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

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

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.

Study Overview

• Status: Completed
• Conditions: Philadelphia Chromosome Positive Chronic Myelogenous Leukemia
• Intervention / Treatment: Drug: Nilotinib + LDE225

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Novartis Investigative Site
• France
  • Marseille, France, 13273
    • Novartis Investigative Site
• Germany
  • Frankfurt, Germany, 60590
    • Novartis Investigative Site
  • Ulm, Germany, 89081
    • Novartis Investigative Site
• Italy
  • RM
    • Roma, RM, Italy, 00161
      • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28006
    • Novartis Investigative Site
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Assessment of the safety and tolerability profile of nilotinib in combination with LDE225	336 days (12 treatment cycles)
Plasma concentration and basic pharmacokinetics (PK) parameters (as Cmax, Tmax, AUC)	Assessment of the PK characteristics of nilotinib administered in combination with LDE225	50 days
Major molecular response (MMR) rates at 3, 6 and 12 months	Determination of the kinetics of major molecular response	336 days (12 treatment cycles)
Complete molecular response (CMR) rates at 3, 6 and 12 months	Determination of the kinetics of complete molecular response	336 days (12 treatment cycles)
Major cytogenic response (MCyR) rates by 3, 6 and 12 months	Determination of major cytogenetic response rates	336 days (12 treatment cycles)
Complete cytogenic response (CCyR) rates by 3, 6 and 12 months	Determination of complete cytogenetic response rates	336 days (12 treatment cycles)

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• Reuslts for CAMN107Y2101 can be found on the Novartis Clinical Trial Results Website

Study record dates

Study Major Dates

• Study Start: January 1, 2012
• Primary Completion (Actual): February 1, 2014
• Study Completion (Actual): February 1, 2014

Study Registration Dates

• First Submitted: October 14, 2011
• First Submitted That Met QC Criteria: October 20, 2011
• First Posted (Estimate): October 21, 2011

Study Record Updates

• Last Update Posted (Actual): December 9, 2020
• Last Update Submitted That Met QC Criteria: December 6, 2020
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: CML; resistant; Chronic myeloid leukemia; Philadelphia positive; nilotinib; Ph+; LDE225; Resistant Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP)
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Chromosome Aberrations; Translocation, Genetic; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Philadelphia Chromosome
• Other Study ID Numbers: CAMN107Y2101; 2011-000282-12 (EudraCT Number)