 2 weeks prior to treatment assignment or who have not recovered from side effects of such therapy

10) Patients actively receiving therapy with strong CYP3A4 inhibitors and/or inducers, and the treatment cannot be either discontinued or switched to a different medication prior to entering the study. Medications that are strong CYP3A4 inhibitors should be discontinued for at least 7 days and strong CYP3A4 inducers for at least 2 weeks prior to the study entry.

11) Patients actively receiving therapy with herbal medicines that are CYP3A4 inhibitors and/or inducers, and the treatment cannot be either discontinued or switched to a different medication prior to entering the study. These herbal medicines may include Echinacea, (including E. purpurea, E. angustifolia and E. pallida), Piperine, Artemisinin, St. John's Wort, and Ginkgo. Herbal medications that are strong CYP3A4 inhibitors should be discontinued for at least 7 days and strong CYP3A4 inducers for at least 2 weeks prior to the study entry

12) Concurrent treatment with CYP2C9 and CYP2B6 substrates with a narrow therapeutic window.

13) Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either safely discontinued or switched to a different medication prior to starting study drug.

14) Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery)

15) Previously documented BCR-ABL Y253H, E255K/V, T315I or F359C/V mutation (as single BCR-ABL mutation or in combination)

16) Patients who are concurrently receiving any other CML treatment other than nilotinib (including planned stem-cell transplant). Patients may have received hydroxyurea and anagrelide that should have stopped at least 4 weeks before entering the study

17) Patients who have not recovered from side effects related to prior CML therapy </= Grade 2

18) Patients who have received any investigational drug (except nilotinib) </= 4 weeks (or who are within 5 half-lives of a previous investigational drug) prior to starting study treatment or who have not recovered from side effects of such therapy

19) Treatment with any hematopoietic colony-stimulating growth factors (e.g. G-CSF, GMCSF, erythropoietin) </= 2 weeks prior to starting study drug or anticipated need of such treatment

20) Prior stem cell transplantation

21) History of other active malignancy within 3 years prior to study entry with the exception of previous or concomitant basal cell skin cancer or previous cervical carcinoma in situ

22) (a) Patients who have neuromuscular disorders that are associated with elevated creatine phosphokinase (e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis and spinal muscular atrophy). Patients on concomitant treatment with drugs that are recognized to cause rhabdomyolysis, such as (but not limited to) HMG CoA inhibitors (statins), clofibrate and gemfibrozil, and cannot be discontinued at least 2 weeks prior to starting LDE225 treatment (b) Patients who are planning on embarking on a new strenuous exercise regimen after initiation of study treatment. NB: Muscular activities, such as strenuous exercise, that can result in significant increases in plasma CK levels should be avoided whilst on LDE225 treatment

23) Breast feeding women and women feeding children with their expressed milk

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Links
Registration Number: NCT01456676
Study Information on Clinical Trials Registry (clinicaltrials.gov)

Other Links:
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Results


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