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Nilotinib and LDE225 in the Treatment of Chronic or Accelerated Phase Myeloid Leukemia in Patients Who Developed Resistance to Prior Therapy

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01456676
First Posted: October 21, 2011
Last Update Posted: September 2, 2016
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.
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
  Purpose
The purpose of this study is to determine the feasibility of administering the combination of nilotinib and LDE225 to patients with chronic or accelerated phase of chronic myeloid leukemia and to establish the maximum tolerated dose (MTD) and/or recommended Phase II dose level (RP2D) of LDE225 in combination with nilotinib.

Condition Intervention Phase
Philadelphia Chromosome Positive Chronic Myelogenous Leukemia Drug: Nilotinib + LDE225 Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Single-arm Dose-finding Phase Ib Multicenter Study of the Oral Smoothened Antagonist LDE225 in Combination With Nilotinib in Chronic or Accelerated Phase of Chronic Myeloid Leukemia Patients Who Have Failed Prior Therapy With Other BCR-ABL Tyrosine-kinase Inhibitors

Resource links provided by NLM:


Further study details as provided by Novartis ( Novartis Pharmaceuticals ):

Primary Outcome Measures:
  • Incidence rate and category of dose limiting toxicities (DLTs) during the first two cycles of therapy [ Time Frame: 56 days (2 treatment cycles at 28 days each) ]
    Determination of the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) of nilotinib in combination with LDE225


Secondary Outcome Measures:
  • No of participants with Adverse drug reactions and serious adverse drug reactions, changes in hematology and blood chemistry values, assessments of physical examinations, vital signs and electrocardiograms [ Time Frame: 336 days (12 treatment cycles) ]
    Assessment of the safety and tolerability profile of nilotinib in combination with LDE225

  • Plasma concentration and basic pharmacokinetics (PK) parameters (as Cmax, Tmax, AUC) [ Time Frame: 50 days ]
    Assessment of the PK characteristics of nilotinib administered in combination with LDE225

  • Major molecular response (MMR) rates at 3, 6 and 12 months [ Time Frame: 336 days (12 treatment cycles) ]
    Determination of the kinetics of major molecular response

  • Complete molecular response (CMR) rates at 3, 6 and 12 months [ Time Frame: 336 days (12 treatment cycles) ]
    Determination of the kinetics of complete molecular response

  • Major cytogenic response (MCyR) rates by 3, 6 and 12 months [ Time Frame: 336 days (12 treatment cycles) ]
    Determination of major cytogenetic response rates

  • Complete cytogenic response (CCyR) rates by 3, 6 and 12 months [ Time Frame: 336 days (12 treatment cycles) ]
    Determination of complete cytogenetic response rates


Enrollment: 11
Study Start Date: January 2012
Study Completion Date: February 2014
Primary Completion Date: February 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Nilotinib + LDE225
The planned dose of nilotinib 400 mg b.i.d (twice a day) was selected for the combination as this is the dose approved for the treatment of the patient population that will be included in the present study. The starting dose for LDE225 chosen for the current study is 400 mg once daily(q.d.). The maximum dose of LDE225 that will be tested in combination with nilotinib is 800 mg once dail.y
Drug: Nilotinib + LDE225
Nilotinib is an aminopyrimidine ATP-competitive inhibitor of the protein tyrosine kinaseactivity of BCR-ABL.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Philadelphia chromosome positive (Ph+) CML in chronic phase (CP) or accelerated phase (AP)with resistance to at least one prior BCR-ABL targeting TKI
  2. Documented chronic phase CML
  3. Adequate end organ function
  4. Female patients of childbearing potential must have a negative serum pregnancy test and must be using highly effective methods of contraception. Male patients with female partners of child-bearing potential must use condoms.

Exclusion Criteria:

  1. Impaired cardiac function
  2. Severe and/or uncontrolled concurrent disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol
  3. History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis
  4. 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
  5. 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.
  6. Previously documented BCR-ABL Y253H, E255K/V, T315I or F359C/V mutation

Other protocol-defined inclusion/exclusion criteria may apply.

  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01456676


Locations
Canada, Ontario
Novartis Investigative Site
Toronto, Ontario, Canada, M5G 2M9
France
Novartis Investigative Site
Marseille, France, 13273
Germany
Novartis Investigative Site
Frankfurt, Germany, 60590
Novartis Investigative Site
Ulm, Germany, 89081
Italy
Novartis Investigative Site
Roma, RM, Italy, 00161
Spain
Novartis Investigative Site
Pamplona, Navarra, Spain, 31008
Novartis Investigative Site
Madrid, Spain, 28006
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01456676     History of Changes
Other Study ID Numbers: CAMN107Y2101
2011-000282-12 ( EudraCT Number )
First Submitted: October 14, 2011
First Posted: October 21, 2011
Last Update Posted: September 2, 2016
Last Verified: September 2016

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
LDE225
nilotinib
Chronic myeloid leukemia
CML
Philadelphia positive
Ph+
resistant
Resistant Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP)

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Philadelphia Chromosome
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Translocation, Genetic
Chromosome Aberrations
Pathologic Processes